Virus World

The results could pave the way for new therapeutic strategies using existing drugs to combat the growing AD crisis. 

Summary: Common HIV drugs could reduce the incidence of Alzheimer’s disease (AD). Utilizing anonymized prescription data from over 225,000 individuals, the study found that HIV-positive patients taking reverse transcriptase (RT) inhibitors showed a significantly lower rate of AD compared to the general population. This discovery builds on previous findings that Alzheimer’s-linked genes might be recombined by enzymes similar to those targeted by HIV treatments. The results could pave the way for new therapeutic strategies using existing drugs to combat the growing AD crisis.

Key Facts:

1. The study analyzed prescription data from 225,000 individuals, revealing that HIV-positive patients over 60 taking RT inhibitors had fewer Alzheimer’s diagnoses compared to their non-HIV counterparts.
2. RT inhibitors, initially developed for HIV, might inhibit similar enzymes in the brain, suggesting a potential mechanism for their effect on Alzheimer’s disease.
3. The research was supported by notable foundations and the NIH, highlighting its credibility and the significant interest in translating these findings into new treatments for AD.

Alzheimer’s disease (AD) currently afflicts nearly seven million people in the U.S. With this number expected to grow to nearly 13 million by 2050, the lack of meaningful therapies represents a major unmet medical need. Scientists at Sanford Burnham Prebys have now identified promising real-world links between common HIV drugs and a reduced incidence of AD. The study, led by Jerold Chun, M.D., Ph.D., was published in Pharmaceuticals. Chun’s new research builds on his lab’s landmark publication in Nature in 2018 that described how somatic gene recombination in neurons can produce thousands of new gene variants within Alzheimer’s disease brains. Importantly, it also revealed for the first time how the Alzheimer’s-linked gene, APP, is recombined by using the same type of enzyme found in HIV.  The enzyme, called reverse transcriptase (RT), copies RNA molecules and changes them into complementary DNA duplicates that can then be inserted back into DNA, producing permanent sequence changes within the cell’s DNA blueprint. HIV and many other viruses rely on RT to hijack a host’s cells to establish a chronic infection, so drugs that block the RT enzyme’s activity have become a common part of treatment cocktails for keeping HIV at bay. The brain appears to have its own RTs that are different from those in viruses, and the research team wondered if inhibiting brain RTs with HIV drugs actually helps AD patients.

To assess the link between real-world RT inhibitor exposure and AD in humans, the team analyzed anonymized medical records with prescription claims from more than 225,000 control and HIV-positive patients, and found that RT inhibitor exposure was associated with a statistically significant reduced incidence and prevalence of AD. “Thus, we looked at HIV-positive individuals taking RT inhibitors and other combined antiretroviral therapies as they aged, and asked the question: How many of them got Alzheimer’s disease?” says Chun. “And the answer is that there were many fewer than might have been expected compared to the general population.” Of the more than 225,000 individuals with claims data in the study, just shy of 80,000 were HIV-positive individuals over the age of 60. More than 46,000 had taken RT inhibitors during a nearly three-year observation period from 2016 to 2019. The data was obtained through a collaboration with health information technology and clinical research firm IQVIA, led by Tiffany Chow, M.D. In living persons with HIV, there were 2.46 Alzheimer’s disease diagnoses per 1,000 persons among HIV-positive individuals taking these inhibitors, versus 6.15 for the general population. This control group was represented by more than 150,000 HIV-negative patients over the age of 60 with medical insurance claims related to treatment for the common cold. “You cannot feasibly run a prospective clinical trial with this number of patients,” Chun adds. “This approach is a way to look at how a drug can act on a large patient population.”

Chun underscores that the drugs patients took in this retrospective study were designed to counter RT activity in HIV and likely only had a limited effect on many different possible forms of the enzyme active in the brain. “What we’re looking at now is very crude,” says Chun. “The clear next step for our lab is to identify which versions of RTs are at work in the AD brain so that more targeted treatments can be discovered, while prospective clinical trials of currently available RT inhibitors on persons with early AD should be pursued.”

Jerold Chun, M.D. Ph.D., is a professor in the Center for Genetic Disorders and Aging Research at Sanford Burnham Prebys.

Additional authors on the study include Tiffany W. Chow, Mark Raupp, Matthew W. Reynolds, Siying Li and Gwendolyn E. Kaeser.

Funding: The work was supported by the National Institute on Aging – NIH (R01AG071465, R01AG065541 and R56AG073965), the Shaffer Family Foundation and the Bruce Ford & Anne Smith Bundy Foundation.

Research published in Pharmaceuticals (March 22, 2024):

https://doi.org/10.3390/ph17040408 

A recent NIH-funded study shows potential for long-term HIV remission in children without medication, marking a significant advance in treatment. Announced at the 2024 Conference on Retroviruses and Opportunistic Infections (CROI) in Denver, Colorado, a groundbreaking study funded by the National Institutes of Health has unveiled that four children born with HIV were able to live for more than a year without detectable levels of the virus after their HIV medication was paused. This finding from the P1115 study hints at the potential for achieving long-term remission in children born with HIV, a significant stride in the ongoing battle against the virus.

Early Intervention: A Ray of Hope

The P1115 study focused on the impact of early intensive antiretroviral therapy (ART) in infants infected with HIV before birth. HIV, a virus that attacks the immune system, can hide within the body, making it challenging to eradicate. However, these children's ability to live more than a year without medication and with no detectable virus brings new optimism to scientists and medical professionals. It suggests that early, aggressive treatment may limit HIV reservoirs, potentially enabling periods of remission in pediatric patients.

The Mississippi Baby: Pioneering Early Treatment

Inspired by the case of the "Mississippi Baby," who was born with HIV and received intensive ART hours after birth and was seemingly cured for a few years, researchers have been motivated to explore the possibility of long-term remission in children. Although the "Mississippi Baby" eventually tested positive for HIV again at age 4, the case provided invaluable insights into the potential benefits of early and aggressive treatment. The NIH has since invested in global research studies, like P1115, to further investigate these possibilities.

Implications for Future Treatment

While all children in the P1115 study eventually saw their HIV return, the period during which some of them had no detectable HIV without taking medication marks a significant discovery. According to Adeodata Kekitiinwa, MBChB, MMed, the study's investigator of record, this trial moves us closer to a paradigm shift in HIV treatment. It raises the possibility that antiretroviral therapy could be used effectively for a "season of life," rather than being a lifelong necessity. This potential shift could dramatically change the approach to treating children born with HIV, offering them a chance at a healthier life without the constant burden of medication. The study's findings not only fuel hope for achieving long-term remission among children born with HIV but also underscore the importance of continuous research and innovation in the field. As scientists work towards unlocking the secrets of HIV remission, these children's stories stand as beacons of possibility, pointing towards a future where HIV can be managed more effectively, and perhaps, eventually overcome.

Highlights

Summary

There is a “window of opportunity” in the weeks after someone is infected with HIV where treatment may lead to better control later on, researchers say. Treatment for human immunodeficiency virus (HIV) four weeks after infection may make it possible to control the virus without medication in the long term, a new study has shown. The finding reinforces the importance of detecting HIV early, according to researchers from the French Institut Pasteur, CEA, Inserm, University of Paris Cité, and the University of Paris-Saclay. Treatment for HIV is called antiretroviral therapy (ART) and can be taken as a pill or an injection. The goal is to reduce a person’s viral load to an undetectable level so the person has no risk of transmitting HIV.

This therapy is now so effective that it can fully control the virus, with researchers even exploring ways to cure it. This latest study looked at the impact of early treatment on primates with simian immunodeficiency virus (SIV), which is closely related to HIV. The researchers found that very early treatment for two years led to controlling the virus even after treatment was interrupted. “We show an association between early treatment and control of the infection after treatment is stopped, and our study indicates the existence of a window of opportunity to promote remission of HIV infection,” Asier Sáez-Cirión, head of the Institut Pasteur’s viral reservoirs and immune control unit and co-senior author of the study, said in a statement. A previous 2013 study in humans had shown a similar possibility, suggesting that early treatment could allow people to stop treatment, with the virus in a “state of remission”. The latest study also showed that the benefits of early treatment were lost if therapy was started just five months later. The findings were published in the scientific journal Nature Communications.

