Virus World

Several SARS-CoV-2 proteins have been shown to counteract the host innate immune response, mostly using in vitro protein expression, which may not fully reflect their role in the context of viral infection. In addition, while each viral protein was characterized in a different experimental system, their relative contribution in immunosuppression remains unclear. Here we used a SARS-CoV-2 bacterial artificial chromosome with en passant mutagenesis to recover a panel of twelve infectious recombinant SARS-CoV-2 viruses, each with mutations in either NSP1, NSP2, NSP3, NSP6, NSP12, NSP13, NSP14, NSP15, NSP16, ORF3a, ORF6 or ORF8. We used the interferon-stimulated response element (ISRE)-driven luciferase assay in 293T-ACE2/TMPRSS2 cells to test the panel, demonstrating that mutations in many proteins, especially in NSP1 and NSP15, increased the type I interferon response relative to the parental wild-type virus.

RNA-seq analysis of mutant-virus infected Calu-3 cells showed that the mutations in NSP1 or NSP15 lead to higher expression of multiple genes involved in innate immune response, cytokine-mediated signaling and regulation of lymphocyte proliferation. Furthermore, mutations in either NSP1 or NSP15 resulted in a greater maturation of human monocyte-derived dendritic cells in vitro. Infection of K18 hACE2 transgenic mice with either NSP1 or NSP15 mutated viruses demonstrated attentuated respiratory tract replication. Analysis of lung immune cells from infected mice by single-cell RNA-seq identified 15 populations of major myeloid and lymphoid cells with changes in the pattern of their activation associated with viral infection. The effects of mutations in NSP1 or NSP15 on these responses are consistent with differences in the immunosuppressive mechanisms utilized by the two proteins. Overall, these data demonstrate different and redundant mechanisms of innate immune antagonism by SARS-CoV-2 and suppression of activation of antigen presenting cells and T and B lymphocytes mediated by multiple viral proteins.

Preprint in bioRxiv (Jan. 29, 2024):

 https://doi.org/10.1101/2024.01.29.577695 

Severe COVID-19 may cause long-lasting alterations to the innate immune system, the first line of defense against pathogens, according to a small study funded by the National Institute of Allergy and Infectious Diseases, part of the National Institutes of Health.  These changes may help explain why the disease can damage so many different organs and why some people with long COVID have high levels of inflammation throughout the body. The findings were published online today in the journal Cell. Researchers led by Steven Z. Josefowicz, Ph.D., of Weill Cornell Medicine in New York City examined immune cells and molecules in blood samples from 38 people recovering from severe COVID-19 and other severe illnesses, as well as from 19 healthy people. Notably, the researchers established a new technique for collecting, concentrating and characterizing very rare blood-forming stem cells that circulate in the blood, eliminating the need to extract such cells from bone marrow.

In these rare stem cells-;the parents of immune-system cells-;taken from people recovering from COVID-19, the scientists identified changes in the instructions for which genes got turned on or off. These changes were passed down to daughter cells, leading them to boost production of immune cells called monocytes. In the monocytes from people recovering from severe COVID-19, the changes in gene expression led the cells to pump out greater amounts of molecules called inflammatory cytokines than monocytes from people who were healthy or had non-COVID-19 illnesses. The researchers observed these changes as much as a year after the participants came down with COVID-19. Due to the small number of study participants, the scientists could not establish a direct association between the cellular and molecular changes and health outcomes. The investigators suspected that an inflammatory cytokine called IL-6 might play role in establishing the changes in gene-expression instructions. They tested their hypothesis both in mice with COVID-19-like disease and in people with COVID-19. In these experiments, some of the subjects received antibodies at the early stage of illness that prevented IL-6 from binding to cells. During recovery, these mice and people had lower levels of altered stem cell gene-expression instructions, monocyte production and inflammatory cytokine production than subjects that didn't receive the antibody. In addition, the lungs and brains of mice that received the antibodies had fewer monocyte-derived cells and less organ damage.

These findings suggest that SARS-CoV-2 can cause changes in gene expression that ultimately boost the production of inflammatory cytokines, and one type of those cytokines perpetuates the process by inducing these changes in stem cells even after the illness is over. Additionally, the findings suggest that early-acting IL-6 is likely a major driver of long-term inflammation in people with severe COVID-19. These findings shed light on the pathogenesis of SARS-CoV-2 infection and may provide new leads for therapies. The results also underscore the importance of staying up to date with recommended COVID-19 vaccines, which are proven to protect against serious illness, hospitalization and death.

