Virus World

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.

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 

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

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 

During infection, HIV places copies of its genome into the DNA of cells, creating what is known as a viral reservoir. In this state, the virus effectively hides from anti-HIV drugs and the body's immune response. In most people, new viral particles are constantly made from this reservoir. Anti-retroviral therapy (ART) can prevent the new viruses from being made but cannot eliminate the reservoir, necessitating daily treatment to suppress the virus.  Some people, known as elite controllers, have immune systems that are able to suppress HIV without the need for medication. Though they still have viral reservoirs that can produce more HIV virus, a type of immune cell called a killer T cell keeps the virus suppressed without the need for medication. Xu Yu, MD, a member of the Ragon Institute of MGH, MIT and Harvard, has been studying the HIV reservoirs of elite controllers. Her research group identified one patient who had no intact HIV viral sequence in her genome, indicating that her immune system may have eliminated the HIV reservoir—what scientists call a sterilizing cure. Yu's team sequenced billions of cells from this patient, known as the San Francisco Patient, searching for any HIV sequence that could be used to create new virus, and found none. This extraordinary finding, the first known incidence of a sterilizing cure without a stem cell transplant, was reported in Nature in 2020 (and Yu discusses in this video).

Yu's group now reports a second untreated HIV-infected patient, known as the Esperanza Patient, who, like the San Francisco Patient, has no intact HIV genomes found in more than 1.19 billion blood cells and 500 million tissue cells sequenced. This report, published in the Annals of Internal Medicine, may represent a second instance of a sterilizing cure. "These findings, especially with the identification of a second case, indicate there may be an actionable path to a sterilizing cure for people who are not able to do this on their own," says Yu, who is also a physician investigator at Massachusetts General Hospital. She further explains that these findings may suggest a specific killer T cell response common to both patients driving this response, with the possibility that other people with HIV have also achieved a sterilizing cure. If the immune mechanisms underlying this response can be understood by researchers, they may be able to develop treatments that teach others' immune systems to mimic these responses in cases of HIV infection. Yu adds: "We are now looking toward the possibility of inducing this kind of immunity in persons on ART through vaccination, with the goal of educating their immune systems to be able to control the virus without ART."

Original research published in Annals of Internal Medicine (Nov. 16, 2021): https://doi.org/10.7326/L21-0297 

/PRNewswire/ -- American Gene Technologies (AGT), a clinical-stage biotechnology company, announced treatment of the first participant in itsPhase I clinical trial to evaluate safety of the cell and gene therapy product AGT103-T. Designated as the RePAIR trial (Restore Potent Antiviral Immune Responses, NCT04561258), participants are infused once with their own CD4 T cells that were enriched, for cells capable of reacting to HIV, and genetically modified to resist infection. The first infusion took place at Washington Health Institute, Washington, D.C. on May 19.  This is a first-in-human study for AGT103-T. The primary endpoint is safety; testing related to secondary endpoints evaluates responses to treatment including changes in the immune response to HIV. Participants treated with AGT103-T will be followed for 6 months in this safety study before enrolling in an FDA-mandated 15-year long-term follow up required for all gene therapy trials. Enrollment, product manufacturing, and treatments are ongoing at AGT's clinical trial sites. "Treating the first person with our product is an important step forward and the culmination of design, development, manufacturing, and approval of the product for human testing. We believe this therapy is capable of changing the body's ability to fight HIV and the first-in-man study signals the first step to understanding what we can achieve with this innovative approach," said Dr. C. David Pauza, Chief Science Officer.

"This project represents a major step forward in the potency of an approach that has significant theoretical and empirical momentum within the HIV cure scientific community," stated CEO Jeff Galvin. He continued, "now that we have seen some evidence that the treatment can be tolerated by patients, I believe we will soon see efficacy signal that will be convincing to the scientific community that the cure for HIV has been achieved or is tremendously close. I couldn't be happier or prouder of the team. I am exceedingly optimistic about the future of this cell therapy and AGT's eventual contribution to the treatment of HIV."...