Lenacapavir, an injection, has been approved by the FDA for multi-drug resistant HIV. HIV is not curable yet, but it can be treated successfully throughout someone's lifespan. "And so, in the field, we want to ensure that the treatments we have—which for now are for a lifetime—become easier, simpler to use, and safer, and remain highly effective for our patients," said Onyema Ogbuagu, MD, who is associate professor of medicine (AIDS) and director of the Yale Antivirals and Vaccines Research Program of the Yale HIV/AIDS Program in the Section of Infectious Diseases of Yale School of Medicine. Through collective pursuit in the research world, a new class of HIV treatment was born: long-acting HIV medications that target the capsid of HIV-1, which is a conical structure that harbors its genome. "Lenacapavir is one of those agents, and it is currently the longest-acting agent approved [by the Food and Drug Administration (FDA)] for HIV treatment," Ogbuagu said. Lenacapavir got FDA approval based on the data in Ogbuagu's study, which has now been published in The Lancet HIV.

Lenacapavir joined a new class of antiretroviral therapy (ART) that "had never existed before," Ogbuagu said. Because of its novelty, the drug has a high chance of success since people have not been exposed to it before. It tackles one of the biggest issues when it comes to medication for treatment of HIV: drug resistance. "We define [HIV multi-drug resistance] by people having resistance to two or more drugs in at least three of the four main classes of drugs, and who have fewer than two effective drugs left" to be used as treatment within each of the different classes, Ogbuagu explained. Some people's viral infection develops resistance to HIV treatments over time. Others have acquired HIV from people who already had developed resistance to multiple HIV medications.

"They are typically people who were on HIV treatments, and, either because they were put on the wrong medication, or they didn't take the medication as prescribed, they can develop resistance to HIV treatments. The people in the study had multi-drug resistance," Ogbuagu explained.

How lenacapavir is being studied

To conduct the third phase of the drug trial, Ogbuagu and colleagues treated three groups of patients with lenacapavir tablets, and with injections that went under the skin. First, they measured how lenacapavir worked on its own to decrease the virus in the bodies of the people who participated in the trial. There were three groups of individuals in the study. One was immediately switched off their failing treatments and placed on lenacapavir, along with at least one or more additional HIV drugs. For the other two, the researchers randomly gave lenacapavir to one group and a placebo to the other in a 2:1 ratio for two weeks. Those who received lenacapavir tablets for the first two weeks took weekly doses. After the two weeks, they added new drugs to replace the current therapy the person was on that had not been effective. Subsequently, they tested people to check the amount of viral copies they had in their bloodstream. "We found that we had suppressed 88% of viral copies in the arm where people had received lenacapavir, and suppressed only 17% in people who received the placebo in the arm," Ogbuagu noted, "and then we followed them out to a year." Ogbuagu added that "for a group of patients with HIV who have very limited treatment options, due to drug resistance, or intolerance, or safety concerns," the drug managed to suppress the virus in over 80% of individuals. "That's incredible," he said.

The clinical trials were done with a relatively small group of people since only 8% or less of all the HIV patient population has multi-drug resistance and met that definition in the study, said Ogbuagu. Still, the study's enrollment numbers were sufficient for the FDA since only a small number of people could meet the criteria of the study. When the study, which was done with FDA oversight, met research goals, the agency approved 927 milligrams of lenacapavir injections, separated into two doses, to be received twice per year. Lenacapavir tablets of 300 milligrams were approved for use only as a loading dose—for an initial lead-in option before switching to the injection in the study. In addition, Ogbuagu and his team decided to use lenacapavir tablets in the trial so that people would not skip any doses if they were going to miss an injection appointment during the peak of the pandemic of COVID-19. "So, we gave people tablets to take once weekly as a bridge," he said. This form of the therapy is not yet approved by the FDA and thus not available to the public. Data at the end of the first year of their trial showed that receiving the injection helped people strengthen their immune system. Ogbuagu expects this will likely to translate to better protection against possible opportunistic infections like salmonella and tuberculosis, and also to lower the associated risk of death.

How this new HIV drug therapy works

In essence, lenacapavir tackles the capsid, a conical structure that harbors the RNA (ribonucleic acid) of HIV and other proteins that HIV uses to enter and replicate in human cells. The medication works in two ways: First, it interrupts viral replication by preventing HIV from reaching the nucleus of an infected cell, which then blocks reproduction. The second mechanism is for cases in which integration of the HIV genome has already occurred. In this instance, lenacapavir interferes with production of viral progeny, "making them defective so that they are not able to infect other cells." Therefore, it works in both early and late stages of the HIV life cycle to disrupt replication. Ogbuagu said that this medication—which tackles the HIV-1 strain—also appears to have a unique ability to prevent HIV-1. He and other investigators are now enrolling patients in other studies to further evaluate it for that purpose. It is also a very potent medication so "a little goes a long way," said Ogbuagu. Patients would only need a lenacapavir injection every 26 weeks, which is approximately every six months. Besides possible, and mostly minor, injection-site reactions, he added that the drug showed itself to be safe and was well-tolerated. Ogbuagu also highlighted that the lenacapavir injection should be combined with one or two other HIV medications as treatment for people who live with HIV multi-drug resistance.

Simplifying treatment options for multi-drug resistant HIV

According to Ogbuagu, lenacapavir "opens the door to simplify treatments for people who previously had not had any good options." The fact that patients must visit the clinic to receive the injection gives the provider more control, as they can be sure the drug is correctly administered and that all doses are given in a timely fashion. This is important for people who face obstacles to receive HIV treatment due to work schedules, housing insecurity, or "too many other social determinants of health challenges" they might have to face. Ogbuagu added that it also reduces "the stigma associated with [taking] a daily pill." "It has been a challenge in the field to have simple treatment for this type of patient," Ogbuagu concludes, "so the approval of lenacapavir is something we should be very proud of."

See Lancet study (July 11, 2023):

https://doi.org/10.1016/S2352-3018(23)00113-3

HIV BREAKTHROUGH - Genetic study identifies Africa-specific variant near CHD1L gene associated with lower HIV-1 viral load in populations of African descent. New research has found a genetic variant that may explain why some people of African ancestry have naturally lower viral loads of HIV, reducing their risk of transmitting the virus and slowing progress of their own illness. The paper, published today in Nature, demonstrates the first new genetic variant related to HIV infection discovered in nearly 30 years of research. It could, in the future, help direct the development of new treatments and approaches for those living with HIV. HIV-1 remains a significant global health crisis, and identifying new targets for therapies is crucial. The study focuses on individuals of African descent due to the disproportionate burden of HIV-1 in Africa and the high genetic diversity in the region. An international team of researchers analysed the DNA of almost 4,000 people of African ancestry living with HIV-1, the most common type of the virus. They identified a variant within a region on chromosome 1 containing the gene CHD1L which is associated with reduced viral load in carriers of the variant. Between 4% and 13 % of people of African origin are thought to carry this particular variant.  Viral load is the amount of a virus in a patient’s system. Higher levels are known to correlate with faster disease progression and increased risk of transmission. But viral load varies widely among infected individuals, influenced by a number of factors including an individual’s genetic makeup. Co-Senior author Professor Manjinder Sandhu, Chair in Population Health and Data Science in the School of Public Health, said: “With more than a million new HIV infections a year, it’s clear that we still have a long way to go in the fight against HIV – we are yet to have a vaccine to prevent infection, have yet to find a cure and still see drug resistance emerging in some individuals. The next step is to fully understand exactly how this genetic variant controls HIV replication.”

Understanding African populations

Most of what we know about the relationship between our DNA and HIV comes from studies among European populations. But given that HIV disproportionately affects people on the African continent – more than 25 million people who are HIV-positive live on the continent – it’s important to better understand the role of genetics in HIV infection in African populations.  Paul McLaren from the Public Health Agency of Canada’s National Microbiology Laboratory and joint first author on the paper, said: “African populations are still drastically underrepresented in human DNA studies, despite experiencing the highest burden of HIV infection. By studying a large sample of people of African ancestry, we’ve been able to identify a new genetic variant that only exists in this population and which is linked to lower HIV viral loads.”

