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 (in both people with HIV and the SIV/macaque model). 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 1999). The latter individual was treated intermittently with ART during acute HIV infection and has maintained viral load below 50 copies/mL 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 Antwerp (see abstracts and links below). In exploratory analyses, these individuals showed low levels of intracellular viral RNA, lower viral fitness, and high proliferative T-cell responses to Gag and Pol peptides.
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 of MGH, MIT and Harvard, is focused primarily 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 below 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.
Retrovirology. 2012 Sep 7;9(1):72. [Epub ahead of print]
Vanham G, Van Gulck E.
Immunotherapy aims to assist the natural immune system in achieving control over viral infection. Various immunotherapy formats have been evaluated in either therapy-naive or therapy-experienced HIV-infected patients over the last 20 years. These formats included non-antigen specific strategies such as cytokines that stimulate immunity or suppress the viral replication, as well as antibodies that block negative regulatory pathways. A number of HIV-specific therapeutic vaccinations have also been proposed, using in vivo injection of inactivated virus, plasmid DNA encoding HIV antigens, or recombinant viral vectors containing HIV genes. A specific format of therapeutic vaccines consists of ex vivo loading of autologous dendritic cells with one of the above mentioned antigenic formats or mRNA encoding HIV antigens.
This review provides an extensive overview of the background and rationale of these different therapeutic attempts and discusses the results of trials in the SIV macaque model and in patients. To date success has been limited, which could be explained by insufficient quality or strength of the induced immune responses, incomplete coverage of HIV variability and/or inappropriate immune activation, with ensuing increased susceptibility of target cells.
Future attempts at therapeutic vaccination should ideally be performed under the protection of highly active antiretroviral drugs in patients with a recovered immune system. Risks for immune escape should be limited by a better coverage of the HIV variability, using either conserved or mosaic sequences. Appropriate molecular adjuvants should be included to enhance the quality and strength of the responses, without inducing inappropriate immune activation. Finally, to achieve a long-lasting effect on viral control (i.e. a “functional cure”) it is likely that these immune interventions should be combined with anti-latency drugs and/or gene therapy.
AIDS Res Ther. 2011 Feb 11;8(1):6.
Van Gulck E, Heyndrickx L, Bracke L, Coppens S, Florence E, Buvé A, Lewi P, Vanham G.
Virology Unit, Department of Microbiology, Institute of Tropical Medicine Antwerp (ITMA), Antwerp, Belgium.
We describe two patients who did not experience a viral rebound after cessation of HAART which was initiated for progressive disease. CD4 T-cell count remained stable in one patient and progressively declined in the other, despite apparent viral control. We failed to identify any immune activation or genetic markers that could offer an explanation for this unusual "secondary controller" status. But their viruses are clearly less fit compared to viruses from rebounders.
PLoS One. 2012;7(5):e37792. Epub 2012 May 30.
Van Gulck E, Bracke L, Heyndrickx L, Coppens S, Atkinson D, Merlin C, Pasternak A, Florence E, Vanham G.
Virology Unit, Microbiology Group, Department of Biomedical Sciences, ITMA, Antwerp, Belgium.
Upon interruption of antiretroviral therapy, HIV-infected patients usually show viral-load rebound to pretreatment levels. Four patients, hereafter referred to as secondary controllers (SC), were identified who initiated therapy during chronic infection and, after stopping treatment, could control virus replication at undetectable levels for more than six months. In the present study we set out to unravel possible viral and immune parameters or mechanisms of this phenomenon by comparing secondary controllers with elite controllers and non-controllers, including patients under HAART. As candidate correlates of protection, virus growth kinetics, and levels of intracellular viral markers, several aspects of HIV-specific CD4+ and CD8+ T-cell function and HIV neutralizing antibodies were investigated. As expected, all intracellular viral markers were lower in aviremic as compared to viremic subjects, but in addition both elite and secondary controllers had lower levels of viral unspliced RNA in peripheral blood mononuclear cells as compared to patients on HAART. Ex vivo cultivation of the virus from CD4+ T cells of SC consistently failed in one patient and showed delayed kinetics in the three others. Formal in vitro replication studies of these three viruses showed low-to-absent growth in two cases and a virus with normal fitness in the third case. T-cell responses to HIV peptides, evaluated in IFN-γ ELISPOT, revealed no significant differences in breadth, magnitude, or avidity between SC and all other patient groups. Neither was there a difference in polyfunctionality of CD4+ or CD8+ T cells as evaluated with intracellular cytokine staining. However, secondary and elite controllers showed higher proliferative responses to Gag and Pol peptides. SC also showed the highest level of autologous neutralizing antibodies. These data suggest that higher T-cell proliferative responses and lower replication kinetics might be instrumental in secondary viral control in the absence of treatment.