Post-treatment control of HIV replication and prospects for a functional cure

In a review article in the open-access journal Retrovirology, Guido Vanham and Ellen Van Gulck provide a detailed accounting of the multitude of immune-based therapy (IBT) studies that have been conducted over the years (both in people with HIV and the SIV/macaque model). [1]

The authors were prompted by the recent resurgence in interest in attempting to induce immune control of HIV in the absence of ongoing antiretroviral therapy (ART), a goal that is now described as achieving a “functional cure.” While the term is new, the goal itself is not: in the late 1990s, it was described more circumspectly as “remission.” Unfortunately, the best results to date from IBT studies involve small and transient diminutions in viral load associated with receipt of some therapeutic vaccine candidates. Despite the disappointments, attempts to achieve more robust control of HIV continue; Vanham and Van Gulck are pursuing a therapeutic vaccine approach involving delivery of HIV antigens to dendritic cells using messenger RNA (mRNA).

The review also highlights the potential value of studying—and trying to learn from—rare individuals who maintain undetectable viral loads after ART interruption, a group now dubbed “post-treatment controllers” or “secondary controllers.” As Vanham and Van Gulck note, a number of cases of post-treatment control have been reported. Most involve individuals treated during acute HIV infection, such as the members of the VISCONTI cohort in France that were described recently at the AIDS 2012 conference and the oft-forgotten original “Berlin Patient” (who featured as a case report in the New England Journal of Medicine in May of 1999). The latter individual was treated intermittently with ART during acute HIV infection and has maintained viral load below 50 copies for many years after stopping treatment entirely (although this case has since been eclipsed by the second Berlin Patient, Timothy Brown, a new book is in the works by author and researcher Nathalia Holt that promises to tell both stories).

Although far less common, there have also been occasional anecdotes regarding possible post-treatment control in individuals with chronic HIV infection, but there is little in the way of published documentation. Vanham and Van Gulck have themselves recently reported on a total of four cases that have been identified in the HIV cohort of the Institute of Tropical Medicine of Antwerp. [2, 3]

In exploratory analyses, these individuals showed low levels of intracellular viral RNA, lower viral fitness and high proliferative T cell responses towards Gag and Pol.

Given the potential importance of this type of research to the broader effort to cure HIV, there appears to be a need for a more coordinated global effort to identify and study possible cases of post-treatment control in chronic infection. The International HIV Controllers Study, led by Bruce Walker from the Ragon Institute, is primarily focused on elite controllers (individuals who control viral load to undetectable levels without requiring ART) but, according to the website, also accepts samples from individuals who have maintained viral load <2,000 copies/mL for at least one year after interrupting ART. The researchers have not yet reported whether any such individuals have joined the study.