Research cites published in Cell (August 18, 2023);

https://doi.org/10.1016/j.cell.2023.07.019 

Newswise — An enzyme that defends human cells against viruses can help drive cancer evolution towards greater malignancy by causing myriad mutations in cancer cells, according to a study led by investigators at Weill Cornell Medicine. The finding suggests that the enzyme may be a potential target for future cancer treatments. In the new study, published Dec. 8 in Cancer Research, scientists used a preclinical model of bladder cancer to investigate the role of the enzyme called APOBEC3G in promoting the disease and found that it significantly increased the number of mutations in tumor cells, boosting the genetic diversity of bladder tumors and hastening mortality. “Our findings suggest that APOBEC3G is a big contributor to bladder cancer evolution and should be considered as a target for future treatment strategies,” said study senior author Dr. Bishoy M. Faltas, assistant professor of cell and developmental biology at Weill Cornell Medicine, and an oncologist who specializes in urothelial cancers at NewYork-Presbyterian/Weill Cornell Medical Center. The APOBEC3 family of enzymes is capable of mutating RNA or DNA—by chemically modifying a cytosine nucleotide (letter “C” in the genetic code). This can result in an erroneous nucleotide at that position. The normal roles of these enzymes, including APOBEC3G, are to fight retroviruses like HIV—they attempt to hobble viral replication by mutating the cytosines in the viral genome.

The inherent hazardousness of these enzymes suggests that mechanisms must be in place to prevent them from harming cellular DNA. However, starting about a decade ago, researchers using new DNA-sequencing techniques began to find extensive APOBEC3-type mutations in cellular DNA in the context of cancer. In a 2016 study of human bladder tumor samples, Dr. Faltas, who is also director of bladder cancer research at the Englander Institute for Precision Medicine and a member of the Sandra and Edward Meyer Cancer Center, found that a high proportion of the mutations in these tumors were APOBEC3-related—and that these mutations appeared to have a role in helping tumors evade the effects of chemotherapy. Such findings point to the possibility that cancers generally harness APOBEC3s to mutate their genomes. This could help them not only acquire all the mutations needed for cancerous growth but also boost their ability to diversify and “evolve” thereafter—enabling further growth and spread despite immune defenses, drug treatments, and other adverse factors. In the new study, Dr. Faltas and his team, including first author Dr. Weisi Liu, a postdoctoral research associate, addressed the specific role of APOBEC3G in bladder cancer with direct cause-and-effect experiments.

APOBEC3G is a human enzyme not found in mice, so the team knocked out the gene for the sole APOBEC3-type enzyme in mice, replacing it with the gene for human APOBEC3G. The researchers observed that when these APOBEC3G mice were exposed to a bladder cancer-promoting chemical that mimics the carcinogens in cigarette smoke, they became much more likely to develop this form of cancer (76% developed cancer) compared with mice whose APOBEC gene was knocked out and not replaced (53% developed cancer). Moreover, during a 30-week observation period, all the knockout-only mice survived, whereas nearly a third of the APOBEC3G mice succumbed to cancer.

To their surprise, the researchers found that APOBEC3G in the mouse cells was present in the nucleus, where cellular DNA is kept using an ‘optical sectioning’ microscopy technique. Previously, this protein had been thought to reside only outside the nucleus. They also found that the bladder tumors of the APOBEC3G mice had about twice the number of mutations compared to the tumors in knockout-only mice. Identifying the specific mutational signature of APOBEC3G and mapping it in the tumor genomes, the team found ample evidence that the enzyme had caused a greater mutational burden and genomic diversity in the tumors, likely accounting for the greater malignancy and mortality in the APOBEC3G mice. “We saw a distinct mutational signature caused by APOBEC3G in these tumors that is different from signatures caused by other members of the APOBEC3 family” said Dr. Liu. Lastly, the researchers looked for APOBEC3G’s mutational signature in a widely used human tumor DNA database, The Cancer Genome Atlas, and found that these mutations appear to be common in bladder cancers and are linked to worse outcomes. “These findings will inform future efforts to restrict or steer tumor evolution by targeting APOBEC3 enzymes with drugs,” said Dr. Faltas.