Reducing viral load

CHD1L is known to play a role in repairing damaged DNA, though it is not clear why the variant should be important in reducing viral load. However, as HIV attacks immune cells, researchers at the University of Cambridge’s Department of Medicine, led by Dr Harriet Groom and Professor Andrew Lever, used stem cells to generate variants of cells that HIV can infect in which CHD1L had either been switched off or its activity turned down. HIV turned out to replicate better in a type of immune cell known as a macrophage when CHD1L was switched off. In another cell type, the T cell, there was no effect – perhaps surprising since most HIV replication occurs in the latter cell type.  Dr Harriet Groom said: “This gene seems to be important to controlling viral load in people of African ancestry. Although we don’t yet know how it’s doing this, every time we discover something new about HIV control, we learn something new about the virus and something new about the cell. The link between HIV replication in macrophages and viral load is particularly interesting and unexpected.

Original study published (August 2, 2023) in Nature:

https://doi.org/10.1038/s41586-023-06370-4 

Background

Methods

Findings

Interpretation

For the first time in humans, a research team has shown that, as early as the first days of infection, HIV is able to create reservoirs where it will hide and persist during antiretroviral therapy. Until now, the scientific community did not know exactly when or how these viral reservoirs—the existence of which is a major obstacle to curing HIV—are established in human beings. In a study published in the journal Immunity, scientists led by Nicolas Chomont, a researcher at the CHUM Research Centre (CRCHUM) and professor at Université de Montréal, found that a small fraction of the virus integrates into the genome of CD4+ T cells in the very first weeks of infection (the acute phase), but does not replicate there. It therefore escapes the notice of the fastest diagnostic tool to date, which detects active viral replication.

CD4+ T cells are HIV's primary targets. They are white blood cells responsible for activating the human body's defense against infections. "With the help of an analysis technique developed in our laboratory, we were able to observe and count the T cells infected by the virus in human samples collected in the earliest stages of the infection," said Chomont, the study's principal author. "We succeeded in detecting the presence of the virus through sequencing even when it was hidden in cells that weren't participating in viral replication." To study these initial phases of the spread of the virus, Pierre Gantner, a former postdoctoral student in Chomont's lab and the study's first author, had access to samples of blood and inguinal lymph node tissue from 25 people in the first acute-infection cohort of the U.S. Military HIV Research Program in Thailand. This cohort, RV254/SEARCH010, was launched more than 10 years ago in collaboration with the Thai Red Cross AIDS Research Centre and has enrolled nearly 800 volunteers. Chomont and his team have been closely cooperating with their colleagues in Thailand since its launch.

Mapping the types of infected cells

Through their analysis technique, the CRCHUM scientists succeeded in counting the CD4+ T cells infected by the virus during the acute phase of the infection. These infected cells increased in number from 10 to 1,000 per million CD4+ T cells in less than seven days, thereby showing the extreme speed with which HIV spreads. The scientists also observed that the characteristics of the cells targeted by HIV in the first weeks of the infection varied quickly and differed depending on whether they were located in the blood or lymph nodes. "For example, we noticed that few Tfh—T follicular helper cells—are infected by the virus during the acute phase of the infection," said Chomont. "Since they play a crucial role in viral replication, the scientific community thought that they were the first to be infected." "In fact, we counted a lot more [infected Tfh] during the chronic phase of the disease, which is about two months after infection. At that point, they are actively contributing to the development of the disease." Until now, these types of studies have been carried out on animal models. Therefore, this is the first time that the early stages of the infection in humans have been described so precisely.

Destabilizing the reservoirs

A large part of global research dedicated to the study of HIV focuses on how to reactivate the virus lying dormant in the reservoirs in order to neutralize it. "'The earlier we start antiretroviral therapy, the more we prevent the virus from replicating and the more we limit the size of the reservoirs. We proved that in 2020," said Chomont. "However, it seems clear that early antiretroviral therapy should be combined with another treatment to force the virus out of its hiding places, because at the time of diagnosis latent reservoirs will have already been established in people infected with HIV." In collaboration with scientists from the United States, Chomont's research team is currently evaluating whether this type of treatment administered in the acute infection phase would prevent the establishment of viral reservoirs.

Cited study published (Feb. 17, 2023) in Immunity:

https://doi.org/10.1016/j.immuni.2023.01.030

In the phase 3 CAPELLA trial. opens in new tab, 36 patients (cohort 1) with drug-resistant virus failing their current regimen were randomized to lenacapavir or placebo. At day 14, all patients in cohort 1 were switched to optimized background therapy (OBT) plus lenacapavir. An additional 36 patients (cohort 2) received OBT plus lenacapavir beginning at enrollment. The primary endpoint (0.5-log reduction in viral load at day 14 in cohort 1) was achieved by 88% (lenacapavir arm) versus 17% (placebo arm). At week 26, patients in cohorts 1 and 2 had similar rates of viral suppression (<50 copies/mL in 81% and 83%, respectively) that was maintained at week 52. Mutations associated with decreased susceptibility to lenacapavir (primarily M66I) developed in eight patients, four of whom re-suppressed virus without a change in therapy. The drug was well tolerated; the most common adverse events were injection-site reactions (ISR) in 62%, and only one patient discontinued therapy because of an ISR. Significant drug-drug interactions occur between lenacapavir and strong UGT1A1 inhibitors, and with potent CYP, P-gp, or UGT inducers including atazanavir-based regimens, etravirine, and rifamycins. No dosage adjustment is necessary in those with creatinine clearance >15 mL/min. Estimated cost. opens in new tab is $42,250 for the first year and $39,000 annually thereafter.

Rare CD4 T cells that contain HIV under antiretroviral therapy represent an important barrier to HIV cure1–3, but the infeasibility of isolating and characterizing these cells in their natural state has led to uncertainty about whether they possess distinctive attributes that HIV cure-directed therapies might exploit. Here we address this challenge using a microfluidic technology that isolates the transcriptomes of HIV-infected cells based solely on the detection of HIV DNA. HIV-DNA+ memory CD4 T cells in the blood from people receiving antiretroviral therapy showed inhibition of six transcriptomic pathways, including death receptor signalling, necroptosis signalling and antiproliferative Gα12/13 signalling. Moreover, two groups of genes identified by network co-expression analysis were significantly associated with HIV-DNA+ cells. These genes (n = 145) accounted for just 0.81% of the measured transcriptome and included negative regulators of HIV transcription that were higher in HIV-DNA+ cells, positive regulators of HIV transcription that were lower in HIV-DNA+ cells, and other genes involved in RNA processing, negative regulation of mRNA translation, and regulation of cell state and fate. These findings reveal that HIV-infected memory CD4 T cells under antiretroviral therapy are a distinctive population with host gene expression patterns that favour HIV silencing, cell survival and cell proliferation, with important implications for the development of HIV cure strategies. HIV-infected memory CD4 T cells under antiretroviral therapy are a distinctive population of cells with transcriptomic patterns that favour HIV silencing, cell survival and cell proliferation.

Published in Nature (Jan. 4, 2023):

https://doi.org/10.1038/s41586-022-05556-6 

HIVACAT T-cell immunogen (HTI) is a novel human immunodeficiency virus (HIV) vaccine immunogen designed to elicit cellular immune responses to HIV targets associated with viral control in humans. The AELIX-002 trial was a randomized, placebo-controlled trial to evaluate as a primary objective the safety of a combination of DNA.HTI (D), MVA.HTI (M) and ChAdOx1.HTI (C) vaccines in 45 early-antiretroviral (ART)-treated individuals (44 men, 1 woman; NCT03204617). Secondary objectives included T-cell immunogenicity, the effect on viral rebound and the safety of an antiretroviral treatment interruption (ATI). Adverse events were mostly mild and transient. No related serious adverse events were observed. We show here that HTI vaccines were able to induce strong, polyfunctional and broad CD4 and CD8 T-cell responses.

