December 11, 2017
What does a cure for HIV infection look like? It sounds like a simple question, but because of the way the virus can persist in the body, there are significant challenges associated with trying to define if a cure might have been achieved. As the research effort to develop a safe, effective, broadly accessible HIV cure expands, the issue of how to measure success remains central, and is important to understand.
There is one individual who is considered to be the first and, so far, only person to be cured. The case of Timothy Ray Brown has been widely publicized, but is worth revisiting.
Brown had been HIV-positive since 1995 and on combination antiretroviral therapy (ART) for four years when, in 2006, he developed the life-threatening cancer acute myelogenous leukemia (AML). The diagnosis led to the need for a stem cell transplant, a risky treatment that essentially creates a new immune system in the recipient by transferring bone marrow cells from a donor. Chemotherapy drugs and radiation are used to wipe out the existing immune system and make way for the donor cells. The procedure is limited to use in life-threatening cancers because it carries a high risk of death, approximately 20-30% (one out of five to one out of three individuals undergoing it).
Brown's doctor, Gero Hütter, had the idea to look for a donor with a rare genetic trait called the CCR5Δ32 (CCR5 delta 32) mutation. People who inherit this mutation from both parents are described as homozygous for CCR5Δ32, and the consequence is that their cells cannot produce a particular protein named CCR5 (people who inherit the mutation from only one parent have lower levels of CCR5).
The relevance for HIV is that the most common strains of the virus use CCR5 as a latch to gain entry into the cells it targets for infection -- predominantly CD4 T cells, which are a vital component of the immune system. Scientists studying gay men who had been highly exposed to HIV but remained uninfected discovered the CCR5Δ32 mutation in the mid-1990s.
Gero Hütter assessed many potential stem cell donors for Timothy Ray Brown and was fortunate to eventually find a match who was homozygous for CCR5Δ32. The treatment was tortuous, with Brown requiring two stem cell transplants and experiencing graft-versus-host disease (GVHD), which occurs when the newly transplanted immune system attacks the recipient's cells, requiring management with immune suppressants.
Ultimately, however, the stem cell transplants succeeded and the AML was cured. Brown's new immune system was made of cells homozygous for CCR5Δ32, so they lacked CCR5. ART was stopped during the procedures and -- although Hütter had cautiously hoped for the outcome -- it was nevertheless a welcome surprise to find that HIV viral load had not rebounded despite the absence of ongoing treatment.
The first report on Brown's case was made in a poster presentation at the Conference on Retroviruses and Opportunistic Infections (CROI) in 2008. For those unfamiliar with scientific conferences, much of the action takes place in sessions where researchers orally present results to a seated audience. But there are also poster halls, where studies deemed preliminary or potentially less important are described on paper pinned to plasterboards. Hütter's poster described Brown's case, and noted that -- at that point -- he had been off ART without detectable HIV rebound in blood, bone marrow, or rectal mucosal tissue for over 285 days -- nearly 10 months.
Many people failed to notice the presentation, or perhaps were skeptical. But activist Martin Delaney, founder of Project Inform, was already advocating for a renewed research focus on curing HIV infection and he drew attention by writing about the results for the organization's website. The news exploded into public awareness about a year later, with articles in the Wall Street Journal and a formal case report published by Hütter in the New England Journal of Medicine.
Brown, who had initially remained anonymous (referred to in reports simply as "The Berlin Patient"), disclosed his identity shortly afterward and has become a champion for the search for a cure. He has also been incredibly selfless in agreeing to participate in studies aiming to better understand his case. There was briefly some controversy in 2012 when analyses of blood and multiple body tissues by several different laboratories identified a few samples that appeared to contain trace amounts of HIV genetic material, but Brown recently celebrated a decade since his stem cell transplants with no sign of any HIV viral load rebound, and this remains the best evidence that a cure has been achieved.
Even now, though, it is not possible to know for sure if all HIV capable of replicating has been eradicated, or if there is some residual inactive virus -- technologies capable of surveying the entire body do not exist.
While clearly great news and encouraging for the HIV research field, Brown's example also highlights that, currently, the question of whether a person is cured can only be answered by following them for many years. This has also been underscored by a number of individuals who have shown signs of being cured, only to later experience viral load rebounds after months or even years off ART.
