Broadly Neutralizing Antibodies and Viral Inducers Decrease Rebound from HIV-1 Latent Reservoirs in Humanized Mice

Abstract

Summary Latent reservoirs of HIV-1 infected cells are refractory to antiretroviral therapies (ART) and remain the major barrier to curing HIV-1. Because latently infected cells are long-lived, immunologically invisible, and may undergo homeostatic proliferation, a “shock and kill” approach has been proposed to eradicate this reservoir by combining ART with inducers of viral transcription. However, all attempts to alter the HIV-1 reservoir in vivo have failed to date. Using humanized mice, we show that broadly neutralizing antibodies (bNAbs) can interfere with establishment of a silent reservoir by Fc-FcR mediated mechanisms. In established infection, bNAbs or bNAbs plus single inducers are ineffective in preventing viral rebound. However, bNAbs plus a combination of inducers that act by independent mechanisms synergize to decrease the reservoir as measured by viral rebound. Thus, combinations of inducers and bNAbs constitute a therapeutic strategy that impacts the establishment and maintenance of the HIV-1 reservoir in humanized mice.

Paired quantitative and qualitative assessment of the replication-competent HIV-1 reservoir and comparison with integrated proviral DNA

“…In particular, Q 2 VOA may be a sensitive assay with which to measure changes in the reservoir that result from immune-targeted interventions (39)(40)(41)(42). Viruses isolated from the replication-competent latent reservoir demonstrated a broad range of neutralization sensitivity to bNAbs, and may also show differing levels of sensitivity to immune-based interventions.…”

Achieving Potent Autologous Neutralizing Antibody Responses against Tier 2 HIV-1 Viruses by Strategic Selection of Envelope Immunogens

“…Neutralizing polyclonal Igs at high concentrations can block infection and have been shown to ameliorate disease pathogenesis in nonhuman primates (NHP) (6,7). Recently, bNmAbs used as therapeutic treatment during chronic infection in macaques and humanized mice led to rapid declines in plasma viremia and temporary viral suppression (8)(9)(10)(11). These studies support the premise that Abs have a greater advantage if present before virus exposure or shortly postinfection before exponential virus replication begins (7) and, if possible, before the establishment of latent viral reservoirs.…”

Adenovirus-Vectored Broadly Neutralizing Antibodies Directed Against gp120 Prevent Human Immunodeficiency Virus Type 1 Acquisition in Humanized Mice

“…bNAb administration was reported to reduce viral rebound from latently infected cells after discontinuation of antiretroviral therapy and inhibited the replication of reservoir-derived virus. 33,34 Interestingly, passive immunotherapy with earlier generation bNAbs also delayed viral rebound in human subjects after HAART interruption. 35 This is significant given that HAART is unable to eradicate latent virus.…”