All participants experienced detectable viral rebound during ATI, and resumed ART when plasma HIV-1 viral load reached either >100,000 copies ml−1, >10,000 copies ml−1 for eight consecutive weeks, or after 24 weeks of ATI. In post-hoc analyses, HTI vaccines were associated with a prolonged time off ART in vaccinees without beneficial HLA (human leukocyte antigen) class I alleles. Plasma viral load at the end of ATI and time off ART positively correlated with vaccine-induced HTI-specific T-cell responses at ART cessation. Despite limited efficacy of the vaccines in preventing viral rebound, their ability to elicit robust T-cell responses towards HTI may be beneficial in combination cure strategies, which are currently being tested in clinical trials. Vaccines that elicit HIV-specific T-cell responses did not prevent viral rebound in people living with HIV upon antiretroviral treatment (ART) interruption, but associated with longer time off ART in some trial participants, suggesting their immunogenicity may benefit future cure approaches.

Published In Nature Medicine (Oct. 27, 2022):

https://doi.org/10.1038/s41591-022-02060-2 

Reports of myocarditis, penile necrosis, and atypical/persistent rash requiring amputation.  Be alert for potentially severe manifestations of monkeypox in patients who are immunocompromised or co-infected with HIV, the CDC told healthcare workers on Thursday. "People who are immunocompromised due to HIV or other conditions are at higher risk for severe manifestations of monkeypox than people who are immunocompetent," the agency said in a health advisory to its Health Alert Network, adding that "the HIV status of all sexually active adults and adolescents with suspected or confirmed monkeypox should be determined."  Of the patients with severe manifestations "for whom CDC has been consulted," the majority had HIV with CD4 counts below 200 cells/mL, indicating "substantial immunosuppression," the agency noted. These severe manifestations have included cases involving atypical or persistent rash requiring amputation of an extremity; secondary bacterial or fungal infections; lesions in sensitive areas resulting in severe pain or urethral or bowel strictures; and comorbidities involving organ systems, including myocarditis, transverse myelitis, bowel lesions, penile necrosis, and others. The news arrives as the U.S. records its third known monkeypox-associated death in Ohio. To date, over 25,000 monkeypox cases have been reported in the U.S., 38% of which involved patients co-infected with HIV. Researchers have highlighted monkeypox severity and outcomes in people with HIV before.

For example, a study in The Lancet about a 2017-2018 monkeypox outbreak in Nigeria reported seven deaths in a population of 122 patients, with four of the seven co-infected with HIV.  More recently, papers on the current outbreak have reported conflicting results about the association between monkeypox severity and HIV co-infection. CDC data involving more than 1,300 monkeypox patients showed a higher rate of hospitalizations for those with HIV (8% vs 3% for those without HIV), with higher rates for those whose HIV was not virally suppressed. Conversely, German researchers reported that the clinical characteristics in HIV-infected versus non-infected monkeypox patients were largely similar. The new CDC advisory recommends that monkeypox treatment include optimization of immune function for people with immunocompromising conditions, such as limiting the use of immunosuppressive medications when "not otherwise clinically indicated," and offering antiretroviral therapy for those living with HIV. 

Severe immunocompromising conditions can including those with autoimmune disease where immunodeficiency is a clinical component; leukemia or lymphoma, transplant recipients; and those treated with high-dose steroids, alkylating agents, antimetabolites, radiation, or tumor necrosis factor (TNF) inhibitors.  On a case-by-case basis, medications such as oral and intravenous tecovirimat (Tpoxx), cidofovir or brincidofovir, and vaccinia immune globulin intravenous should be considered, "although there are no data on effectiveness in treating human monkeypox with these medical countermeasures," according to the CDC. Clinicians should gather repeat lesion swabs in patients with persistent monkeypox DNA, and continue tecovirimat beyond 14 days (but not more than 90 days), "until there is clinical improvement," the advisory stated. Modifications to the dose, frequency, and duration of tecovirimat may be necessary, depending on the patient's clinical condition, disease progression, or therapeutic response. The advisory encouraged clinicians to consult with the CDC Monkeypox Response Clinical Escalations team when appropriate.  The following severe manifestations seen in monkeypox patients were reported to the CDC, although the advisory did not include information about HIV status:

• Atypical or persistent rash with coalescing or necrotic lesions, or both, some of which have required extensive surgical debridement or amputation of an affected extremity

• Lesions on a significant proportion of the total body surface area, which may be associated with edema and secondary bacterial or fungal infections among other complications

• Lesions in sensitive areas (including mucosal surfaces such as the oropharynx, urethra, rectum, and vagina) resulting in severe pain that interferes with activities of daily living

• Bowel lesions that are exudative or cause significant tissue edema, leading to obstruction

• Severe lymphadenopathy that can be necrotizing or obstructing (such as in airways)

• Lesions leading to stricture and scar formation resulting in significant morbidity such as urethral and bowel strictures, phimosis, and facial scarring

The CDC advisory also noted reports of individuals with severe monkeypox involving multiple organ systems and associated comorbidities, including oropharyngeal lesions inhibiting oral intake; pulmonary involvement with nodular lesions; neurologic conditions, including encephalitis and transverse myelitis; cardiac complications, including myocarditis and pericardial disease; ocular conditions including severe conjunctivitis; sight-threatening corneal ulcerations; and urologic involvement including urethritis and penile necrosis. The advisory also urged healthcare providers and public health jurisdictions to encourage patients to enroll in the AIDS Clinical Trials Group STOMP trial to evaluate the efficacy of tecovirimat for monkeypox.

CDC Health Advisory published September 29, 2022:

https://emergency.cdc.gov/han/2022/han00475.asp 

Highlights

Summary

NIH-funded research networks provide evidence on cabotegravir and rilpivirine in additional populations. Long-acting, injectable antiretroviral therapy (ART) suppressed HIV replication better than oral ART in people who had previously experienced challenges taking daily oral regimens and was found safe in adolescents with HIV viral suppression, according to two studies presented today at the 2024 Conference on Retroviruses and Opportunistic Infections (CROI) in Denver. Both studies were sponsored by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, in collaboration with other NIH institutes.

“The HIV community is just beginning to unpack the enormous potential of long-acting antiretroviral medications for HIV treatment and prevention, and we need population-specific data for everyone to benefit,” said NIAID Director Jeanne Marrazzo, M.D., M.P.H. “These findings open up new possibilities for millions of people with HIV, particularly those whose health suffers due to challenges of daily pill taking.”

NIH funded this research to build on the clinical trials that underpinned the Food and Drug Administration approval(link is external) of long-acting cabotegravir and rilpivirine in 2021 for people with a consistent history of viral suppression. The studies were conducted in collaboration with ViiV Healthcare and Johnson & Johnson and intended to provide evidence on the use of the drug regimen in populations for whom limited data exist....

Dormant HIV actively produces RNA and proteins during anti-retroviral therapy. Patients with HIV usually carry a reservoir of HIV-infected cells that can re-emerge if anti-retroviral therapy stops. These reservoirs have long been thought to be dormant, but two independent groups of researchers report that a subset of these cells spontaneously produce HIV RNA and proteins that may impact patients’ HIV-specific immune responses. Their findings are published in the journal Cell Host & Microbe in the articles titled: “Spontaneous HIV expression during suppressive ART is associated with the magnitude and function of HIV-specific CD4+ and CD8+ T cells” and “An active HIV reservoir during ART is associated with maintenance of HIV-specific CD8+ T cell magnitude and short-lived differentiation status.” “It’s a deceptively dormant virus,” said immunovirologist Daniel Kaufmann, MD, of the University Hospital of Lausanne, the University of Lausanne, and l’Université de Montréal, and who is senior author on one of the papers. “Even in people who are treated, HIV continues to have some activity, and it continues to interact with the immune system. We have to understand if these ongoing interactions have clinically relevant consequences.”

