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Juan Lama
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Highlights - HIV induces rapid CD4+ T cell loss by activating the CARD8 inflammasome
- HIV protease encapsulated in viral particles is detected by CARD8 during viral entry
- CARD8 activation contributes to the progression of disease in HIV infection
- The “natural” hosts of SIV have acquired loss-of-function mutations in CARD8
Summary While CD4+ T cell depletion is key to disease progression in people living with HIV and SIV-infected macaques, the mechanisms underlying this depletion remain incompletely understood, with most cell death involving uninfected cells. In contrast, SIV infection of “natural” hosts such as sooty mangabeys does not cause CD4+ depletion and AIDS despite high-level viremia. Here, we report that the CARD8 inflammasome is activated immediately after HIV entry by the viral protease encapsulated in incoming virions. Sensing of HIV protease activity by CARD8 leads to rapid pyroptosis of quiescent cells without productive infection, while T cell activation abolishes CARD8 function and increases permissiveness to infection. In humanized mice reconstituted with CARD8-deficient cells, CD4+ depletion is delayed despite high viremia. Finally, we discovered loss-of-function mutations in CARD8 from “natural hosts,” which may explain the peculiarly non-pathogenic nature of these infections. Our study suggests that CARD8 drives CD4+ T cell depletion during pathogenic HIV/SIV infections. Published in Cell (Feb. 29, 2024):
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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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For hundreds of thousands of years, monkeys and apes have been plagued by simian immunodeficiency virus (SIV), which still devastates primate groups in Africa. Luckily, as humans evolved from these early primates, we picked up a mutation that made us immune from SIV — at least until the early 20th century, when the virus evolved to get around our defenses, giving rise to human immunodeficiency virus (HIV) and an AIDS pandemic that today affects an estimated 38 million people worldwide. University of California, Berkeley, researchers have now discovered how that long-ago human mutation interfered with SIV infection, a finding that could provide clues for the development of new therapies to thwart HIV and similar viral infections. The barrier was a mutation in human cells that blocked SIV from forcing these cells to shed thousands more copies of the virus. As a result, humans could not re-infect one another. This genetic mutation interfered with the ability of an SIV protein to tightly bind two human proteins and send them for destruction within the cell, instead of fighting the virus. The researchers used cryo-electron microscopy, or cryoEM, to determine the structure of this protein complex and discovered that the mutation so effectively disrupted the protein binding sites that it took SIV a long time to find a work-around. “The binding site involved is structurally very complex, so essentially it is not possible to adapt to it once the tight binding is lost. The virus had to invent a completely different way to do the same thing, which took a long time in evolution,” Hurley said. “This conferred an advantage on our prehistoric ancestors: From chimps on down, every primate was susceptible to SIV, but humans were immune. That gave humans probably a grace period of tens to hundreds of thousands of years to develop without having to deal with this disease. I tend to think that really gave a leg up to humans in early evolution.” Because budding is an important step in the spread of many viruses, primates long ago evolved natural defenses, including proteins on the surface of cells that staple the budding virions to the cell and prevent them from leaving. As they accumulate, the immune system recognizes these unbudded virions as abnormal and destroys the whole cell, virus and all. In monkey, ape and human cells, the staple is called tetherin, because it tethers the budding virion to the cell membrane. In the constant arms race between host and pathogen, SIV evolved a countermeasure that exploits another normal cell function: its recycling system. Cells have ways to remove proteins sitting on the surface, through which cells constantly take up and recycle tetherin if there’s no indication it is needed to fight an invading virus. It does this by dimpling the membrane inward to form a little bubble inside the cell, capturing tetherin and other surface proteins in this vesicle and then digesting all the contents, including tetherin. SIV’s countermeasure was to produce a protein, called Nef, that revs up the recycling of tetherin, even during an infection. This enables virions to bud off and search for new victims. Results published online August 22, 2019 in Cell Host & Microbe: https://doi.org/10.1016/j.chom.2019.08.002
