HIV-1 persists in a stable pool of latently infected resting memory CD4+ T cells. Patients on combination antiretroviral therapy (cART) experienced plasma viral rebound after discontinuation of cART. Current approaches to purging the latent reservoirs involve pharmacologic reactivation of HIV-1 transcription by agents that reverse viral latency. The next step is to eliminate infected cells in which HIV-1 gene transcription has been induced by latency reversal agents (LRAs), which may require induction of viral-specific host immune responses. Antibodies targeting HIV-1 envelope protein can mediate killing of infected cells through antibody effector functions such as antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP). Recent progress in broadly reactive neutralizing antibodies (bNAb) brought new hope to purge the HIV-1 latent reservoirs. Antibody passive administration led to delay of virus rebound and reduction of cell-associated viral DNA in both human and humanized mouse studies, which was antibody Fc receptor-dependent. Combination bNAb therapy for the elimination of HIV-1 reservoirs may be a promising strategy and heavily relies on antibody Fc-dependent cytolysis or phagocytosis of HIV-1-infected cells. Studies on how to enhance ADCC and ADCP functions may provide major implications to the design of HIV cure strategies. While ADCC functions mediated by NK cells have been intensively studied, the contribution of macrophages to viral reservoir clearance has been marginalized in the past due to technical difficulties. Our preliminary results demonstrated that blocking anti-phagocytic signal mediated by CD47/SIRP? interaction accelerated phagocytosis of target cells express surface HIV-1 Env with the presence of HIV-1- specific antibodies. We have also established a novel humanized mouse model of HIV-1 latency, which support efficient reconstitution of circulating monocytes and tissue macrophages. Here we propose to use both in vitro and in vivo models to study the role of ADCP in clearing HIV-1 reservoirs and to develop novel therapeutic strategies to enhance macrophage ADCP functions.
HIV-1 persists in a stable pool of latently infected resting memory CD4+ T cells. Thus, virus eradication with combination antiretroviral therapy alone will not be possible. This proposal aims to test CD47/SIRP? signaling blockade strategy to enhance antibody-dependent phagocytosis of the latent viral reservoirs.