Previous studies have shown that when “dormant” HIV reservoir cells are reactivated in the lab, they produce viral RNA and proteins, but it wasn’t clear whether this phenomenon was happening inside the bodies of people with HIV. “We wanted to understand if this phenomenon is real and, if it is, what parts of the virus are being expressed and do they have an impact on the immune system,” explained Kaufmann. The researchers took blood samples from 18 people with HIV who had all been on antiretrovirals for more than three years. Then, they used a lab method called RNA flow cytometry to sort CD4+ or “helper” T cells based on whether they were infected with HIV and, then further, whether they were actively producing HIV RNA or proteins. The researchers also characterized the T cells by role—e.g., whether they were the type of T helper cell that combats intracellular viruses or the type that combats extracellular bacteria—to determine whether any subtypes of CD4+ T cells were more likely to host HIV reservoirs. “Our technique allows us to look at the individual cells to see if they contain the virus and which parts of the virus they are expressing,” said Mathieu Dubé, an immunovirologist at l’Université de Montréal and first author on the paper led by Kaufmann. “For each patient, we could estimate how many of these cells are still active, and we could also look for associations between viral characteristics and cell characteristics.” The researchers observed that 14 of the 18 patients had HIV reservoirs that spontaneously produced viral RNA. For seven of the 18 patients, the viral reservoirs also produced viral proteins including p24, a component of HIV’s shell. “Most of the virus that remains in the body is defective or junk virus that cannot really multiply, but we found these defective viruses can still produce virus RNA and sometimes proteins,” said Kaufmann.

“Our data suggest that the RNA and proteins produced by these viral reservoirs could be drivers of inflammation,” said Kaufmann. “This could be important because a subset of the people who are successfully treated with anti-retroviral therapy for HIV still have negative consequences of living with the infection—for example, accelerated cardiac disease, frailty, and premature osteoporosis.” The second paper, led by immunologist Lydie Trautmann, PhD, at the Vaccine and Gene Therapy Institute of Oregon Health and Science University, also reported that a subset of CD4+ T cells spontaneously express viral RNA during anti-retroviral therapy. “Our study suggests that residual immune dysfunction driven by the active HIV reservoir on anti-retroviral therapies could contribute to the lack of viral control after analytical treatment interruption by preventing the differentiation of functional stem-like self-renewing HIV-specific CD8+ T cells that can mount efficient rapid recall responses,” the authors wrote. “Therefore, HIV remission strategies will likely need to target transcriptionally active proviruses producing viral proteins during anti-retroviral therapies to harness HIV-specific CD8+ T cells to control rebounding of the virus after therapy cessation.”

Research cited published in Cell and Host Microbe (September 2023):

https://doi.org/10.1016/j.chom.2023.08.006 

The AIDS epidemic has been a global public health issue for more than 40 years and has resulted in ~40 million deaths. AIDS is caused by the retrovirus, HIV-1, which is transmitted via body fluids and secretions. After infection, the virus invades host cells by attaching to CD4 receptors and thereafter one of two major chemokine coreceptors, CCR5 or CXCR4, destroying the host cell, most often a T lymphocyte, as it replicates. If unchecked this can lead to an immune-deficient state and demise over a period of ~2–10 years. The discovery and global roll-out of rapid diagnostics and effective antiretroviral therapy led to a large reduction in mortality and morbidity and to an expanding group of individuals requiring lifelong viral suppressive therapy. Viral suppression eliminates sexual transmission of the virus and greatly improves health outcomes.

HIV infection, although still stigmatized, is now a chronic and manageable condition. Ultimate epidemic control will require prevention and treatment to be made available, affordable and accessible for all. Furthermore, the focus should be heavily oriented towards long-term well-being, care for multimorbidity and good quality of life. Intense research efforts continue for therapeutic and/or preventive vaccines, novel immunotherapies and a cure. In HIV infection, the virus invades and destroys the immune system of the host. This Primer by Bekker and colleagues summarizes the epidemiology, mechanisms, diagnosis and treatment of HIV infection, and discusses patient quality of life and open research questions for this condition.

Published August 17, 2023:

https://www.nature.com/articles/s41572-023-00452-3 

Studies in living brain tissue found that specialized immune cells in the brain can harbor latent but replication-competent HIV.  As a part of its life cycle, human immunodeficiency virus-1 (HIV-1) inserts a copy of its DNA into human immune cells. Some of these newly infected immune cells can then transition into a dormant, latent state for a long period of time, which is known as HIV latency. Although current antiretroviral therapy (ART) against HIV can successfully block the virus from replicating further, it cannot eradicate latent HIV. If treatment is discontinued, the virus can rebound from latency and reignite the progression of HIV infection to AIDS. Scientists at the HIV Cure Center at the UNC School of Medicine, University of California, San Diego (UCSD), Emory University, and the University of Pennsylvania, have been searching for where exactly these latent cells are hiding in the body. Their newly reported studies indicate that brain microglial (BM)—specialized brain-resident immune cells with a decade-long lifespan—can serve as a stable viral reservoir for latent HIV. “We now know that microglial cells serve as a persistent brain reservoir,” said Yuyang Tang, PhD, assistant professor of medicine in the division of infectious diseases and member of the UNC HIV Cure Center. “This had been suspected in the past, but proof in humans was lacking. Our method for isolating viable brain cells provides a new framework for future studies on reservoirs of the central nervous system, and, ultimately, efforts towards the eradication of HIV.” Tang is first author of the team’s published paper in The Journal of Clinical Investigation, which is titled, “Brain microglia serve as persistent HIV reservoir despite durable antiretroviral therapy.”

HIV is a tricky virus to study. During infection, the virus specifically targets CD4+ lymphocytes which are the key coordinators of the immune response. Over time, the virus kills enough CD4+ cells to cause immunodeficiency. Past research has shown that latent HIV can hide within a few of the surviving CD4+ T cells throughout the body and the bloodstream. However, it’s been suspected that there are other viral reservoirs hidden within the central nervous system (CNS) in people with HIV who are receiving effective ART. But as the authors noted, “… rigorous evidence of viral persistence in the CNS cells of humans on durable suppressive ART is incomplete … Brain microglia (MG) may serve as a human immunodeficiency virus 1 (HIV) reservoir and ignite rebound viremia following cessation of antiretroviral therapy (ART), but they have yet to be proven to harbor replication-competent HIV. Unlike peripheral blood cells, it is extremely difficult to access and analyze brain tissues for the study of HIV reservoirs. Since these types of cells cannot be safely sampled in people taking ART, the potential viral reservoir in the brain has remained an enigma for many years. For their reported research the team first studied the brains of macaques infected with simian immunodeficiency virus (SIV), a virus that is closely related to HIV, from the Yerkes National Primate Research Center at Emory University to get a better understanding of how to extract and purify viable cells from primate brain tissue. The researchers used physical separation techniques and antibodies to selectively remove cells that were expressing microglial surface markers. Then, they isolated and separated the highly pure brain myeloid cells (BrMCs) from the CD4+ cells that were passing through the brain tissue. Using these techniques, researchers then obtained samples that were donated by HIV+ people (people with HIV; PWH) who were enrolled in “The Last Gift” Study at UCSD. As a part of this unique and important effort, altruistic HIV+ people, who are taking ART but suffering from other terminal illnesses, will their bodies to further the HIV research project.

“ … we first developed protocols to isolate highly pure populations of BrMCs and MG from the tissues of nonhuman primates (NHPs),” the authors explained. “We then adapted these protocols to the study of human brain tissues containing large numbers of viable cells after rapid autopsy to explore whether human BrMCs produce replication-competent HIV.” Co-author David Margolis, MD, the Sarah Kenan distinguished professor of medicine, microbiology & immunology, and epidemiology, further noted, “The samples are from people living with HIV, who are on therapy but facing a fatal disease of some kind. They were willing to not just donate their bodies to science, but also participate in the research program in the months leading up to their death. It’s an extraordinary program that made this critical research possible.” The scientists’ findings confirmed that MGs from an individual with HIV, being treated using ART, harbored replication-competent HIV. They acknowledged that although their study was limited by the small number of available samples from human donors on ART, they believe that the findings are consistent with NHP studies. “Our observations support the concept that brain MG are a stable reservoir of quiescent infection and may be a source of viral rebound upon treatment interruption,” they concluded. “Future efforts to clear HIV infection will have to include assessments of the persistence of HIV within CNS MG.” Now that the researchers know that latent HIV can take refuge in microglial cells in the brain, they are now considering plans to target this type of reservoir. Since latent HIV in the brain is radically different from the virus in the periphery, researchers believe that it has adapted special characteristics to replicate in the brain.