Investigators believe that an effective HIV vaccine would need to produce broadly neutralizing antibodies that would work on different strains of the virus. A phase 1 trial of a novel approach for HIV vaccination successfully stimulated production of rare immune cells needed to start the process of generating antibodies against the virus. Notably, the targeted response was detected in 97% of participants who received the vaccine, according to a press release. This study demonstrates proof of principle for a new vaccine concept for HIV, a concept that could be applied to other pathogens, as well,” said William Schief, PhD, whose laboratory developed the vaccine, in a press release. “With our many collaborators on the study team, we showed that vaccines can be designed to stimulate rare immune cells with specific properties, and this targeted stimulation can be very efficient in humans. We believe this approach will be key to making an HIV vaccine and possibly important for making vaccines against other pathogens.”

HIV affects more than 38 million people globally and is known to be one of the most difficult viruses to target with a vaccine. One of the major challenges is because the virus constantly evolves into different strains to evade the immune system. Investigators have worked for decades to create a vaccine that would stimulate the immune system to create rare but powerful antibodies called broadly neutralizing antibodies (bnAbs). According to the press release, bnAbs are specialized blood proteins that could attach to HIV spikes and disable them via important yet difficult-to-access regions that don’t vary much from strain to strain. “We and others postulated many years ago that in order to induce bnAbs, you must start the process by triggering the right B cells—cells that have special properties giving them potential to develop into bnAb-secreting cells,” Schief explained in the press release. “In this trial, the targeted cells were only about 1 in a million of all naïve B cells. To get the right antibody response, we first need to prime the right B cells. The data from this trial affirms the ability of the vaccine immunogen to do this.”

The strategy of targeting naïve B cells with specific properties is called germline-targeting, because these young B cells display germline genes. Investigators believe the approach could also be applied to vaccines for other challenging pathogens, such as influenza, dengue, Zika, hepatitis C virus, and malaria. The clinical trial, IAVI G001, enrolled 48 healthy adult volunteers who received either a placebo or 2 doses of the vaccine compound along with an adjuvant developed by GSK. According to the investigators, the novel design, the clinical trial, and the molecular B cell analyses provide a roadmap for further progress in an HIV vaccine. “This is a tremendous achievement for vaccine science as a whole,” said Dennis Burton, PhD, scientific director of the IAVI Neutralizing Antibody Center and director of the NIH Consortium for HIV/AIDS Vaccine Development, in a press release. “This clinical trial has shown that we can drive immune responses in predictable ways to make new and better vaccines, and not just for HIV. We believe this type of vaccine engineering can be applied more broadly, bringing about a new day in vaccinology.”

February 3, 2021:  https://www.scripps.edu/news-and-events/press-room/2021/20210203-hiv-vaccine.html. 

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. 

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

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

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 

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”.

She’s the third person ever to be cured. Researchers announced that the new approach holds the potential for curing more people of racially diverse backgrounds.  A woman of mixed race appears to be the third person ever to be cured of H.I.V., using a new transplant method involving umbilical cord blood that opens up the possibility of curing more people of diverse racial backgrounds than was previously possible, scientists announced on Tuesday. Cord blood is more widely available than the adult stem cells used in the bone marrow transplants that cured the previous two patients, and it does not need to be matched as closely to the recipient. Most donors in registries are of Caucasian origin, so allowing for only a partial match has the potential to cure dozens of Americans who have both H.I.V. and cancer each year, scientists said. The woman, who also had leukemia, received cord blood to treat her cancer. It came from a partially matched donor, instead of the typical practice of finding a bone marrow donor of similar race and ethnicity to the patient’s. She also received blood from a close relative to give her body temporary immune defenses while the transplant took. Researchers presented some of the details of the new case on Tuesday at the Conference on Retroviruses and Opportunistic Infections in Denver, Colo.

The sex and racial background of the new case mark a significant step forward in developing a cure for H.I.V., the researchers said.

