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The Odyssey of Therapeutic Vaccines for HIV

Spring 2012

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New Dawn Fades

Once again, however, scientific advances served to undermine the rationale behind these studies. Specifically, the idea that ART could be safely interrupted as long as CD4 T-cell counts were maintained was shown to be erroneous by the sobering results of the Strategic Management of Antiretroviral Therapy (SMART) trial. SMART had the specific goal of assessing whether intermittent, CD4-guided ART could be as effective as continuous ART, but the trial had to be stopped early because individuals in the intermittent arm experienced a doubling in risk of illness and death. Analyses demonstrated that these events were associated with inflammation resulting from unsuppressed viral load, prompting additional investigations into the link between inflammatory markers, uncontrolled HIV replication, and health outcomes. This type of research has now been conducted in multiple cohorts in diverse global settings, and it has reinforced the conclusions from SMART: inflammatory markers are linked to viral load and show significant associations with morbidity and mortality; measures of cumulative exposure to viral load prior to ART initiation have also been shown to be associated with risk of morbidity and mortality after starting ART.

The window of opportunity for therapeutic HIV vaccines therefore narrowed once more, as it was clear that slight diminutions in viral load would be insufficient to offer benefit. Some therapeutic vaccine developers have unfortunately been slow to acknowledge this shift in the research landscape; for example, Bionor Pharma conducted a trial attempting to show that their candidate Vacc-4x could delay the need to restart ART after a six-month interruption, but the SMART results had already shown that this type of trial design was risky and outdated. The company has since conducted an analysis (not planned in the original trial design) looking at viral loads among study participants, claiming that vaccination was associated with a difference off therapy of around 1 log (22,300 vs. 61,900 copies). But it is known that a viral load of 22,300 copies likely poses long-term health risks and is not low enough to retard disease progression; furthermore, prior studies strongly suggest that the duration of such an effect is likely to be transient.

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Third Time's a Charm?

Although it will present a problem for the commercial development plans of some companies, it is clear that the bar for therapeutic vaccines has been raised. The key question has become, Is it possible for a therapeutic vaccine to generate HIV-specific immune responses capable of completely containing viral replication when ART is interrupted? This may seem like a dauntingly high hurdle given results to date, but it dovetails with emerging research that has recently resurrected therapeutic HIV vaccines for the third time. This research is in pursuit of the ultimate goal: a cure for HIV infection.

Presentations at the 2012 Conference on Retroviruses and Opportunistic Infections (CROI) conspired to highlight this new rationale for therapeutic vaccines. A major focus of cure research is identifying and eliminating the reservoirs of HIV-infected cells that persist in the body despite ART (latently infected cells). For several years, scientists have been evaluating compounds that can awaken dormant HIV, but it has been unclear if this strategy will be sufficient to ensure that infected cells are killed. At CROI, Liang Shan from Robert Siliciano's laboratory at Johns Hopkins presented compelling evidence that simply rousing HIV is not sufficient; CD8 T cells are needed to deliver the coup de grace and kill the infected cells. Shan showed that in most people with chronic HIV infection, HIV-specific CD8 T cells were not functional enough to accomplish the task, but required stimulation with HIV antigens prior to being mixed with infected CD4 T cells -- essentially a laboratory dish equivalent of therapeutic vaccination. The study was published in the journal Immunity on March 8, 2012 and the authors are unequivocal about the implications, writing: "Our study strongly suggests that boosting CTL [CD8 T cell] responses through vaccination prior to virus reactivation may be essential for eradication of HIV-1 infection."

There is another complementary reason for studying therapeutic HIV vaccines in the context of cure research. Studies have shown that a portion of the latently infected CD4 T cells that persist in the face of ART are specific for HIV antigens, suggesting that stimulation with a therapeutic vaccine might also reactivate the virus in these cells. A study of therapeutic vaccines in children with HIV has offered some support for this idea, as it uncovered evidence of a transient decline in the numbers of latently infected CD4 T cells during immunizations. An ongoing trial in adults -- named Eramune 02 -- intends to explore this possibility in greater detail.


The Road Ahead

Despite the history of controversy and uncertainty, the ascendency of cure research has provided a strong and scientifically sound rationale for further studies of therapeutic HIV vaccines. The goals are now far clearer: to achieve containment of HIV replication and prevention of disease in the absence of ongoing treatment (now described as a "functional cure"), or complete elimination of the virus (a "sterilizing cure"). The first evaluations of therapeutic vaccines in this new context are getting underway, but significant questions remain to be answered, particularly in terms of delineating the ideal immune responses that should be induced and evaluating whether they can be effective and sustained. Researchers also need to explore which other antilatency strategies should be combined with therapeutic vaccines, and whether different vaccine candidates should themselves be combined to achieve the best results. There might even be a role for therapeutic vaccines in the context of gene-therapy approaches, as a means to boost numbers of gene-modified, HIV-specific CD4 T cells. While there is clearly some road ahead, there is at least a sense, finally, that therapeutic HIV vaccines are headed in the right direction.

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This article was provided by Treatment Action Group. It is a part of the publication TAGline.
 
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