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Juan Lama
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A promising vaccine that clears an HIV-like virus from monkeys is closer to human testing after a new, weakened version of the vaccine has been shown to provide similar protection as its original version. The vaccine uses a form of the common herpes virus cytomegalovirus, or CMV—was live-attenuated, or weakened so CMV couldn't spread as easily. The new version still managed to eliminate SIV, the monkey version of HIV, in 59 percent of vaccinated rhesus macaques. That result is similar to earlier findings involving the vaccine's original, non-attenuated version. The immunity generated by the attenuated vaccine was also long-lasting, as nine of 12 vaccinated monkeys could still fight off SIV infection three years later. "These papers are important because they recapitulate the previously reported unique CMV vector efficacy with a genetically modified vector that is highly attenuated and therefore potentially safer for clinical use" said Louis Picker, M.D., a corresponding author on both papers. "In addition, this new work demonstrates most vaccinated rhesus monkeys that are protected against SIV can also be protected against a second challenge years after initial vaccination. This is a level of durability that would be very important for a human HIV vaccine". The CMV vaccine platform has been licensed by Vir Biotechnology, Inc., of San Francisco, which plans to lead a clinical trial with a human version of the CMV-based HIV vaccine. The studies were published on July 17 on Science Translational Medicine: https://doi.org/10.1126/scitranslmed.aaw2607 https://doi.org/10.1126/scitranslmed.aaw2603
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Juan Lama
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Using gene-editing to remove a retrovirus is a step towards a cure for HIV infection in humans. Scientists have used Crispr gene-editing to remove an HIV-like virus from monkey DNA, a major step towards a cure for HIV infection in humans. In a study led by neurovirologist Kamel Khalili of Temple University in Philadelphia, researchers constructed a modified adenovirus containing a Crispr-Cas9 gene-editing system. That 'construct' (called 'AAV9-CRISPR-Cas9') was then injected into rhesus macaque monkeys to deliver the Crispr system into cells. The monkey cells were infected with SIV (Simian Immunodeficiency Virus), a close relative of HIV (Human Immunodeficiency Virus). Both are retroviruses — viral parasites that cut-and-paste their genetic material into a host's DNA. SIV infects macaques and other non-human primates in the same way that HIV infects people, making it a good model for studying retroviral infection — and testing how to remove those viruses from the human genome. The gene-editing construct was designed to target specific sites where the retrovirus was integrated into the macaque genome. It was able to reach tissues where viruses like SIV and HIV can hide for years without being detected, known as reservoirs, such as bone marrow, lymph nodes, T cells of the immune system and the brain. According to the study, the construct was precise and has a low risk of cutting the wrong places in DNA ('off-target' sites). The research has obvious implications for preventing or treating AIDS (Acquired Immunodeficiency Syndrome) in humans by curing a patient of HIV infection. Original study published in Nature Comm. (November 27, 2020): https://doi.org/10.1038/s41467-020-19821-7
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A series of animal and human studies published this week are providing a sad footnote to a controversial 2016 experiment in monkeys that pointed to a possible cure for HIV but was later flagged for a glaring omission in its design. The animal studies failed to replicate the promising results of the original paper, while a clinical trial in humans using a similar strategy largely failed as well. In 2016, researchers published a study in the well-respected journal Science. They experimented with rhesus macaque monkeys, infecting them with the simian immunodeficiency virus (SIV), a close relative of the HIV virus that causes AIDS in people. Then they gave the monkeys a short combination dose of the standard HIV treatment—antiretroviral therapy (ART)—and an antibody that targeted a protein, called a4b7, found in immune cells. Current treatments for HIV can drive levels of the virus so low as to make a person completely not contagious and relatively healthy. But HIV seeds itself into reservoirs of the immune system, where some amount of it is able to survive these drugs. If someone stops taking their daily dose of ART or the treatment otherwise starts to fail, the virus can then emerge from its dormancy and wreak havoc again. Earlier research had suggested HIV uses a4b7 to help