“The fact that she’s mixed race, and that she’s a woman, that is really important scientifically and really important in terms of the community impact,” said Dr. Steven Deeks, an AIDS expert at the University of California, San Francisco who was not involved in the work. Infection with H.I.V. is thought to progress differently in women than in men, but while women account for more than half of H.I.V cases in the world, they make up only 11 percent of participants in cure trials. But Dr. Deeks said he did not see the new approach becoming commonplace. “These are stories of providing inspiration to the field and perhaps the road map,” he said. Powerful antiretroviral drugs can control H.I.V., but a cure is key to ending the decades-old pandemic. Worldwide, nearly 38 million people are living with H.I.V., and about 73 percent of them are receiving treatment.  A bone marrow transplant is not a realistic option for most patients. Such transplants are highly invasive and risky, so they are generally offered only to people with cancer who have exhausted all other options. There have only been two known cases of an H.I.V. cure so far. Referred to as “The Berlin Patient,” Timothy Ray Brown stayed virus-free for 12 years, until he died in 2020 of cancer. In 2019, another patient, later identified as Adam Castillejo, was reported to be cured of H.I.V., confirming that Mr. Brown’s case was not a fluke. Both men received bone marrow transplants from donors who carried a mutation that blocks H.I.V. infection. The mutation has been identified in only about 20,000 donors, most of whom are of Northern European descent.

A new paradigm for HIV treatment is on the horizon as FDA gives nod for startup to begin trials of CRISPR-based gene therapy as a HIV cure.  The US Food and Drug Administration (FDA) has given the nod for Excision BioTherapeutics to begin trials testing CRISPR gene editing as a treatment for HIV. EBT-101 will be a first-in-human, CRISPR-based one-time gene therapy to be evaluated in individuals with HIV. On 15 September Excision announced that the FDA had accepted its Investigational New Drug (IND) application for EBT-101 as a potential functional cure for chronic HIV. The IND clearance will allow the firm to start a first-in-human Phase I/II trial to evaluate the safety, tolerability and efficacy of EBT-101 in healthy individuals living with HIV. “The clearance of our IND application for EBT-101 represents an important milestone for Excision and is the result of years of commitment to developing a functional cure for individuals living with HIV,” said Excision CEO Daniel Dornbusch. “Although antiviral treatments can manage HIV infection, they require life-long treatment, cause side effects, and do not provide the possibility of a functional cure. We are grateful for the FDA’s engaged review and acceptance of the IND for EBT-101 and look forward to initiating the Phase I/II clinical trial later this year.” EBT-101 uses CRISPR to cut out or excise HIV that has wrapped around the DNA in cells. It has been HIV’s ability to coil itself into DNA that has made it so difficult to treat and largely the reason that past curative efforts have fallen flat. The therapy harnesses an adeno-associated virus (AAV) at a relatively low dose to deliver the one-time treatment.  Excision said that the investigational programme employs CRISPR-Cas9 and two guide RNAs that target three sites within the HIV genome, “thereby excising large portions of the HIV genome and minimizing potential viral escape”.

The upcoming trial will be one of the first attempts to directly extract the latent virus from DNA. In preclinical studies, the therapy demonstrated the ability to excise HIV proviral DNA in human primary cells as well as multiple animal models including non-human primates. In later studies, after evaluating the safety and tolerability of the therapy, Excision hopes to take patients off their regular antiviral meds to test EBT-101 as a cure. “EBT-101 has demonstrated removal of proviral DNA in multiple animal models and offers an opportunity for individuals living with HIV to potentially cease life-long therapies,” said Excision’s CMO Lisa Danzig. “The Excision team looks forward to this important collaboration with our principal investigators, scientific advisors and regulators, to conduct a safe and informative trial with this first-in-class approach to a viral disease target previously considered to be incurable.” The news of the trial comes just weeks after it was announced that J&J’s recent efforts at an HIV vaccine had failed and news broke that Moderna is set to begin trials of its HIV vaccine based on mRNA technology. HIV can now be well managed with antiretroviral medications, but these are a lifelong commitment and cause side effects. For the last few decades, an elusive HIV vaccine has been considered ‘the holy grail’ in stopping the spread of the highly stigmatised disease, but CRISPR-based gene editing would represent a brand-new therapeutic approach.