Reporting in their paper, the team noted, “Phenotyping studies characterized brain-derived virus as macrophage tropic based on the ability of the virus to infect cells expressing low levels of CD4. The lack of genetic diversity in virus from the brain suggests that this macrophage-tropic lineage quickly colonized brain regions.” NF-κB signaling is one of the critical signaling pathways that control HIV expression elsewhere in the body. When NF-κB signaling is “turned off,” HIV enters latency in the peripheral blood. However, latent HIV in the brain is not impacted by the activation of NF-κB signaling. Researchers are unsure why that is, but once an answer is found, they will be one step closer to knowing how to selectively target and eradicate the virus in the brain or peripheral blood. In addition to understanding the inner workings of the brain reservoir, the researchers are also trying to determine the true size of the latent HIV brain reservoir. “HIV is very smart,” said senior author Guochun Jiang, PhD, assistant professor in the UNC department of biochemistry and biophysics and member of the UNC HIV Cure Center. “Over time, it has evolved to have epigenetic control of its expression, silencing the virus to hide in the brain from immune clearance. We are starting to unravel the unique mechanism that allows latency of HIV in brain microglia”. Added Margolis, who is also the director of the UNC HIV Cure Center, “It is very hard to know how big the reservoir is. The problem with trying to eradicate HIV is like trying to eradicate cancer. You want to be able to get it all, so it won’t come back.”

Original research published in The Journal of Clin. Investigation (June 15, 2023):

https://doi.org/10.1172/JCI167417 

NIH-funded study confirms white blood cell subtype as HIV reservoir, suggests new target for cure efforts. A subset of white blood cells, known as myeloid cells, can harbor HIV in people who have been virally suppressed for years on antiretroviral therapy, according to findings from a small study supported by the National Institutes of Health. In the study, researchers used a new quantitative method to show that HIV in specific myeloid cells—short-lived monocytes and longer-lived monocyte-derived macrophages—can be reactivated and infect new cells. The findings, published in Nature Microbiology(link is external), suggest that myeloid cells contribute to a long-lived HIV reservoir, making these cells an important but overlooked target in efforts to eradicate HIV. “Our findings challenge the prevailing narrative that monocytes are too short-lived to be important in cure efforts,” said study author Rebecca Veenhuis, Ph.D.(link is external), an assistant professor of molecular and comparative pathobiology and of neurology at Johns Hopkins University School of Medicine, Baltimore. “Yes, the cells are short-lived, but our follow-up data show that HIV can persist in monocytes over several years in people who are virally suppressed. The fact that we can detect HIV in these cells over such a long period suggests something is keeping the myeloid reservoir going.” The study, led by Veenhuis and colleagues at Johns Hopkins University School of Medicine, was supported by the National Institute of Mental Health, the National Institute of Allergy and Infectious Diseases, and the National Institute on Drug Abuse, all part of NIH. Antiretroviral medications are effective in treating HIV because they prevent the virus from infecting new cells and multiplying. However, HIV may still exist in cells that are in a resting, or latent, state, creating an HIV reservoir. CD4 T cells, a type of white blood cell, are the most well-studied HIV reservoir. Identifying HIV reservoirs is critical to cure efforts, as latent HIV can be reactivated if people stop taking antiretroviral medications. Monocytes are immune cells that circulate in the blood for about 3 days before traveling to tissue in various parts of the body, including the brain, where they can mature into macrophages. To date, it has not been clear whether latent HIV in these cells can become active again and infect other cells. “What’s really important in the long run is understanding how monocytes contribute to the tissue macrophage reservoir,” explained Janice Clements, Ph.D.(link is external), senior author on the study and professor of molecular and comparative pathobiology at Johns Hopkins University School of Medicine. “If monocytes can carry virus to the brain, or lung, or another part of the body and infect resident macrophages that are self-renewing and live almost indefinitely, that’s a real problem.”  

In the study, Veenhuis, Clements, and colleagues first measured HIV DNA in myeloid cells in a sample of 30 participants with HIV, all of whom were virally suppressed and had been on antiretroviral therapy for at least 5 years. They found detectable levels of HIV genetic material in monocytes and macrophages, though the levels were much lower than those observed in CD4 T cells. In some participants, the HIV genetic material found in monocytes was intact, which suggests it may be capable of infecting other cells if reactivated. They then used the new quantitative method they developed to directly measure viral spread from HIV found in myeloid cells. The researchers isolated monocytes from blood samples taken from 10 participants and nurtured the monocytes in cultures that contained antiretroviral drugs, to replicate the participants’ baseline physical state. After the monocytes differentiated into macrophages, the researchers introduced an immune activating agent and then added fresh white bloods cells to allow for the virus to spread to new cells. The researchers collected samples from the cell cultures several times over the next 12 days. They included checkpoints throughout the process to ensure that infected CD4 T cells did not interfere with their measurements. The results showed that cultures from five of the 10 participants had detectable HIV genetic material in monocyte-derived macrophages that could be reactivated to infect other cells and produce more virus. The participants who had these reactivatable reservoirs of HIV in monocyte-derived macrophages had higher overall levels of HIV DNA material.   Follow-up data from three participants showed that this reservoir can be long-lived, harboring latent HIV for months to several years. These reservoirs were stable and could be reactivated over time, indicating that monocyte-derived macrophages could contribute to viral rebound if antiretroviral treatment is disrupted. The researchers note that this study is small and larger studies with more diverse participant pools will be essential to accurately estimate the proportion of people who have latent HIV in myeloid cells. Investigating the mechanisms that replenish the monocyte reservoir over time is a critical next step in this research. “These findings underscore the importance of broadening the scope of HIV cure efforts,” said Joshua A. Gordon, M.D., Ph.D., director of the National Institute of Mental Health. “Shifting away from a sole focus on CD4 T cells to thinking about CD 4 T cells and myeloid cells together, in context, will propel the field toward more promising strategies for eradicating HIV.”

Published in:

 https://doi.org/10.1038/s41564-023-01349-3 

A woman is in remission for HIV after she received HIV-resistant stem cells from umbilical cord blood to treat her leukaemia. A transplant of stem cells from the umbilical cord has resulted in a mixed-race woman going into remission for HIV for the first time. The woman, known as the New York patient, has been clear of detectable HIV since 2017, after she received HIV-resistant stem cells that had been harvested from umbilical cord blood to treat her leukaemia. Stem cells are produced by bone marrow and can turn into different types of blood cells.Several people have previously gone into remission from HIV after receiving stem cells from adult donors who carry two copies of a naturally occurring mutation of the CCR5 gene. This delta 32 mutation prevents the virus from entering and infecting healthy cells. With any stem cell transplant, recipients can only receive donations from people with matching tissue types to reduce the risk that their immune system will attack the transplanted tissue. Since tissue types are inherited, a person’s ethnicity influences their ability to find a match. Having two copies of the CCR5 mutation is rare, existing in only around 1 per cent of people of northern European ancestry and being even rarer in other populations.

To overcome the lack of suitable adult donors, doctors carried out a study where they infused umbilical cord blood into the New York patient, who identifies as mixed race. She also received stem cells from a relative. Umbilical cord blood can contain fewer stem cells than adult blood so mixing it with stem cells from a relative gives the cord blood a “kick start”, Yvonne Bryson at the University of California, Los Angeles, who co-led the study, said in a statement. Using umbilical cord blood makes it easier to find transplant matches, as large repositories of frozen samples have been donated by people who gave birth in hospitals, says Jingmei Hsu at the New York Presbyterian Hospital. “Having a bank [of cord blood] really opened the door to help more patients,” she says. Most people with HIV can lower the amount of the virus in their blood to undetectable levels by taking antiretroviral drugs, which stop the virus from replicating in their body. Stem cell transplants would therefore only be considered for people with HIV who also have advanced blood cancer, which can be treated with the procedure. The New York patient no longer requires antiretroviral drugs and is also in remission for her leukaemia. The transplant involves using chemotherapy, and sometimes radiation, to kill a person’s red blood cells, before infusing the individual with a donor’s stem cells. The recipient is given immunosuppressant drugs to reduce the risk of their immune system rejecting the transplant, which makes infections more likely.

