HIV cure research: Trying to eliminate a virus that ‘hides out’
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After more than 40 years, scientists have yet to find a cure for HIV, a complex virus that can be suppressed with potent medications to undetectable levels in the body but not eliminated.
Infectious Disease News Chief Medical Editor Paul A. Volberding, MD, professor emeritus of medicine at the University of California, San Francisco, worries that the world is losing focus on HIV/AIDS.
Source: Courtesy of Paul A. Volberding, MD
“I think that the appropriate attention that we have given to COVID-19 is, of course, understandable, but I am a little afraid that we’re losing sight of HIV at a time when we really have the tools to control the epidemic,” Volberding said last year on the 40th anniversary of the first published report of AIDS.
We spoke with Volberding and other experts about recent breakthroughs in research and promising advances in the ongoing effort to cure HIV.
“I think HIV could prove to be curable,” Volberding said in an interview for this story, “and that, in and of itself, would be spectacular.”
‘Proof of principle’
Although there is no cure for HIV, three people have achieved sustained HIV remission in the absence of ART after undergoing a stem cell transplant.
The “Berlin patient,” later identified as Timothy Ray Brown, was the first. After undergoing a bone marrow transplant in 2007 as part of treatment for leukemia, Brown remained free of detectable HIV without treatment for more than a decade before his death in 2020 following a recurrence of leukemia.
Adam Castillejo, known as the “London patient,” also achieved sustained HIV remission after undergoing a similar procedure for Hodgkin’s lymphoma. In 2020, Ravindra K. Gupta, PhD, a professor in the division of infection and immunity at the University College London, and colleagues estimated that Castillejo’s probability of remission for life is 98% in the context of 80% donor chimerism — the proportion of his cells that are from the donor — and greater than 99% with 90% donor chimerism.
Joining this short list of cured patients was an unnamed middle-aged woman from the United States dubbed the “New York patient” who achieved sustained treatment-free HIV remission after undergoing a haplo-cord stem cell transplant for high-risk acute myeloid leukemia in 2017 — 4 years after being diagnosed with HIV.
All three patients received cells from donors with the CCR5-delta 32 mutation, which creates natural resistance by preventing HIV from entering human cells. The cases were all initially presented at the Conference on Retroviruses and Opportunistic Infections (CROI) in 2008, 2019 and this year, respectively.
Yvonne J. Bryson, MD, chief of pediatric infectious diseases at the David Geffen School of Medicine at the University of California, Los Angeles, explained during a presentation at CROI this year that the CCR5-delta 32 mutation occurs in less than 1% of people. Bryson said the success of the New York patient’s treatment provides hope that transplanted cord blood cells can be used to achieve HIV remission for people requiring transplantation while also providing additional proof that HIV reservoirs can be cleared sufficiently for remission in the setting of resistant target cells.
“The key to success in these cases is that infected CD4 T cells along with uninfected CD4 T cells in the recipient are eliminated in the course of the transplant process,” Janet M. Siliciano, PhD, professor of medicine in the division of infectious diseases at Johns Hopkins University School of Medicine, told Healio | Infectious Disease News. “This elimination is not virus-specific.”
Simply put, remission in these cases is a result of the recipient’s immune system being replaced with one from donor cells that are resistant to HIV infection.
“These cases are interesting but are not relevant to the vast majority of people living with HIV,” Siliciano said. “Stem cell transplantation has substantial risks and can be done only when the patient has [a] life-threatening malignancy requiring this form of treatment.”
Still, experts said the cases can provide insight for researchers seeking a cure for HIV. Carl W. Dieffenbach, PhD, director of the Division of AIDS at the National Institute of Allergy and Infectious Diseases, said Brown’s case demonstrated that a cure was possible using “some pretty challenging methodologies.”
“The same with the London patient — in each case, there’s additional information that’s been gained,” Dieffenbach told Healio | Infectious Disease News. “And I think the New York patient was particularly interesting from a transplant perspective, because the transplant was so different, using cord blood.”
Dieffenbach said the technical advances made in each case will be important for the for the field going forward, although he agreed that the treatment is not suitable for most people.
“I think it still is absolutely clear to everybody that this is not for the general population,” he said. “It is clearly limited to people with lethal cancers, lymphomas, and leukemias, but it also gives hope to those patients.”