Excision BioTherapeutics, Inc. (Excision) has secured $60 million in investor financing to advance CRISPR-based gene editing constructs developed by Kamel Khalili, PhD, Laura H. Carnell Professor and Chair of the Department of Neuroscience, Director of the Center for Neurovirology, and Director of the Comprehensive NeuroAIDS Center at the Lewis Katz School of Medicine at Temple University (LKSOM). The funding will allow these treatments to be advanced into a Phase 1/2 clinical trial in patients with chronic HIV infection. The funding secured by Excision will also provide Temple scientists and Excision the ability to research CRISPR technology on other viral diseases at LKSOM including JC Virus for Progressive Multifocal Leukoencephalopathy, Herpes Simplex Virus and other viral diseases. Those additional studies will be led by Ilker K. Sariyer, DVM, PhD, Associate Professor of Neuroscience and Neurovirology at LKSOM. “The funding secured is a momentous occasion for Excision and Temple and the many individuals living with HIV and other viral diseases,” said John M. Daly, MD, FACS, Interim Dean & Dean Emeritus and Harry C. Donahoo Professor of Surgery at LKSOM. “These continued research and clinical trials bring us one step closer to having new technology available to suppress and eradicate multiple viral diseases.”

In research recently published by Nature Communications, Dr. Khalili along with Tricia H. Burdo, PhD, Associate Professor and Associate Chair of Education in the Department of Neuroscience at LKSOM, who is an expert on the utilization of the SIV (simian immunodeficiency virus)-infected antiretroviral therapy (ART)-treated rhesus macaque model for HIV pathogenesis and cure studies; Dr. Sariyer; Rafal Kaminski, PhD, Assistant Professor of Neuroscience and Assistant Professor in the Center for Neurovirology at LKSOM; Pietro Mancuso, PhD, an Assistant Scientist in Dr. Khalili’s laboratory; Chen Chen, a Research Technician in Dr. Khalili’s laboratory; other scientists in Dr. Khalili's, Dr. Burdo’s, Dr. Sariyer’s and Dr. Kaminski’s laboratories; and colleagues demonstrated success in editing the genome of simian immunodeficiency virus (SIV), a virus closely related to HIV, the cause of AIDS, from non-human primates. Dr. Khalili and Dr. Burdo were senior co-investigators on the study and Dr. Mancuso was first author.  The success of Dr. Khalili’s HIV discoveries has led Temple into a partnership with Excision to support the continued development of the CRISPR technology. In this partnership Dr. Khalili serves as Co-Founder and Chief Scientific Consultant, and holds equity in Excision, which has licensed the viral gene editing technology from Temple University. Dr. Burdo contributes to preclinical research and development, serves on the Scientific Advisory Board and holds equity in Excision. “This transformative financing will accelerate and support the research we have developed over the past decade,” said Dr. Khalili. “We have proven the technology and candidate programs in vitro and in vivo in both small animal models and primate models. We are optimistic that ongoing research will demonstrate the potential for a future therapeutic to generate functional cures for viral infectious diseases.”

Editor’s Note: Kamel Khalili is Co-Founder and Chief Scientific Consultant, and holds equity in Excision BioTherapeutics, which has licensed the viral gene editing technology from Temple University. Kamel Khalili and Rafal Kaminski are named inventors on patents that cover the viral gene editing technology. Tricia Burdo is a consultant for and holds equity in Excision BioTherapeutics. Ilker Sariyer is a consultant for Excision. Dr. Khalili , Dr. Burdo, Dr. Sariyer and Dr. Kaminski are employed by Temple University, and both they and LKSOM faculty within the department conduct research activities sponsored by the company. Questions regarding their affiliations with Temple University may be directed to coisom@temple.edu.  In addition to owning the viral gene editing technology that Excision is licensing, Temple University also holds an equity interest in Excision. As a result of these interests, Temple University could ultimately potentially benefit financially from the outcome of this research. These interests have been reviewed and approved by Temple University in accordance with its Institutional Conflict of Interest policy. Questions about this can be directed to coitemple@temple.edu.

