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Juan Lama
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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
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Juan Lama
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Treatments that can reactivate latent HIV and SIV in animals. HIV-1 can evade the immune system by hiding out in a dormant form. Two studies describe interventions that can effectively reactivate the latent virus in animals, potentially rendering it vulnerable to immune-mediated death. ‘Shock and kill’ might sound like a military strategy, but in fact it describes the dominant model currently used in the search for a cure for HIV-1 infection. Although antiretroviral therapy (ART) is highly effective at limiting the extent of the infection, the virus can hide out in a ‘latent’ form in immune cells called CD4+ T cells, undergoing little or no transcription and thus remaining undetected by the immune system1,2. When ART is stopped, these viral-reservoir cells can rapidly fuel HIV rebound. The theory behind ‘shock and kill’ involves the use of drugs that reverse this latency and could increase viral gene expression (shock), rendering the viral-reservoir cells vulnerable to elimination (kill) by other cells of the immune system. Writing in Nature, two groups3,4 describe distinct interventions in animal models that cause what seem to be the most robust and reproducible disruptions of viral latency reported so far. ‘Shock and kill’ might sound like a military strategy, but in fact it describes the dominant model currently used in the search for a cure for HIV-1 infection. Although antiretroviral therapy (ART) is highly effective at limiting the extent of the infection, the virus can hide out in a ‘latent’ form in immune cells called CD4+ T cells, undergoing little or no transcription and thus remaining undetected by the immune system1,2. When ART is stopped, these viral-reservoir cells can rapidly fuel HIV rebound. The theory behind ‘shock and kill’ involves the use of drugs that reverse this latency and could increase viral gene expression (shock), rendering the viral-reservoir cells vulnerable to elimination (kill) by other cells of the immune system. Writing in Nature, two groups3,4 describe distinct interventions in animal models that cause what seem to be the most robust and reproducible disruptions of viral latency reported so far. The authors demonstrated that AZD5582 treatment led to marked increases in the levels of viral RNA in CD4+ T cells in a range of tissues in both species, indicating that transcription of the virus had been activated. This was combined with a substantial rise in virus levels in the blood. AZD5582 is not optimized for use in humans; nonetheless, these results suggest that pharmacological activation of the non-canonical NF-κB pathway could be an attractive way to trigger HIV-1-gene expression as part of a shock-and-kill approach (Fig. 1). In the second study, McBrien et al.4 used an entirely different, though complementary, approach to disrupting viral latency. Again, the authors used both ART-treated humanized mice infected with HIV-1 and ART-treated, SIV-infected rhesus macaques. They combined two immunological interventions. The first involves antibody-mediated depletion of CD8+ T cells — immune cells previously shown to act in concert with ART to reduce levels of viral transcription5. The second, administered concurrently, involves treatment with a drug called N-803, which strongly activates the signalling molecule interleukin-15 (IL-15), and which has been previously shown6 to activate HIV-1 transcription in vitro. Like Nixon and colleagues, the researchers found that their treatment caused substantial increases in virus levels in the blood, and in viral RNA in cells from various tissues. At first glance, the combined interventions used by McBrien and colleagues might seem contradictory, because IL-15 is one of the strongest activators of CD8+ T cells7,8. But the synergistic effects of these two interventions raise the provocative possibility that the best strategies for targeting viral-reservoir cells involve a mix of immune interventions — suppressing immune components that seem to have a role in stabilizing viral latency (such as CD8+ T cells) while activating others that can effectively disrupt latency (such as IL-15 signalling).... Published in Nature (Jan. 22, 2020): https://doi.org/10.1038/d41586-020-00010-x
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Juan Lama
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The herpes simplex virus, commonly known as the cold sore virus, is a devious microbe. It enters the body through regions lined with mucous membranes—mouth, nose and genitals—but quickly establishes lifelong viral hideouts inside nerve cells. After initial infection, the virus lurks dormant only to be reawakened periodically to cause outbreaks marked by the eruption of cold sores or blisters. In a handful of people, the consequences of viral re-awaking can be devastating, including blindness and brain inflammation. Antiviral medications can prevent recurrent outbreaks, but they are not always effective, so for decades, researchers have sought a solution that would quiet the virus for good. Now, using human fibroblast cells infected with herpes simplex virus (HSV), researchers at Harvard Medical School have successfully used CRISPR-Cas9 gene editing to disrupt not only actively replicating virus but also the far-harder to reach dormant pools of the virus, demonstrating a possible strategy for achieving permanent viral control. The team's findings are described Dec. 2 in eLife. "This is an exciting first step—one that suggests it is possible to permanently silence lifelong infections—but much more work remains to be done," said study lead investigator David Knipe, the Higgins Professor of Microbiology and Molecular Genetics in the Blavatnik Institute at Harvard Medical School. Notably, the research represents the first successful instance of disrupting latent viral reservoirs through gene editing. Latent reservoirs are notoriously impervious to antiviral medications and have also proven hard to gene-edit. The experiments also identify the mechanisms by which actively replicating virus becomes uniquely vulnerable to gene editing. These very mechanisms may also explain why latent forms of the virus are less amenable to this technique. Specifically, the experiments reveal that the DNA of an actively replicating virus is more exposed to the Cas9 enzyme—the molecular scissors in the CRISPR-Cas9 gene-editing system. This is because actively replicating viruses have fewer protective histones that wrap around their DNA to shield it. "The absence of protective histones makes the DNA more accessible and easier to cut, so it's essentially identified HSV's Achilles heel," Knipe said. The new findings offer a model system for using gene editing in a localized way to disrupt active replication in specific sites. However, Knipe cautions, the arch-challenge of delivering gene-editing therapy to neurons—where the virus hides and enters a state of dormancy—remains to be solved, Knipe added... Published in eLife (December 2, 2019): https://doi.org/10.7554/eLife.51662