It takes several months for the donor’s stem cells to repopulate the recipient’s blood cells, says Mario Stevenson at the University of Miami, Florida. “That window is a very high-risk window for the individual.” The recipient’s body can also reject the transplant in a complication known as graft versus host disease (GvHD), when immune cells among the donated stem cells attack the recipient’s own cells. With previous cases in which people with HIV went into remission after receiving adult stem cell transplants, some scientists believed that a relatively severe GvHD response was necessary to activate dormant HIV-infected cells so they could be more effectively eliminated, says Stevenson. The New York patient, however, experienced only mild GvHD symptoms, such as gastrointestinal discomfort, while still going into remission for HIV, he says. The other patients had more severe complications, such as hearing loss and extreme weight loss. According to Hsu, the New York patient’s milder symptoms were probably due to the use of umbilical cord blood. This blood hasn’t been exposed to many toxins or infections, she says. Its T-cells, a type of immune cell involved in GvHD, are therefore less reactive to cells that may not be a perfect match, she says. “With more success, like this story, we can open doors for all patients in these very, very high-risk situations,” says Hsu.

Case report study published (March 16, 2023) in Cell:

https://doi.org/10.1016/j.cell.2023.02.030 

But the risks associated with the procedure mean it is unlikely to be widely used in its current form. A 53-year-old man in Germany has become at least the third person with HIV to be declared cleared of the virus after a procedure that replaced his bone marrow cells with HIV-resistant stem cells from a donor. For years, antiretroviral therapy (ART) has been given to people with HIV with the aim of lowering the virus to almost undetectable levels and preventing it from being transmitted to other people. But the immune system keeps the virus locked up in reservoirs in the body, and if an individual stops taking ART the virus can begin replicating and spreading. A true cure would eliminate this reservoir, and this is what seems to have happened for the latest patient, whose name has not been released. The man, who is being referred to as the ‘Düsseldorf patient’, stopped taking ART in 2018 and has remained HIV-free since.

The stem-cell technique involved was first used to treat Timothy Ray Brown, often referred to as the Berlin patient. In 2007, he had a bone marrow transplant, in which those cells were destroyed and replaced with stem cells from a healthy donor, to treat acute myeloid leukaemia. The team treating Brown selected a donor with a genetic mutation called CCR5Δ32/Δ32, which prevents the CCR5 cell-surface protein from being expressed on the cell surface. HIV uses that protein to enter immune cells, so the mutation makes the cells effectively resistant to the virus. After the procedure, Brown was able to stop taking ART and remained HIV-free until his death in 2020. In 2019, researchers revealed that the same procedure seemed to have cured the London patient, Adam Castillejo. And, in 2022, scientists announced that they thought a New York patient who had remained HIV-free for 14 months might also be cured, although researchers cautioned that it was too early to be certain. Ravindra Gupta, a microbiologist at the University of Cambridge, UK, who led the team that treated Castillejo, says the latest study “cements the fact that CCR5 is the most tractable target for achieving a cure right now”.

Yet another experimental HIV vaccine has failed. The National Institute of Allergy and Infectious Diseases reported Wednesday that a phase 3 clinical trial of an HIV vaccine was stopped because the vaccine was ineffective at preventing infection. The vaccine was being developed by Janssen, the vaccine division of Johnson & Johnson. The Mosaico trial, which enrolled 3,900 volunteers in multiple countries, was halted after a scheduled data review by a data and safety monitoring board found there were roughly as many new HIV infections among people in the vaccine arm as in the placebo arm. The trial was studying the vaccine in cisgender men and transgender people who have sex with cisgender men and/or transgender people. “We are disappointed with this outcome and stand in solidarity with the people and communities vulnerable to and affected by HIV,” Penny Heaton, Janssen’s global therapeutic area head for vaccines, said in a statement. “We remain steadfast in our commitment to advancing innovation in HIV, and we hope the data from Mosaico will provide insights for future efforts to develop a safe and effective vaccine.” In 2021, a Phase 2b trial of a similar candidate HIV vaccine was halted when a data and safety monitoring board determined that it was not preventing infections. The Imbokodo trial was studying the vaccine in women in sub-Saharan Africa.

“For our research partners and others who have waged a decades-long effort to develop vaccines to end the HIV/AIDS pandemic, these results are disappointing,” Susan Buchbinder, co-chair of the Mosaico trial, said in a statement. “Although HIV continues to prove uniquely challenging for development of a vaccine, the HIV research community remains fully committed to doing just that, and each study brings us a step closer to this realization,” she said. Buchbinder is director of Bridge HIV, a grant-funded research unit at the San Francisco Department of Public Health, and a clinical professor at the University of California, San Francisco. The trial was conducted by the HIV Vaccine Clinical Trials Network based at the Fred Hutchinson Cancer Center in Seattle. Veteran HIV vaccine trialist Larry Corey acknowledged yet another setback in the decades-long quest to find an effective HIV vaccine. “HIV is a constantly changing and very challenging adversary. We can become disappointed when our best efforts don’t produce the results we’re looking for,” said Corey, principal investigator of the network’s leadership and operations center. “We have, however, come a long way and made many discoveries since the time when life expectancy was very short following an HIV diagnosis.” The vaccine was based on “mosaic” immunogens targeting HIV subtypes. The goal was to induce immune responses to a broad range of HIV strains. It was given in four injections over the course of a year. The vaccine used the same antigen delivery system employed by J&J’s Covid-19 vaccine, a common cold virus known as adenovirus 26. Volunteers were enrolled in the trial only after they were offered HIV pre-exposure prophylaxis, the antiretroviral drugs that can prevent infection. Those who accepted PrEP were steered towards services where they could access the drugs. People who did not want them, however, were considered for the study. Anyone in the trial who later changed their mind and wanted to use PrEP was also given access to the drugs, but remained in the trial.

At least five experimental HIV vaccines, tested over nine trials, have failed to show efficacy at the Phase 3 stage of development, said Mitchell Warren, executive director of AVAC, the AIDS Vaccine Advocacy Coalition. This latest failure hangs a big question mark over this field of research, he suggested. “I’m not sure we know exactly where the next big investment is going to come from because there’s not an obvious vaccine candidate in HIV that is next up in our efficacy pipeline,” Warren said. “This is another reason why this result is disappointing. This was the last true product in development. And the other activities in the field, which are very exciting … [are] quite upstream. Important upstream science, but not products that are going to be in efficacy trials anytime soon.” Stephaun Wallace, director of external relations for the HIV Vaccine Trials Network, noted work is being done on a candidate HIV vaccine using messenger RNA, the platform successfully used by Pfizer and its partner BioNTech as well as by Moderna to create their Covid-19 vaccines. The HIV work uses the Moderna platform. Exploration of the mRNA platform as a possible basis for an HIV vaccine is still in the safety testing phase, he said. Warren questioned, though, whether the answer is a different vaccine delivery system, suggesting the problem is probably the immune targets at which the various vaccines have aimed. He noted, for instance, that the J&J platform — adenovirus 26 — worked against Covid, but not against HIV. “These are the harsh reminders that it’s not that we don’t have great [vaccine] platforms,” he said. “Our challenge is figuring out exactly what is the target, what is the insert? … We have the vehicles. We don’t even know what passengers to put in the vehicles.” Wallace acknowledged the path ahead will be difficult, but said he remains optimistic that at some point, HIV vaccine efforts will meet success. “I’m pretty certain that with continued public support and interest in this area that we will see the day that an HIV vaccine is developed,” he said.