Gilead Sciences has inked a collaboration, option and license deal with Gritstone Oncology to create a vaccine-based immunotherapy as a cure for HIV. Cure is not a word used lightly by the biopharmaceutical industry, particularly in terms of HIV. The disease is effectively treated and controlled with cocktails of antiviral drugs, but actual cures have been elusive. The partnership will leverage Gritstone’s proprietary prime-boost vaccine platform. This is made up of self-amplifying mRNA (SAM) and adenoviral vectors using antigens developed by Gilead. Gilead is a viral expert, with a dominant place in the hepatitis and HIV arena, as well as having the only approved antiviral drug for COVID-19, remdesivir. Gritstone develops immunotherapies against multiple cancer types and infectious diseases. Gritstone has two key technology platforms. One is its proprietary machine learning platform, Gritstone EDGE, that predicts antigens presented on the surface of cells, such as cancer cells or cells infected by viruses. The second is Gritstone’s capabilities in developing and manufacturing potent immunotherapies using those antigens.

Under the terms of the deal, Gilead is paying Gritstone $30 million in cash up front and a $30 million equity investment. Gilead will handle a Phase I trial for the HIV-specific vaccine and will hold an exclusive option for an exclusive license to develop and commercialize it beyond Phase I. Gritstone will be up for an additional $725 million in regulatory and commercial milestones, as well as mid-single-digit to low double-digit tiered royalties on net sales.  “While HIV treatment has advanced dramatically over the past three decades, people living with HIV still face a lifetime of therapy,” said Diana Brainard, senior vice president, Virology Therapeutic Area, Gilead. “Curing HIV remains the ultimate aspiration for Gilead’s HIV research and development efforts.” Brainard added, “Gritstone’s vaccine technology has the potential to educate the immune system to specifically recognize and destroy HIV-infected cells by leveraging SAM and adenoviral vectors. This, along with our other partnerships and internal programs, reflects Gilead’s commitment to continuing innovation to discover a cure for HIV and bring about an end to the HIV epidemic.” There were not a lot of technical details related to the collaboration, but it appears Gritstone will utilize simian immunodeficiency virus (SIV)-derived antigens. These are similar to HIV-1. “The resulting strong, durable and broad anti-SIV CD8+ T cell responses and T cell data captured the attention of Gilead’s virology team. We jointly performed further experiments that generated additional compelling data, which was also complemented by our exciting clinical data with neoantigens in cancer patients," said Karin Jooss, Gritstone’s executive vice president of Research and chief scientific officer. 

"We are delighted to now advance our partnership and product candidates for the treatment of patients with HIV infection.” On January 20, Gritstone entered into licensing deal with Genevant Sciences to Genevant’s lipid nanoparticle (LNP) technology to develop SAM vaccines against SARS-CoV-2, the virus that causes COVID-19. Genevant’s LNP platform is already clinically validated and part of Gritstone’s SAM neoantigen-based cancer immunotherapy that is currently in Phase II studies. “We are pleased to extend our longstanding and productive collaboration with the Genevant team to include our newly launched COVID-19 program,” said Andrew Allen, co-founder, president and chief executive officer of Gritstone. “As we continue to see new strains of SARS-CoV-2 emerge, we identified an opportunity to apply our key strengths to an innovative COVID-19 vaccine. Specifically, extending the antigenic content of a COVID-19 vaccine beyond Spike alone may open up a route to clinical protection even if Spike mutations reduce antibody binding. We believe our approach could make an important impact on COVID-19 by eliciting robust neutralizing antibody responses and plentiful anti-viral CD8+ T cells to both Spike and other key viral antigens.” This is of particular interest because of the rise of variant COVID-19 strains out of the UK, South Africa and Brazil, which appears to have mutations in the Spike protein that allows the virus to be more contagious than earlier strains and are less targeted by the existing vaccines and antibody therapies. At this time, the variants are not “slipping” the vaccines, meaning they are completely avoiding them, but the vaccines do appear to be less efficacious against the South African variant in particular.

