Optimization of Fc effector activity of anti-HIV antibodies to target HIV reservoir

摘要

ABSTRACT A major barrier to HIV cure is the persistence of HIV-1-infected cells that constitute the HIV reservoir. Although current antiretroviral pharmacologic strategies have no impact on the elimination of the HIV reservoir, anti-HIV- 1 antibodies can specifically target these cells through Fc effector activity, suggesting their potential clinical use for the control of HIV-1 infection. In several pre-clinical evaluation studies, administration of broadly neutralizing anti-HIV-1 antibodies (bNAbs) provided both effective pre-exposure prophylaxis and durable suppression of virus replication in chronically infected models of in vivo HIV-1 infection. More importantly, recent evaluation of the protective activity of these bNAbs in HIV-1-infected patients revealed the capacity of these bNAbs to confer viremic control, as evidenced by the reduction in plasma viremia following bNAb administration. Interactions of the Fc domain of bNAbs with FcγRs expressed on the surface of effector leukocytes contribute to their in vivo antiviral activity by inducing opsonization and clearance of viral particles as well as elimination of HIV-infected cells. Given the importance of Fc effector activity of bNAbs to induce clearance of HIV-infected cells, the proposed studies aim to develop and characterize Fc-optimized bNAbs with improved Fc effector function. The activity of these bNAbs will be evaluated in vitro in well-established cytotoxicity assays, and in vivo in humanized mouse models of HIV-1 infection, as well as in SHIV-infected rhesus monkeys. Fc-optimized bNAbs for enhanced effector activity are expected to specifically target HIV- infected cells, providing sustained disease control and augmented therapeutic potential compared to conventional bNAbs.