Many Weill Cornell Medicine physicians and scientists maintain relationships and collaborate with external organizations to foster scientific innovation and provide expert guidance. The institution makes these disclosures public to ensure transparency. For this information, see profile for Dr. Faltas.

Research Cited  published (Dec. 08, 2022) in Cancer Research:

https://doi.org/10.1158/0008-5472.CAN-22-2912 

Can prior exposure to other respiratory viruses like the common cold before infection by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the pathogen responsible for the coronavirus disease 2019 (COVID-19), offer protection against COVID-19?  Researchers at the Yale School of Medicine found that rhinovirus, which is the virus that is most commonly responsible for the common cold, accelerates interferon-stimulated genes (ISG), which are early response molecules in the immune system. The increased expression of these genes was found to prevent SARS-CoV-2 replication within airway tissues that were previously infected with rhinovirus. The study, which was published in the Journal of Experimental Medicine, shed light on the use of interferons (IFNs), which are immune system proteins, in COVID-19 patients. The researchers also noted that IFN treatment could be used for prophylactic purposes in high-risk patients who have been exposed to SARS-CoV-2.

The study

The initial replication of SARS-CoV-2 in the upper respiratory tract is needed to establish infection. In SARS-CoV-2 infection, the virus enters lung cells through the angiotensin-converting enzyme 2 (ACE2) receptor. The cell-free and macrophage-phagocytosed virus can then spread to other organs and infect ACE2-expressing cells at local sites, which can cause multi-organ injury. Previous studies demonstrated that at the later stages of COVID-19, high IFN levels coincide with a more severe disease that is likely due to a hyperactive immune response. However, recent evidence has demonstrated that ISG instead offers protection during SARS-CoV-2 infection. This work was largely inspired by previous studies that found that common cold viruses may offer protection against the influenza virus. The researchers aimed to determine whether rhinoviruses would provide a similar beneficial effect against SARS-CoV-2.

Study findings

First, the team sought to capture early host-virus dynamics in the human nasopharynx using serial patient samples. Through the use of transcriptomics and biomarker-based tracking in these samples, the researchers observed a robust induction of ISG in the airway mucosa of these COVID-19 patients. Furthermore, ISG levels were found to align with viral load levels in these patients, with patients with the highest viral load tending to have higher ISG expression levels than those with the lowest viral loads. The researchers also studied the functional consequences of modulating the host innate immune response in primary human airway epithelial air-liquid interface organoid cultures. When the researchers infected lab-grown human airway tissue with SARS-CoV-2, they found that the viral load in the tissue doubled every six hours for the first three days. Meanwhile, the replication of SARS-CoV-2 was halted entirely in the tissue that was previously exposed to rhinovirus. When the antiviral defenses were blocked, SARS-CoV-2 successfully replicated in the tissues previously exposed to the common cold virus. The results showed that SARS-CoV-2 induces an IFN response in the nasopharynx across diverse patient groups. The same protective defenses were found to slow infection with SARS-CoV-2 even without prior exposure to rhinovirus.

Study takeaways

Taken together, the current study found that the defenses mediated by ISG at the time of SARS-CoV-2 exposure play an important role in determining infection severity. The heterologous antiviral response that is triggered by a different virus can therefore offer protection against SARS-CoV-2. The study findings also explain the phenomenon that occurs when common colds are frequent at certain times of the year, during which the rates of infections with other viruses like influenza tend to decrease. However, the researchers fear that such respiratory viruses can become stronger as a result of their dormancy over the past year due to social distancing measures. When these restrictions are eased, cases of common colds and other viral infections may arise. IFN treatment now holds promise as a preventive treatment for COVID-19. The researchers warned that the efficacy of this treatment approach will likely depend on the timing of its use. Based on theories, IFN treatment could be used as a prophylactic measure in high-risk patients. Currently, IFN treatments are being investigated in clinical trials, which have shown their beneficial use if given early in the course of the infection. In addition to vaccination efforts, finding a potential preventive measure for COVID-19 remains crucial as the world continues to grapple with this disease.

Original findings published in the Journal of Exp. Medicine (June 15, 2021):

Amid the worsening Ebola outbreak in the Congo, now threatening to spill into Rwanda, a new study suggests that an existing, FDA-approved drug called nitazoxanide could potentially help contain this deadly, highly contagious infection. The study, published in the Cell Press journal iScience, also showed how the drug works: It enhances the immune system's ability to detect Ebola, normally impeded by the virus.