Some rare people may purge most HIV from their bodies, leaving only broken copies of the virus or copies locked in molecular prisons, from which there is no escape. Twice, people infected with HIV have had levels of the virus in their bodies drop to undetectable levels after bone marrow transplants, never to return (SN: 3/5/19). Now it appears that a person may have cleared functional HIV with no outside help. If true, it would be the first known instance of a spontaneous cure. Analysis of more than 1.5 billion cells taken from a patient known as EC2 showed no functional HIV copies in any of them, researchers report August 26 in Nature. The person still had some nonfunctional copies of the virus. While no one can say for sure that intact virus isn’t hiding in a cell somewhere in this person’s body, the finding suggests that some people’s immune systems can get the upper hand, essentially eliminating the pernicious and persistent virus. A second person, EC1, had just one functional copy of HIV in more than 1 billion blood cells analyzed. And that copy of HIV was stuck in what is essentially a genetic supermax prison. That genetic lockup may be key to being able to naturally control the virus. Those two people are part of a rare group of people known as elite controllers, meaning they are able to maintain very low or undetectable levels of HIV without antiretroviral drugs. These people have no symptoms or clear signs of damage from the virus. “It’s not even that we’re talking about a few months or a few years. It’s extremely long-term,” says Satya Dandekar, an HIV researcher at the University of California, Davis School of Medicine who was not involved in the study. In contrast, for 99.5 percent or more of the world’s 35 million people infected with the virus, drugs are the only way to keep the virus down.

Researchers want to know how elite controllers quash the virus for long periods of time. It has been difficult to figure it out, Dandekar says, because no one has recorded the first fight scenes between HIV and the elite controllers’ immune systems. “We miss the initial punches the immune system has thrown at the virus.” And by the time anyone recognizes an elite controller, the fight is already won. About a quarter of elite controllers have genetic variants in key immune system genes that may help them get a handle on the virus, says Joseph Wong, a virologist at the University of California, San Francisco. But that explains what’s going on in only a minority of elite controllers, and isn’t something easily transferred to others, he says. It’s possible that the elite controllers were infected with “wimpy” versions of HIV, Dandekar says. So the researchers examined the HIV viruses embedded in DNA from 64 elite controllers and 41 HIV-infected people taking antiretroviral drugs. The elite controllers had maintained undetectable levels of virus without drugs from one to, in EC2’s case, 24 years. The median was nine years. HIV is a retrovirus, which means that it stores its genetic information as RNA. An enzyme called reverse transcriptase copies those RNA instructions into DNA, which can then insert into the host’s DNA. Reverse transcriptase is error prone, often resulting in defective or incomplete copies of the virus. So the researchers went into the study thinking that elite controllers might be loaded with these nonfunctional versions, which can’t make infectious virus, says Xu Yu, an immunologist at the Ragon Institute of MGH, MIT and Harvard in Boston. “But to our surprise, that’s not the case,” she says. Instead, most elite controllers in the study have more intact virus than expected. So Yu and colleagues looked to see where the virus had landed in patients’ DNA....

Published in Nature (August 26, 2020):

https://doi.org/10.1038/s41586-020-2651-8

The National Institutes of Health and the Bill and Melinda Gates Foundation will together invest at least $200 million over the next four years to develop gene-based cures for sickle cell disease and HIV with an attribute even rarer in the world of genetic medicine than efficacy, the groups announced on Wednesday: The cures, they vowed, will be affordable and available in the resource-poor countries hit hardest by the two diseases, particularly in Africa.