pull off its disappearing trick inside cells, so it was hoped that using both treatments at once could eradicate the virus completely, or at least provide a sustained remission that would let people no longer need daily ART. And in the 2016 study, that’s what it seemed to do for the monkeys. Nine months after their treatment, their immune systems looked perfectly normal and no traces of SIV could be found. It was understandably seen as the first step to an HIV cure. In science, though, no single study is the final word. Researchers at the National Institute of Allergy and Infectious Diseases (NIAID) and elsewhere quickly began to carry out their own larger studies that would replicate the original study’s design. Another U.S. government study was planned to test out the human version of the a4b7 antibody—an existing anti-inflammatory drug called vedolizumab—in a small clinical trial with people. “We conducted these studies because we felt that the results reported in the 2016 Byrareddy study had the potential to transform the HIV cure field if the findings were reproducible and generalizable,” Dan Barouch, director of the Center for Virology and Vaccine Research at Beth Israel Deaconess Medical Center at Harvard Medical and senior author of one of the studies, told Gizmodo via email. As all this was going on, however, it came to light that one of the study’s co-authors, Francois Villinger, now a pathologist at the University of Louisiana at Lafayette, had provided the research team a different type of SIV virus than was stated in the paper. To spare the technical details here, this version of the virus wasn’t programmed to produce a protein made by SIV in the wild, at least not for the first weeks of infection. According to the authors, only Villinger was aware of the omission. And he told the journal’s editors that he used the modified virus because it more closely mimicked how HIV behaves in humans (wild SIV tends to kill monkeys very quickly, while HIV infection is usually slower to kill). “While there was no malfeasance, there was clearly a major negligence in our studies reported in the Science paper,” Ansari Aftab, senior author of the 2016 study, told Gizmodo via email.... The earlier study not replicated was published in Science on Oct.14, 2016: https://doi.org/10.1126/science.aag1276 Recent study failing to replicate above work published September 6, 2019 in Science: https://doi.org/10.1126/science.aaw7765
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Efforts to develop an effective HIV vaccine have repeatedly stumbled on one tough research strain, SIVmac239. Nicknamed the 'death star' strain, it has defeated multiple anti-HIV vaccine and antibody candidates, until now. Scientists have just beaten the 'death star' with a gene-therapy-style, nontraditional vaccine that prompts muscle cells to manufacture protective proteins. A team at the Scripps Research Florida campus reports successfully beating that challenge. In a paper published in the journal Science Translational Medicine today, lead authors Michael Farzan, PhD, and Mathew Gardner, PhD, describe their destruction of the "death star" strain and another especially hard-to-fight strain, suggesting it may be possible to protect uninfected individuals from multiple forms of HIV. Their nontraditional vaccine achieved another critical goal: durability. This means it protected the research animals from infection long-term, with a single inoculation, Farzan says. "We have solved two problems that have plagued HIV vaccine studies to date -- namely, the absence of duration of response and the absence of breadth of response," Farzan says. "No other vaccine, antibody or biologic protects against the two viruses for which we have demonstrated robust protection." Conventional vaccine approaches typically use a piece of virus or other immunogen to activate an immune system response. Because HIV replicates and changes so quickly, that approach has proven challenging. Farzan's approach uses a safe virus to fight the dangerous one, and relies on muscle cells rather than immune cells to generate protective agents. Here's how: A harmless, lab-made adeno-associated virus (AAV) carries within it a protective protein designed by Farzan and colleagues to stop HIV infectivity. Called eCD4-Ig, the protective protein features two HIV co-receptors, CD4 and CCR5. The latter was discovered by Farzan and his team over a decade ago. Farzan's viral vaccine is injected into muscle. It "infects" the muscle cells, which causes them to produce the protective eCD4-Ig. During exposure to HIV, the HIV virus is attracted to eCD4-Ig. It binds, and then "undergoes conformational change prematurely, and it's no longer able to infect," Farzan says.... The study was published on July 24 in the journal Science Translational Medicine: https://doi.org/10.1126/scitranslmed.aau5409
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