Towards HIV-1 remission: potential roles for broadly neutralizing antibodies

Abstract

Current antiretroviral drug therapies do not cure HIV-1 because they do not eliminate a pool of long-lived cells harboring immunologically silent but replication-competent proviruses - termed the latent reservoir. Eliminating this reservoir and stimulating the immune response to control infection in the absence of therapy remain important but unsolved goals of HIV-1 cure research. Recently discovered broadly neutralizing antibodies (bNAbs) exhibit remarkable breadth and potency in their ability to neutralize HIV-1 in vitro, and recent studies have demonstrated new therapeutic applications for passively administered bNAbs in vivo. This Review discusses the roles bNAbs might play in HIV-1 treatment regimens, including prevention, therapy, and cure.

Figure 2. bNAbs in prevention and cure regimens.

(A) The potency and long in vivo half-lives of bNAbs may enable biannual passive administrations to protect against infection in healthy individuals at high risk of HIV-1 exposure. In the schematic shown, uninfected individuals can receive intravenous infusions of long-acting monoclonal bNAbs for prophylactic protection against HIV-1 acquisition. The plot shows the estimated peak plasma bNAb levels following infusion and extrapolates the decay based on bNAb pharmacokinetics measured in human pilot studies (21). The predicted protective plasma concentration is estimated based on NHP studies (14, 19). (B) Schematic of the natural course of HIV-1 viremia (black) and latent reservoir stability (red) with the current standard of care, highly active ART (HAART) (solid lines). The goal of the shock and kill intervention is to clear the latent reservoir and prevent viral rebound following therapy discontinuation (dotted line). (C) The shock and kill regimen indicated in B is shown schematically.

Figure 1. Potential immune effector functions of bNAbs.

(A) bNAbs can prevent infection by directly neutralizing cell-free virions, which prevents infection and accelerates viremia decline through antibody-mediated viral clearance. (B) bNAbs can potentially bind to infected cells and mediate antiviral activity through Fc-FcR interactions that engage NK cells for ADCC or macrophages for phagocytosis and cellular destruction. (C) Immune complexes formed by bNAbs bound to viral antigen can be taken up by dendritic cells and may stimulate host adaptive immune responses, including increased antiviral cytotoxic T cell activity and B cell maturation.