The effort reflects growing concerns that scientific advances in genetic medicine, both traditional gene therapies and genome-editing approaches such as CRISPR, are and will continue to be prohibitively expensive and therefore beyond the reach of the vast majority of patients. Spark Therapeutics’ Luxturna, a gene therapy for a rare form of blindness, costs $425,000 per eye, for instance, and genetically engineered T cells (CAR-Ts) to treat some blood cancers cost about the same.  With CRISPR-based treatments already being tested in clinical trials for sickle cell disease, the blood disorder beta thalassemia, and another form of blindness, and with additional CRISPR treatments in development, scientists, ethicists, and health policy experts have grown increasingly concerned that the divide between haves and have-nots will grow ever-wider.

Gene-based treatments “are largely inaccessible to most of the world by virtue of the complexity and cost of treatment requirements, which currently limit their administration to hospitals in wealthy countries,” the NIH said in a statement. To help right that, its collaboration with the Gates Foundation aims to develop “curative therapies that can be delivered safely, effectively and affordably in low-resource settings.” Scientists whose research focuses on gene-based cures welcomed the infusion of funding and the recognition that genetic cures are on track to be unaffordable to the majority of patients. But they noted one irony. The most effective sickle cell drug, hydroxyurea, has hardly even been studied in sub-Saharan Africa, let alone made widely available. Yet a 2019 study found that giving children the drug cut their death rate by two-thirds and halved the pain crises that are common in sickle cell disease, caused by misshapen red blood cells that cannot flow through blood vessels. The NIH-Gates collaboration “is tremendously exciting and has the potential to have a great impact on sickle cell disease in sub-Saharan Africa,” said Dr. Vijay Sankaran of the Dana-Farber/Boston Children’s Cancer and Blood Disorders Center, who has done pioneering research on genetic cures for the disease. “But my hesitation is that even the inexpensive therapies we have today, such as hydroxyurea, are largely unavailable there. The question is, how do we best approach this disease, with therapies that are working today or with genetic therapies that might work?”...

A mouse study with engineered “CAR T cells” shows a novel way to stop the virus. Drugs work stunningly well to control HIV—but not in everyone, and not without side effects. That's why a small cadre of patients known as elite controllers has long fascinated researchers: Their immune system alone naturally suppresses HIV for decades without drugs. Now one team, inspired by success in mice, hopes to endow HIV-infected people with tailormade immune cells that target HIV, in effect creating elite controllers in the clinic.

The immune strategy has risks, but it builds on increasingly popular cancer treatments with T cells engineered to have surface proteins, called chimeric antigen receptors (CARs), that can recognize markers on the surfaces of tumor cells and destroy the cancer. Such CAR T cells can also be tailored to identify and eliminate HIV-infected cells. This approach was tested in HIV-infected humans long before CAR T cells proved their worth against cancer, but it roundly failed. The field wants "to move what's been learned from cancer back to HIV, completing the circle," says Steven Deeks, an HIV/AIDS clinician at the University of California, San Francisco, who first tested a CAR T cell against the virus in the late 1990s. The new study—conducted by researchers from the University of Pittsburgh in Pennsylvania; the biotech company Lentigen in Gaithersburg, Maryland; and the Albert Einstein College of Medicine in New York City—uses a far more sophisticated CAR approach than the one Deeks tested. "It's promising and seems to be more potent than what's been tried in the past," says stem cell biologist Hans-Peter Kiem, who has tested CAR T cells in leukemia and lymphoma patients at the Fred Hutchinson Cancer Research Center in Seattle, Washington.

For the new work, published online this week in Science Translational Medicine, the researchers engineered T cells to include genes encoding two kinds of CARs, each targeting a different part of HIV's surface protein. In test tube studies, this "duoCAR T" cell powerfully killed white blood cells infected with a diverse array of HIV variants, the group reports. The team also gave near simultaneous injections of CAR T cells and HIV-infected human cells to the spleens of mice with a "humanized" immune system. (Rodents cannot normally be infected with the AIDS virus.) When the group harvested spleens from the mice a week later, five of six mice had no detectable HIV DNA and their average viral levels had dropped 97.5%.

Published on August 7 2019 in Science Translational Medicine:

https://doi.org/10.1126/scitranslmed.aav5685