Mary N. Carrington, PhD, senior principal scientist at the Frederick National Laboratory for Cancer Research and head of the HLA Immunogenetics Section at the Laboratory of Integrative Cancer Immunology, told Healio | Infectious Disease News that aside from being limited to patients with these conditions, allogenic transplantation is expensive and can have devastating health consequences.
She added, however, that the cases “have served as proof of principle that an HIV-infected patient can be cured of HIV, so they have been important indeed.”
Together, they amount to more than just three case reports, Volberding said.
“They begin to build a case series and, finally, enough cases that we might hope to really learn something that holds them in common. That’s what we really need to know,” he said. “We know that this can happen rarely, but is this something that we know enough about to be able to predict in advance? Why do some people have this outcome and others don’t? Knowing this could give us real insight into the nature of the cure.”
Sterilizing cure
Two other women have apparently achieved a sterilizing cure of HIV through their own immune systems, without undergoing stem cell transplantation. Both women are elite controllers — people with HIV who can suppress the virus without ART. Elite controllers represent less than 0.5% of all people with HIV.
Xu G. Yu, MD, group leader at the Ragon Institute of MGH, MIT and Harvard, and colleagues, including Siliciano, analyzed more than a billon cells from each woman and were unable to detect any evidence of HIV. After Yu and colleagues reported the first case in Nature in 2020, she told Healio | Infectious Disease News that the case produced several key takeaways for cure researchers, including that “quality, rather than quantity, of the HIV reservoirs define a state of a functional cure of HIV.”
The woman was part of a larger study of elite controllers that demonstrated that “HIV was often found in locations of the human genome that researchers call ‘gene deserts,’” Yu explained. Yu and colleagues reported the second case in November in the Annals of Internal Medicine.
“In these inactive parts of the human genome, human DNA is never turned on, and thus, HIV cannot be effectively expressed but remains in a ‘blocked and locked’ state. This means that viral genomes at these positions are blocked from being expressed and therefore are incapable of causing disease,” Yu said. “Our data indicate that for future evaluation of cure strategies, not only the changes in the quantity of intact viruses, but also the changes in the chromosomal locations and integration sites of intact viruses should be analyzed as an outcome parameter or endpoint.”
She said the first case gave scientists “a blueprint of what a functional cure of HIV looks like,” showing that achieving a cure for HIV does not necessarily mean eliminating all intact HIV viruses.
“We need to target only those viruses that are located in active parts of the human genome where they can be actively expressed,” Yu said. “In the future, we will consider immunotherapeutic interventions that are specifically designed to eliminate those HIV sequences that are integrated in active parts of the human genome. The remaining sequences that are integrated in inactive parts of the human genome do not seem to cause disease, and it looks like they can largely be ignored.”
The two cases have been “hugely enlightening,” Carrington said, “and hold the promise of providing the mechanisms that are involved in clearing the virus with one’s own immune system, giving hope that such mechanisms could be spurred into action therapeutically.”
“There could be many more HIV-infected individuals who went on to clear the virus but identifying them is not so straightforward since they no longer would have symptoms — and perhaps never did have them severe enough to send them to a clinic — so they may never be identified as having had an HIV infection,” Carrington said.
A virus that ‘hides out’
There is plenty of other activity in HIV cure research, according to Volberding.
“As somebody who is watching the field closely, there have been a number of directions, ranging from drugs to try to kick the virus into gear so it can be the subject of attack by even antiviral drugs, to other approaches taking a more immunologic look at ways that we could try to, in a sense, convince the immune system to do a better job at controlling viral replication,” Volberding said. “Finding infected cells and eliminating them — that would be the Holy Grail.”
Siliciano explained the approach called “shock and kill.”
“The idea is to turn on virus production in latently infected cells so that infected cells can be identified by the immune system and eliminated,” Siliciano said. “Unfortunately, we don’t yet have a way to turn on latent HIV.”
Dieffenbach noted other methods being explored by researchers, including gene therapy and the CRISPR/Cas9 gene-editing technology, but said cure research is “really challenged still by understanding the reservoir completely.”
“One fundamental principle of HIV has always been the notion that once someone has become infected with HIV, they have it for life. It actually becomes part of your DNA,” he said. “Until we find that magic sauce that says we can identify the cell that’s carrying the infectious virus that’s latent from a cell that’s not, we’re stuck with this.”
The feeling of being stuck goes back decades, Volberding said.