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Juan Lama
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Summary: HIV can persist in the nervous system, even when the virus is suppressed. Even when the virus is suppressed, neurocognitive problems associated with the infection can persist. Investigators from the University of North Carolina, the University of Pittsburgh, and Yale University studied participants enrolled in the AIDS Clinical Trials Group (ACTG) HIV Reservoirs Cohort Study. This primarily male group–aged 45 to 56–of long-term HIV survivors had infections controlled with ART for on average nine years. Researchers analyzed each participant’s CSF for HIV DNA and then compared these data to each participants’ results from standard neurocognitive evaluations. About half of participants had viral DNA in cells in the CSF, indicating the presence of latent virus, even though standard HIV RNA ‘viral load’ tests of the cell-free CSF fluid were positive in only 4% of participants. Investigators also found that 30% of individuals with persistent HIV DNA in the CSF experienced clinical neurocognitive impairment compared with 11% of individuals whose CSF did not contain viral DNA. The new findings suggest that the presence of persistent HIV-infected cells in the central nervous system (CNS), despite long-term ART, may play a role in neurocognitive impairment. The authors note that the overall frequency of neurocognitive impairment in this group was relatively low and that the association does not confirm that HIV DNA causes HAND. Overall, the current study found that examining CSF cells revealed a higher-than-expected prevalence of persistent HIV in the CNS, which may be a significant obstacle to efforts to eradicate HIV from the body. The study was published on July 15, 2019 in the J. Clinical Invest.: https://doi.org/10.1172/JCI127413
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Juan Lama
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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
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Juan Lama
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It's a leading research strategy for eliminating HIV from the body: "shock and kill." The idea is to activate the dormant virus from within the immune cells where it hides, then eliminate it. One obstacle has been finding a safe way to wake up the virus. In two complementary Nature papers, researchers now report that they have come closer to that goal. The papers are from researchers at the Yerkes National Primate Research Center of Emory University and the University of North Carolina at Chapel Hill, funded by the National Institutes of Health. The papers rely on studies involving two animal models of HIV infection. Each study took a different approach. But both yielded promising results, disrupting viral latency at levels not seen before. That means that the virus came out of its hiding places, even in the presence of antiretroviral drugs that had stopped it from replicating for months. The findings do not represent a cure and follow-up studies in animals, as well as clinical studies in humans, are needed and planned. But the results represent an advance because they could potentially be combined with other approaches directed against the virus, the scientists say. "If our goal is to cure HIV/AIDS, then we have to disrupt viral latency," says Guido Silvestri, MD, co-senior author of one of the Nature papers. "What we're doing now is a new combination approach that provides unprecedented levels of virus reactivation." Silvestri is interim chair of pathology and laboratory medicine at Emory University School of Medicine, chief of microbiology and immunology at Yerkes National Primate Research Center, and a Georgia Eminent Research Scholar. Past results of latency reversal experiments were not as sustained and extensive, says co-senior author J. Victor Garcia, Ph.D., director of the International Center for the Advancement of Translational Science and professor at the University of North Carolina School of Medicine.... Origina publications published in Nature (January 22, 2020): https://doi.org/10.1038/s41586-020-1946-0 https://doi.org/10.1038/s41586-020-1951-3
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Juan Lama
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Latent herpes virus reactivation has been documented in more than half of astronauts during space shuttle and International Space Station missions, and according to a recent study funded by NASA, the cause is stress.“Herpes virus is a broad category of viruses, beyond the small subset that cause sexually transmitted diseases.Most humans become infected early in life with one or more, and never fully clear these viruses,” Satish Mehta, PhD, senior scientist in the immunology/virology lab at the Johnson Space Center in Houston, told Infectious Disease News. Results showed that 47 out of 89 (53%) astronauts on short space shuttle flights, and 14 out of 23 (61%) on longer space station missions shed herpes viruses in their saliva or urine samples. According to the study, astronauts shed four of the eight major human herpes viruses: Epstein-Barr, varicella-zoster and herpes simplex-1 in saliva and cytomegalovirus in urine. The researchers said most astronauts were asymptomatic, with only six developing symptoms. “Larger quantities and increased frequencies for these viruses were found during spaceflight as compared to before or after flight samples and their matched healthy controls,” Mehta and colleagues wrote. Mehta explained why: “[The] short answer is stress. In people with reduced immunity, such as the elderly or stressed individuals, these viruses can awaken and cause disease,” he said. “Although NASA believes there is no clinical risk to astronauts during orbital spaceflight, there is concern that during deep space exploration missions, there may be clinical risks related to viral shedding. Although we do not have a serious clinical problem related to herpes viruses, their reactivation is an excellent ‘flag,’ or biomarker, for stress and reduced immunity.” In the study, Mehta and colleagues noted that continued viral shedding after a flight can pose a potential risk for crew who may encounter infants, seronegative adults or immunocompromised people, so protocols have been put in place. The study was published in February 2019 in Frontiers in Microbiology - Virology: https://doi.org/10.3389/fmicb.2019.00016
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