HIV Reservoirs and Viral Eradication Transformative Science Group

The Cure TSG was created in 2011 to address the formidable challenge of making progress toward a cure of HIV-1 through elimination of HIV-1 reservoirs (i.e., virus eradication) or suppression of reservoirs in the absence of antiretroviral therapy (i.e., functional cure). There are many obstacles to achieving a cure of HIV-1 infection. Some are well-recognized, such as long-lived, latently-infected resting CD4+ memory T-cells that persist despite antiretroviral therapy (ART), but others reservoirs are poorly defined and likely underappreciated, such as latent or productive infection of other cell types, including bone marrow stem cells, tissue macrophages, microglia, and astrocytes. In addition, complex cellular mechanisms influence HIV-1 latency and expression and these mechanisms are likely to vary by HIV-1 integration site, cell type, cell activation state and organ location. Most studies of persistent HIV-1 infection have focused on blood because of its ease of acquisition, but blood is not the major reservoir of HIV-1 and is unlikely to be representative of important reservoirs in the gastrointestinal (GI) tract, bone marrow, lymph nodes, liver/spleen, genital tract, brain, and other anatomic sites. Characterization of persistent HIV-1 reservoirs in these locations, before and after novel interventions, will require aggressive and repeated tissue sampling and sensitive, high-throughput virologic assays to quantify HIV-1 and characterize its state of persistence (i.e., latent, partially or fully expressed). As such, the complexity of HIV-1 persistence requires a broad approach that will involve TSG members and guest scientists from many different disciplines, both within and outside the ACTG, and from academia and industry.

The overall scientific priorities of the Cure TSG are: 1) to fully characterize reservoirs of HIV-1 in patients on suppressive ART; 2) to identify and validate high-throughput, quantitative molecular markers of HIV-1 reservoirs to serve as surrogates for infectious virus recovery from latently-infected resting CD4+ memory T-cells and viral rebound after cessation of ART for use as therapeutic endpoints in interventional studies; 3) to better understand how virus eradication was achieved by allogeneic stem cell transplant from a CCR5 Δ32/Δ32 donor (Hütter et al, NEJM 2009); 4) to better define the relationships between immune activation, immune exhaustion, and viral persistence in blood and tissues; and 5) to identify the most promising, new therapies for evaluation in pilot “proof-of-concept” studies with careful measurements of HIV-1 reservoirs before, during, and after dosing. With regard to the latter objective, candidate therapies should have been evaluated for preclinical “proof-of-concept” efficacy in ex vivo experiments with cells from patients on long-term suppressive. “Proof-of-concept” efficacy in SIV/macaque models of suppressive ART are also desirable.

The scientific priorities of the TSG are likely to evolve rapidly with the emergence of new data in the field.

HIV Reservoirs and Viral Eradication Transformative Science Group Scientific Research Agenda