The Challenge of Defining an HIV Cure

December 11, 2017

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Remission vs. Post-Treatment Control

The other link among these five cases is that the period of remission seems to have been caused by the few latently infected CD4 T cells that were present remaining dormant (asleep), rather than the immune system actively controlling HIV.

No significant immune responses against HIV could be detected in any of the individuals, which was expected by researchers because of the swiftness with which ART was started in the Mississippi baby and PrEP demonstration project cases (suppressing the virus before the immune system mounted a response), and due to the fact that the Boston and Mayo Clinic patients developed new immune systems -- which had not yet encountered HIV -- from their HIV-negative stem cell transplant donors.

The absence of immune responses appears to make this type of remission distinct from a somewhat different form that has also received attention in mainstream media coverage of HIV cure research.

Typically referred to as virologic remission or post-treatment control, the best-known examples are the VISCONTI cohort, an unusual group of HIV-positive individuals identified in France who began ART early in infection, continued for several years, and then interrupted and have maintained viral loads at low or undetectable levels, in some instances for over a decade.

A number of other individual case reports have broad similarities, including a perinatally infected French teenager and a nine-year-old South African child who have displayed control of HIV viral load for 12 and 8.75 years, respectively, after limited periods of ART.

Post-treatment controllers generally display immune responses against HIV, including antibody and CD4 and CD8 T cell responses, although there is considerable individual variability. The prevailing belief is that these cases represent some sort of active containment of HIV replication by the immune system. Attempting to induce immunological control of HIV is another avenue being pursued by cure researchers (see "Enhancing Immunity").


Elite Controllers

One concern about post-treatment control as a model for an HIV cure relates to the parallels with rare HIV-positive individuals known as elite controllers, who suppress viral replication to undetectable levels for many years without ART. This phenomenon is associated with strong and effective immune responses targeting the virus, particularly CD8 T cells and CD4 T cells. Certain genetic traits that influence the performance of CD8 T cells are known to increase the likelihood of becoming an elite controller.

Unfortunately, however, studies have found that elite control is not necessarily completely protective against disease progression. The efforts of the immune system to control HIV can be associated with increased levels of inflammation and a slow decline in CD4 T cell numbers, ultimately leading to AIDS, albeit it at a far slower pace than is observed in individuals with higher viral loads.

Prospects for long-term health may therefore be better in instances where remission is associated with latently infected cells remaining dormant (or, ideally being eliminated entirely), as opposed to HIV being actively controlled by immune responses -- it is early days, however, and firm conclusions cannot yet be drawn.

Notably, there is a subset of elite controllers who exhibit extraordinarily strong control of HIV, and they may offer cure researchers a model of immune-mediated containment without the potential for detrimental effects.

Looking Ahead

The complexities associated with discerning what an HIV cure looks like with some degree of certainty can be headspinning, but should not be disheartening. Even having cured just one person, and attained temporary remission in several more, is a far from trivial achievement. The increasingly global expansion of cure research promises to bring answers to the difficult questions that still face the field, and hopefully draws an easily taken, effective, and scalable cure ever closer.

Can We Do It Again?

Attempts to Repeat Timothy Ray Brown's Outcome in Additional HIV-Positive Individuals Requiring Stem Cell Transplants

Understandably, researchers are pursuing the possibility of duplicating the results obtained in Timothy Ray Brown in other HIV-positive people who require stem cell transplants to treat cancers. Several ongoing research programs (such as the amfAR-supported international IciStem collaboration) are attempting to find appropriate donors who are homozygous for the CCR5∆32 mutation for HIV-positive individuals in this situation. A number of transplants have been performed but, so far, no other cases of HIV cures have been publicly reported.

A publication by Gero Hütter has summarized six cases in which HIV-positive individuals received stem cells from donors homozygous for the CCR5∆32 mutation, but all died due to either the cancers or complications of the procedures -- illustrating the risks of the approach, and its limited applicability as a curative intervention.

Cheat Sheet
Key points to know about HIV cure research

One person, Timothy Ray Brown, is considered cured and there are several other cases where HIV viral load did not rebound for an extended period after an ART interruption (referred to as remission)

These outcomes remain rare and resulted from exceptional circumstances -- stem cell transplants for HIV-positive people with cancers or extremely early initiation of ART -- but they are providing important clues to researchers working to develop a cure

There are more numerous -- but still relatively rare -- examples of individuals who have controlled HIV viral load to low levels either naturally (elite controllers) or after an ART interruption (typically after beginning treatment early), but it is uncertain how long this immune-mediated control can last and if it may come at some cost to long-term health

While many different therapeutic approaches are being studied, so far no broadly usable interventions have led to cures or remission -- the best reported results involve small reductions in the HIV reservoir (its hiding places in the body) and some cases of short-term control of HIV viral load to low levels after ART interruption

[Note from This article was originally published by Positively Aware in Dec., 2017. We have cross-posted it with their permission.]

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This article was provided by Positively Aware. Visit Positively Aware's website to find out more about the publication.

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