HIV Cure via Direct Cytotoxic Depletion of the HIV Reservoir
Combination antiretroviral therapy (cART) for the treatment of HIV infection has been a tremendous medical success, which continues to make strides.1 cART has dramatically reduced morbidity and mortality associated with HIV infection, allowing those that are infected to live for years without progressing to AIDS. cART does not clear the infection, however, and infected people must remain on treatment indefinitely. There have been several instances of HIV cure or remission. The “Berlin patient” received total ablative chemotherapy and radiation treatment for cancer followed by bone marrow transplantation from a CCR5?32/?32 donor. The “London patient” received allogeneic HSCT from a CCR5?32/?32 donor following anti-CD52 antibody treatment to deplete T cells. That both people received CCR5-deficient bone marrow suggests that ablation of this chemokine receptor makes an important contribution to eradication of HIV.
In preliminary work, we therefore tested the impact of a depleting CCR5-CD3 bi-specific antibody (bsAb) on the viral reservoir and rebound following antiretroviral treatment interruption (ATI). Infant rhesus macaques in this study were infected with SIVmac251; treated with cART beginning seven days after infection; depleted two days later, on day 9 of infection; and cART was withdrawn at day 136. While control animals universally rebounded within two weeks of ATI, four of seven treated macaques rebounded only after an extended period of >3 months or did not rebound at all. One macaque has not rebounded more than 2.5 years after ATI, despite depletion of CD8+ T cells in the interim. Our data demonstrate that a cytotoxic approach targeting the cellular reservoir had a significant impact on the viral reservoir and on the timing of rebound when administered early after infection.
Here, we propose to test whether this approach to reservoir depletion is additive or synergistic with administration of neutralizing antibodies (nAb), which have also been shown to delay rebound.2 These experiments take advantage of a number of unique resources: (i) previously SHIV-infected and cART-treated animals from ongoing studies at CNPRC; the CCR5/CD3-bsAb that we developed and is provided at no charge by the NIH Non-human Primate Reagent Resource (NHPRR); and rhesusized 3BNC117 antibody, also provided at no charge by NHPRR.
We hypothesize that anti-CD3/CCR5 bispecific antibodies and neutralizing antibodies each contribute to SHIV reservoir reduction in infected macaques starting cART six weeks after infection, and predict that this reduction will permit delayed rebound after ATI.