Nitazoxanide, or NTZ, is currently used to treat gastrointestinal infections caused by parasites such as Giardia and Cryptosporidium. It has been shown to be safe and even comes in a formulation for children. Study leader Anne Goldfeld, MD, of the Program in Cellular and Molecular Medicine at Boston Children's, hopes that, with further testing and validation, it could be part of the solution for Ebola. "Currently, there is no easily deployable therapy for Ebola virus," she says. "There are some very promising vaccines, but there is no oral, inexpensive medication available."

The Ebola virus caused more than 10,000 deaths in the 2014-2016 West African epidemic and more than 1,800 lives (as of August 6th) in the current outbreak in the Democratic Republic of the Congo. The virus is very good at evading human immune defenses. Though very small, it has two genes devoted to blocking immune responses. Goldfeld and collaborators Chad Mire, PhD and Thomas Geisbert, PhD at the University of Texas Medical Branch, Galveston, showed in Biosafety Level 4 laboratory experiments that NTZ inhibits the Ebola virus (isolated from an earlier outbreak). Additional experiments performed in collaboration with Sun Hur, PhD of Boston Children's showed that NTZ works by broadly amplifying the interferon pathway and cellular viral sensors, including two known as RIG-I and PKR. By deleting RIG-I and PKR in human cells through CRISPR editing, Goldfeld and University of Texas colleagues showed that NTZ works through these molecules to inhibit Ebola virus.

Goldfeld hopes to move into animal studies soon, especially given that NTZ has already been used in millions of people with minimal side effects. If effective, it could thus be easily repurposed for Ebola treatment or prevention.

The study was published on August 8, 2019 in iScience (Open Access:

https://doi.org/10.1016/j.isci.2019.07.003

An ancient conflict between hosts and pathogens has driven the innate and adaptive arms of immunity. Knowledge about this interplay can not only help us identify biological mechanisms but also reveal pathogen vulnerabilities that can be leveraged therapeutically. The humoral response to SARS-CoV-2 infection has been the focus of intense research, and the role of the innate immune system has received significantly less attention. Here, we review current knowledge of the innate immune response to SARS-CoV-2 infection and the various means SARS-CoV-2 employs to evade innate defense systems. We also consider the role of innate immunity in SARS-CoV-2 vaccines and in the phenomenon of long COVID.

Published in Cell. Mol. Immunology (Nov. 20, 2023):

https://doi.org/10.1038/s41423-023-01104-y 

For a long time, it has been known that viral infections can be more severe in males than females, but the question as to why has remained a mystery – until possibly now. The answer may lie in an epigenetic regulator that enhances the function of specific anti-viral immune cells, referred to as natural killer (NK) cells. A research team from UCLA has recently published a study in the peer-reviewed journal Nature Immunology. The study revealed that female mice and humans possess an additional copy of a gene called UTX, which is linked to the X chromosome. UTX functions as an epigenetic regulator that enhances the anti-viral function of NK cells while suppressing their numbers. “While it is well-known that males have more NK cells compared to females, we did not understand why the increased number of NK cells was not more protective during viral infections. It turns out that females have more UTX in their NK cells than do males, which allows them to fight viral infections more efficiently,” said co-senior author Dr. Maureen Su, professor of microbiology immunology and molecular genetics, and of pediatrics, at the David Geffen School of Medicine at UCLA.

The researchers noted that this held true whether or not the mice had gonads (ovaries in females; testes in males), indicating that the observed trait was not linked to hormones. Furthermore, female mice with lower UTX expression had more NK cells which were not as capable of controlling viral infection. “This implicates UTX as a critical molecular determinant of sex differences in NK cells,” said the study’s lead author Mandy Cheng, graduate student in molecular biology at UCLA. “While it is well-known that males have more NK cells compared to females, we did not understand why the increased number of NK cells was not more protective during viral infections. It turns out that females have more UTX in their NK cells than do males, which allows them to fight viral infections more efficiently,” said co-senior author Dr. Maureen Su, professor of microbiology immunology and molecular genetics, and of pediatrics, at the David Geffen School of Medicine at UCLA. The researchers noted that this held true whether or not the mice had gonads (ovaries in females; testes in males), indicating that the observed trait was not linked to hormones. Furthermore, female mice with lower UTX expression had more NK cells which were not as capable of controlling viral infection. “This implicates UTX as a critical molecular determinant of sex differences in NK cells,” said the study’s lead author Mandy Cheng, graduate student in molecular biology at UCLA.