An immune response that likely evolved to help fight infections appears to be the mechanism that drives human immunodeficiency virus (HIV) into a latent state, lurking in cells only to erupt anew, researchers at Duke Health report. Publishing Nov. 14 in the journal Nature Microbiology, the research team provides new insights into the vexing process that makes HIV particularly stealthy, but could also play a role in other viral infections. "HIV has proven to be incurable because of a small number of latently HIV-infected T-cells that are untouched by both antiviral drugs and the immune response," said senior author Bryan R. Cullen, Ph.D., professor in the Department Molecular Genetics and Microbiology at Duke University School of Medicine. "These cells, which are very long lived, can spontaneously emerge from latency and start producing HIV even years after infection, thus necessitating the life-long use of antiretrovirals," Cullen said. "The origin of these latently infected cells has remained unknown despite considerable effort." The findings from Cullen and colleagues offer important insights, pointing to a protein complex called SMC5/6, which is involved in a host cell's chromosome function and repair. HIV enters the body, infects the immune system's CD4+ T-cells, then makes a genome-length DNA molecule that it integrates into a host cell chromosome where it is then copied to generate viral RNAs and proteins. If this so-called DNA provirus is prevented from integrating into the host cell DNA, for example by a drug that blocks this process, then it fails to make any viral RNAs and proteins and becomes inert. In contrast, DNA proviruses that are able to integrate are normally able to drive a productive HIV infection.

Cullen and his team found that in a small number of infected cells, the SMC5/6 protein complex initiates a process that silences the DNA provirus before it integrates into a host cell chromosome. These proviruses remain inert even after integration and result in latent infections, lying low until prompted to erupt into an active infection. "Our research suggests that latency results not from any intrinsic properties of the infecting HIV but rather from an unfortunate side effect of a cellular innate immune response that probably evolved to silence invasive foreign DNA," Cullen said. The researchers found that a molecule that shuts down SMC5/6's silencing action showed promising results as a potential therapeutic strategy as it inhibited the establishment of latent HIV infections. Reactivated proviruses are vulnerable to natural immune system responses and anti-retroviral drugs. "Although antiretroviral therapies can reduce the viral load in AIDS patients to below the level of detection, these drugs fail to eradicate HIV-1," Cullen said. "While there has been considerable effort expended on trying to develop therapies that can activate latent HIV-1 and help antiretroviral therapies clear the body of infectious virus, this effort has so far failed to identify drugs that are both effective and non-toxic. Our study represents a potentially important step toward achieving this goal." "Clearly, understanding the mechanism that results in HIV-1 latency may provide insights into how latent HIV-1 proviruses can be reactivated and then destroyed," Cullen said. In addition to Cullen, study authors include Ishak D. Irwan and Hal P. Bogerd.

Study cited published in Nature Microbiology (Nov. 14, 2022):

https://doi.org/10.1038/s41564-022-01264-z 

An experiment tests whether the gene-editing technology can stop the virus from replicating, which would ultimately wipe out the infection. 

IN JULY, AN HIV-positive man became the first volunteer in a clinical trial aimed at using Crispr gene editing to snip the AIDS-causing virus out of his cells. For an hour, he was hooked up to an IV bag that pumped the experimental treatment directly into his bloodstream. The one-time infusion is designed to carry the gene-editing tools to the man’s infected cells to clear the virus. Later this month, the volunteer will stop taking the antiretroviral drugs he’s been on to keep the virus at undetectable levels. Then, investigators will wait 12 weeks to see if the virus rebounds. If not, they’ll consider the experiment a success. “What we’re trying to do is return the cell to a near-normal state,” says Daniel Dornbusch, CEO of Excision BioTherapeutics, the San Francisco-based biotech company that’s running the trial. HIV attacks immune cells in the body called CD4 cells and hijacks their machinery to make copies of itself. But some HIV-infected cells can go dormant—sometimes for years—and not actively produce new virus copies. These so-called reservoirs are a major barrier to curing HIV. “HIV is a tough foe to fight because it’s able to insert itself into our own DNA, and it’s also able to become silent and reactivate at different points in a person’s life,” says Jonathan Li, a physician at Brigham and Women’s Hospital and HIV researcher at Harvard University who’s not involved with the Crispr trial. Figuring out how to target these reservoirs—and doing it without harming vital CD4 cells—has proven challenging, Li says. While antiretroviral drugs can halt viral replication and clear the virus from the blood, they can’t reach these reservoirs, so people have to take medication every day for the rest of their lives. But Excision BioTherapeutics is hoping that Crispr will remove HIV for good.

Crispr is being used in several other studies to treat a handful of conditions that arise from genetic mutations. In those cases, scientists are using Crispr to edit peoples’ own cells. But for the HIV trial, Excision researchers are turning the gene-editing tool against the virus. The Crispr infusion contains gene-editing molecules that target two regions in the HIV genome important for viral replication. The virus can only reproduce if it’s fully intact, so Crispr disrupts that process by cutting out chunks of the genome. In 2019, researchers at Temple University and the University of Nebraska found that using Crispr to delete those regions eliminated HIV from the genomes of rats and mice. A year later, the Temple group also showed that the approach safely removed viral DNA from macaques with SIV, the monkey version of HIV. That was an important step toward testing the treatment in people, says Kamel Khalili, a professor of microbiology at Temple University who led the work and is a cofounder of Excision Biotherapeutics. “You don’t want to eliminate the viral genome but at the same time cause any disruption in another part of the human genome and then create another set of problems for the patients,” he says. “We had to make sure that we identified a region within HIV that did not overlap with the human genome.”  Dornbusch thinks this strategy will spare patients from serious side effects and “off-target” edits—unintentional cuts elsewhere in the genome that could cause problems such as cancer. The regions targeted by the company’s Crispr therapy are also in a part of the genome that tends to stay the same even when HIV evolves. That’s important because the virus mutates rapidly, and the researchers don’t want a moving target. This isn’t the first time scientists have tried to use gene editing in the hope of curing people with HIV, but other efforts have focused on a protective mutation in a gene called CCR5. In the 1990s, scientists found that people with this naturally occurring mutation didn’t get HIV when exposed to it. The mutation—known as delta 32—thwarts the virus’s ability to get inside immune cells. In 2009, California-based Sangamo Therapeutics used an older editing technology called zinc finger nucleases to add that protective mutation into patients’ T cells—an important part of the immune system. Those trials have had limited success.

In 2017, Chinese scientists combined Crispr with a bone marrow transplant in an attempt to cure a patient with HIV and leukemia. In a typical transplant, donor stem cells are transferred to a recipient to replace their cancerous blood cells. These cells go on to form new, healthy blood cells. To also address the patient’s HIV, researchers edited the donor stem cells with Crispr to disable CCR5. But after the transplant, only a small percentage of the patient’s bone marrow cells ended up with the desired edit. Then in 2018, Chinese scientist He Jiankui used Crispr to edit the CCR5 mutation into the genomes of twin baby girls to make them resistant to HIV. Fraught with ethical violations, the experiment was widely condemned by scientists. He’s research was suspended by the Chinese government, and he served a three-year prison sentence. While the twins were born healthy, only some of their cells were successfully edited, meaning the girls might in fact not be immune to HIV. As of 2022, two people have now been cured of HIV after receiving bone marrow transplants from donors with the CCR5. Known as the Berlin patient and the London patient, both had cancer and received transplants to treat their disease. But these transplants aren’t a viable option for most people—they’re highly risky, and donors with the delta 32 mutation are scarce. But a third person was declared cured of HIV earlier this year after she received a new type of transplant involving umbilical cord blood.

The Excision trial will eventually enroll nine participants and test three dosage amounts to determine which is most effective. Investigators will measure each person’s viral load and CD4 count before receiving the therapy and after they stop taking antiretroviral drugs. The ultimate goal is to get viral loads down to an undetectable level—that is, less than 200 copies of HIV per milliliter of blood. At this level, HIV can’t be passed on through sex. The challenge for Excision will be getting Crispr to enough cells to bring HIV down to undetectable levels. The company is using an engineered virus to shuttle the gene-editing components to patients’ HIV-infected CD4 cells. But so far, there’s little human data on how well Crispr works when it’s delivered directly to the body. “It’s possible that you get the virus to such low levels that if a person’s immune system were intact, they might be able to keep the virus at bay such that they don’t have to take antiretroviral therapy anymore,” says Rowena Johnston, vice president and director of research for amfAR, the Foundation for AIDS Research.

And even though these drugs are very effective, Johnston says, many people would rather be completely free of the virus. A single Crispr infusion—if it works—would eliminate the need for daily pills. “People with HIV still live with a lot of stigma and internalized shame,” she says. “I think a cure is something that addresses that much better than lifelong therapy, regardless of how easy that therapy becomes.”