“Once we had such potent therapies available, there was almost immediately optimism — I certainly had it — that that would be enough,” he said. “If we could suppress the virus enough, that would result in a cure. Or if we continue therapy enough, we would finally get rid of the virus.”
The problem, Volberding said, is that available therapies do not eliminate the genome, allowing HIV to reactivate. HIV is able to basically “hide,” Carrington said.
“The virus hides out in the host genome,” she said. “Antiretroviral therapy keeps the virus in check, but the virus is still there and can be produced at a very low level, even at undetectable levels in the blood, in people receiving therapy.”
Once therapy is stopped, the cells harboring replication-competent viruses are able to produce HIV at greater levels unchecked, which can infect other T cells, Carrington explained.
“Antiretroviral therapy deters viral replication, but it does not directly eliminate cells that contain replication-competent viruses in their genomes,” Carrington said.
In one study presented at CROI this year, researchers found that ART shrinks the viral reservoir to a point, but then it stabilizes.
“There’s all these tricks that HIV has,” Dieffenbach said. “I think we remain still in the space of discovery.”
HIV and COVID-19
The COVID-19 pandemic has pulled resources from efforts to study or respond to other infectious diseases, including HIV/AIDS.
Sources: 1. Bryson Y, et al. LB 65. Presented at: Conference on Retroviruses and Opportunistic Infections; Feb. 12-16, 2022 (virtual meeting); 2. Turk G, et al. Ann Intern Med. 2021;doi:10.7326/L21-0297; 3. Xu G. Yu, MD.
“I’ve said before: I was absolutely concerned about the pandemic in that it might divert efforts and resources from HIV cure research. I am absolutely not criticizing that — we’re doing exactly what we absolutely need to do with a pandemic — but I think that is one of the major downsides to COVID-19 and HIV,” Volberding said.
Research indicates that pandemic-related disruptions to HIV care and resources could lead to a more than 10% increase in new HIV infections among men who have sex with men alone because of reductions in HIV testing, viral suppression, treatment initiation, PrEP initiation and PrEP adherence, and that HIV screening and diagnoses decreased by 24% and 29%, respectively, compared with prepandemic periods.
A ray of hope has been the success of COVID-19 messenger RNA vaccines. Development of the vaccines was informed by years of HIV vaccine research, and things are starting to come back around. In March, the NIH announced that it had initiated a phase 1 clinical trial to test three HIV mRNA vaccine candidates. [Editor’s note: For more on that story, click here.]
“We have made so much progress in HIV,” Dieffenbach said. “We really have a few absolutely essential questions that we need to solve in order to help us truly have the scientific tools that will help end the epidemic — one is a vaccine; the other is a cure.”
- References:
- Allers K. Blood. 2010;doi:10.1182/blood-2010-09-309591.
- Bryson Y, et al. LB 65. Presented at: Conference on Retroviruses and Opportunistic Infections; Feb. 12-16, 2022 (virtual meeting).
- Chang JJ, et al. Abstract 142. Presented at: Conference on Retroviruses and Opportunistic Infections; Feb. 12-16, 2022 (virtual meeting).
- Gupta RK, et al. Abstract 346LB. Presented at: Conference on Retroviruses and Opportunistic Infections; March 8-11, 2020; Boston.
- Gupta RK, et al. Lancet HIV. 2020;doi:10.1016/ S2352-3018(20)30069-2.
- Jiang C, et al. Nature. 2020;doi:10.1038/s41586-020-2651-8.
- Mitchell KM, et al. Lancet HIV. 2021;doi:10.1016/S2352-3018(21)00022-9.
- NIH. Drug-delivery technology leads to sustained HIV antibody production in NIH study. https://www.niaid.nih.gov/news-events/drug-delivery-technology-leads-sustained-hiv-antibody-production-nih-study. Accessed on March 18, 2022.
- Scientists identify second HIV patient whose body appears to have rid itself of the virus. https://www.eurekalert.org/news-releases/934789. Published Nov. 15, 2021. Accessed March 28, 2022.
- Turk G, et al. Ann Intern Med. 2021;doi:10.7326/L21-0297.
- For more information:
- Mary N. Carrington, PhD, can be reached at carringm@mail.nih.gov.
- Carl W. Dieffenbach, PhD, can be reached at cdieffenba@niaid.nih.gov.
- Janet M. Siliciano, PhD, can be research at jsilicia@jhmi.edu.
- Paul A. Volberding, MD, can be reached at Paul.Volberding@ucsf.edu.
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