The most famous of these remission cases is "the Mississippi baby." Born to a mother whose HIV infection was not diagnosed until in labor, the neonate was started on ART within hours of delivery. The treatment was maintained for around 18 months, at which time the mother and baby temporarily stopped attending medical follow-up visits. When they returned, doctors learned that ART had been interrupted in the infant but, surprisingly, HIV viral load remained undetectable. The case drew widespread media coverage, and there was optimism that it represented another cure.
The initial theory was that the rapid institution of ART may have prevented the formation of the HIV "reservoir," which consists primarily of long-lived CD4 T cells that have become infected by the virus but then entered a de-activated or resting state that allows HIV genetic material to persist in a silent or "latent" form (see "Latent Tendencies").
Latently-infected CD4 T cells, as they are called, can become active if ART is interrupted, leading to renewed virus production and viral load rebound. In essence, the cells act as a hiding place for the virus, from which it can emerge when the coast is clear of ART. For this reason, they are seen as the most important obstacle to accomplishing an HIV cure.
The Mississippi baby remained off ART for a little over two years with no measurable HIV, but then experienced a return of detectable viral load necessitating the restarting of treatment, confounding the hope that the virus had been cleared. Researchers believe that the very early start of ART had greatly limited the size of the reservoir of latently infected CD4 T cells, but a few likely were present in a resting state, and eventually one or more became activated, leading to renewed HIV production. Resting CD4 T cells can become activated for a number of reasons, most commonly due to encountering an infectious agent or other substance that they recognize and respond to -- part of their job as immune system cells.
The outcome in the Mississippi baby emphasized that HIV can persist at levels undetectable by current technologies (see "Measuring the HIV Reservoir") and that long-term monitoring is essential even if it might initially appear that an individual has been cured.
Several adult cases have since mirrored the experience of the Mississippi baby. The closest echo is a recent report of an individual who was diagnosed with HIV extremely early (within approximately 10 days), due to acquiring the infection during a short window of time between screening for a pre-exposure prophylaxis (PrEP) demonstration project and the day they were started on the first dose of the PrEP drug Truvada.
Combination ART was begun as soon as the diagnosis was confirmed and maintained for 34 months before an analytical treatment interruption was undertaken (see "Time Out"). HIV remained undetectable for 224 days off ART, but then viral load rebounded.
The Boston patients are two HIV-positive men who, like Timothy Ray Brown, required stem cell transplants to treat cancers. They did not receive cells from donors with the CCR5Δ32 mutation, but nevertheless HIV became undetectable after the procedures. ART was maintained throughout, leading researchers to suspect that their new donor-derived immune system cells may have been protected from the virus. Both individuals, like Brown, also developed some GVHD after their transplant, which was thought to have potentially contributed to the clearance of HIV-infected cells. ART was eventually interrupted, and in one case HIV remained undetectable for 12 weeks, and in the other 32 weeks, before viral load reemerged and treatment was reinstituted.
At the 2017 CROI, researchers from Mayo Clinic in Rochester, Minnesota described another HIV-positive man with similarities to the Boston patients. Also a recipient of a stem cell transplant from a donor lacking the CCR5Δ32 mutation as part of treatment for cancer, the individual continued on ART after the procedure and displayed declining levels of HIV reservoirs that ultimately became undetectable. A little over two years after the procedure, an analytical treatment interruption was performed leading to a period of remission from detectable HIV that lasted 288 days. Viral load tests then revealed that HIV replication had restarted, and the individual resumed ART.
These five cases of temporary remission are linked by the fact that all appeared to result from the HIV reservoir being very small at the time of ART interruption. The size in the two Boston patients has been estimated as 290-2,900 latently infected cells and 40-730 latently infected cells, respectively (an estimated reduction of more than 1,000-fold compared to the pre-transplant baseline).
This is important because it indicates that a central goal of HIV cure research -- shrinking the size of the HIV reservoir -- can at least significantly delay the rebound of HIV when ART is interrupted. Mathematical modeling studies suggest that achieving even greater reservoir reductions -- on the order of over 10,000-fold (greater than 99.99%) -- could lead to a lifelong cure in the majority of individuals. So while the task may be daunting, there is a target to aim at. Another implication of the modeling work is that complete eradication of latent HIV -- which some scientists believe is likely impossible -- may not be a prerequisite for a cure.
The experience of the Boston and Mayo Clinic patients also provides evidence that receipt of a stem cell transplant from a donor homozygous for the CCR5Δ32 mutation was likely key for Timothy Ray Brown's cure, which offers encouragement to researchers pursuing gene therapy approaches (see "Gene Therapy in HIV Cure Research").
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