Research Cited Published in Nature Immunology (March 16, 2023):

https://doi.org/10.1038/s41590-023-01463-8 

The Ebola Virus Disease (EVD) is a rare and deadly disease in people and nonhuman primates. The viruses that cause EVD are located mainly in sub-Saharan Africa. People can get EVD through direct contact with an infected animal (bat or nonhuman primate) or a sick or dead person infected with Ebola virus. The virus is extremely skilled at escaping the immune system’s defenses. However, new hope comes from a study by Mount Sinai researchers, who report they have uncovered the complex cellular mechanisms of Ebola virus. Their research may help to identify potential pathways to treatment and prevention. The findings are published in the journal mBio, “Expression of the Ebola Virus VP24 Protein Compromises the Integrity of the Nuclear Envelope and Induces a Laminopathy-Like Cellular Phenotype.”  “Ebola virus (EBOV) VP24 protein is a nucleocapsid-associated protein that inhibits interferon (IFN) gene expression and counteracts the IFN-mediated antiviral response, preventing nuclear import of signal transducer and activator of transcription 1 (STAT1),” wrote the researchers. “Proteomic studies to identify additional EBOV VP24 partners have pointed to the nuclear membrane component emerin as a potential element of the VP24 cellular interactome. Here, we have further studied this interaction and its impact on cell biology. We demonstrate that VP24 interacts with emerin but also with other components of the inner nuclear membrane, such as lamin A/C and lamin B.” The team reported “how a protein of the Ebola virus, VP24, interacts with the double-layered membrane of the cell nucleus (known as the nuclear envelope), leading to significant damage to cells along with virus replication and the propagation of disease.”

“The Ebola virus is extremely skilled at dodging the body’s immune defenses, and in our study we characterize an important way in which that evasion occurs through disruption of the nuclear envelope, mediated by the VP24 protein,” said co-senior author Adolfo García-Sastre, PhD, professor of microbiology, and director of the Global Health and Emerging Pathogens Institute of the Icahn School of Medicine at Mount Sinai. “That disruption is quite dramatic and replicates rare, genetic diseases known as laminopathies, which can result in severe muscular, cardiovascular, and neuronal complications.” The researchers collaborated with research partners from CIMUS at the Universidad de Santiago de Compostela in Spain, and the Bernhard Nocht Institute for Tropical Medicine in Hamburg, Germany. Together, they identified the cellular membrane components that interact with VP24 to prompt nuclear membrane disruption.  The researchers demonstrated that VP24 disrupts signaling pathways that are meant to activate the immune system’s defenses against viruses. “We believe our discovery of the novel activities of the Ebola VP24 protein and the severe damage it causes to infected cells will help to promote further research into effective ways to treat and prevent the spread of deadly viruses, perhaps through a new inhibitor,” added García-Sastre. “Indeed, that research will hopefully identify even more precisely the molecular mechanisms by which viruses like Ebola invade the body and find ways to cleverly avoid its immune defenses.”

Published in mBio (July 6, 2021):

 https://doi.org/10.1128/mBio.00972-21  

Merck has struck a deal to buy OncoImmune for its COVID-19 treatment CD24Fc. The $425 million cash acquisition will give Merck control of a fusion protein linked to improvements in clinical status in a phase 3 trial of severe and critical COVID-19 patients.  OncoImmune began 2020 by presenting data on the effect of CD24Fc in allogeneic hematopoietic stem cell transplant patients. The use of CD24Fc in the population was underpinned by evidence that CD24 fusion proteins negatively regulate damage-associated molecular patterns, thereby countering a mechanism that may amplify graft-versus-host disease. As evidence of the effect of SARS-CoV-2 accrued, OncoImmune spied an opportunity to use CD24Fc to treat the sickest COVID-19 patients. OncoImmune began a clinical trial in April to test the theory that CD24Fc fortifies an innate immune checkpoint against excessive inflammation. With OncoImmune sharing interim phase 3 results to support the theory in September, Merck has agreed to pay $425 million upfront to buy the biotech. The deal is centered on CD24Fc. OncoImmune is spinning out other assets to form a new biotech owned by its existing shareholders. Merck is set to invest $50 million in the new biotech. The deal, which features undisclosed regulatory milestones and sales-based payments, adds another element to Merck’s attack on COVID-19. Merck tasked a research group to the virus in late January but was slower than some of its peers to disclose efforts to combat COVID-19. The Big Pharma made its splash in the last week of May, when it disclosed three deals for vaccines and antivirals.

Merck now has two COVID-19 vaccines in the clinic, albeit at an earlier stage than rival candidates, and an antiviral in phase 2/3 development. Those programs cover assets that may prevent infection and treat patients with mild-to-moderate COVID-19. OncoImmune moves Merck into another area of the COVID-19 response.   OncoImmune is testing CD24Fc in severe or critical COVID-19 patients. Participants in the phase 3 required supplemental oxygen support, noninvasive ventilation, high flow oxygen devices, invasive ventilation or extracorporeal membrane oxygenation. An interim review took place once 146 patients in the placebo-controlled trial experienced clinical recovery. The review linked CD24Fc to a 60% higher probability of improvement in clinical status versus placebo and a more than 50% lower risk of death or respiratory failure. The median recovery time in the CD24Fc group was six days, compared to 10 days in the control cohort.  The results suggest CD24Fc may help a population failed by multiple other drugs. The World Health Organization recommends against the use of remdesivir in hospitalized patients, anti-SARS-CoV-2 antibodies have failed in the population and efforts to repurpose existing inflammatory disease drugs floundered. Dexamethasone is a rare example of a drug that improved outcomes in severe patients.  Some patients in the OncoImmune trial received drugs including dexamethasone and remdesivir. In patients who received corticosteroids, such as dexamethasone, median time to recovery was 15 days. Median recovery time in patients who received corticosteroids and CD24Fc was five days.

A subpopulation of lung cells endures infection by the influenza A virus by patching up its DNA as the attack unfolds, researchers reported July 29 in Nature Microbiology. The cells, called club cells, normally secrete surfactants to coat the lining of the lungs. Even when struck with the flu, the cells carry on producing proteins and proinflammatory cytokines to alert the immune system of the onslaught.

“Now we have a population of cells we know are going to be hyperinflammatory on the back side of an infection,” says coauthor Nicholas Heaton, a molecular geneticist and microbiologist at the Duke School of Medicine, in an announcement. Although hyperinflammation thwarts invading viruses, it can actually be fatal to influenza patients. Depleting club cell counts may help solve the same problem in chronic obstructive pulmonary disease or asthma, says Heaton. 

Published July 29 2019 inNature Microbiology:

https://doi.org/10.1038/s41564-019-0509-3

A new protein called KHNYN has been identified as a missing piece in a natural antiviral system that kills viruses by targeting a specific pattern in viral genomes, according to new findings published today in eLife. Studying the body's natural defenses to viruses and how viruses evolve to evade them is crucial to developing new vaccines, drugs and anticancer treatments.

The genetic information that makes up the genomes for many viruses is comprised of building blocks called RNA nucleotides. Recently, it was discovered that a protein called ZAP binds to a specific sequence of RNA nucleotides: a cytosine followed by a guanosine, or CpG for short. The human immunodeficiency virus (HIV) normally escapes being inhibited by ZAP because it has evolved to have few CpGs in its genome. However, when CpGs are added back to the virus, ZAP promotes its destruction. This helps us understand why HIV with more CpGs multiplies less successfully, and likely explains why many strains of HIV have evolved to have few CpGs.

But a mystery remained because ZAP is unable to break down the viral RNA by itself. "As ZAP can't degrade RNA on its own, we believed that it must recruit other proteins to the viral RNA to destroy it," says lead author Mattia Ficarelli, a Ph.D. student in Chad Swanson's Lab, Department of Infectious Diseases, King's College London. "So, in the current study, we set out to identify new human proteins that are essential for ZAP to target viral RNAs for destruction."

After discovering that KHNYN interacts with ZAP, the team tested what happens when they increased the amount of KHNYN produced in cells infected with a typical HIV that has few CpGs, or an HIV genetically engineered to have many CpGs. Increasing KHNYN production in the cells reduced the typical HIV's ability to multiply about five-fold and decreased the ability of the CpG-enriched HIV to multiply by about 400-fold.

The findings were published today in the journal eLife:

https://doi.org/10.7554/eLife.46767.001