Broadly Neutralizing Antibodies for HIV Eradication

Abstract

Passive transfer of antibodies has long been considered a potential treatment modality for infectious diseases, including HIV. Early efforts to use antibodies to suppress HIV replication, however, were largely unsuccessful, as the antibodies that were studied neutralized only a relatively narrow spectrum of viral strains and were not very potent. Recent advances have led to the discovery of a large portfolio of human monoclonal antibodies that are broadly neutralizing across many HIV-1 subtypes and are also substantially more potent. These antibodies target multiple different epitopes on the HIV envelope, thus allowing for the development of antibody combinations. In this review, we discuss the application of broadly neutralizing antibodies (bNAbs) for HIV treatment and HIV eradication strategies. We highlight bNAbs that target key epitopes, such as the CD4 binding site and the V2/V3-glycan-dependent sites, and we discuss several bNAbs that are currently in the clinical development pipeline.

The “less-is-more” in therapeutic antibodies: Afucosylated anti-cancer antibodies with enhanced antibody-dependent cellular cytotoxicity

“…HIV-1 is well known for its mortality and high rate of viral escape. Broadly neutralizing antibodies against HIV-1 gp120 have demonstrated efficacy in reducing viral load in animal studies and clinical trials 113 . Antibodies against RSV, EBOV and HIV have been glycoengineered to become afucosylated to further improve their anti-viral activity 84 …”

Progress in HIV vaccine development

“…Excellent reviews on this topic have been recently published. [70][71][72] BnAb, antibodies capable of neutralizing diverse circulating strains from multiple clade groups, can be present in 20-30% of individuals with HIV-1 infection. They usually develop 2-4 y after HIV-1 infection, in the presence of continual antigen stimulation from viral replication.…”

HDAC inhibition induces HIV-1 protein and enables immune-based clearance following latency reversal

“…Viral protein production is critically important to investigational immunotherapies (5,17,18,32,33), and thus, it is equally important to assess viral protein production following latency reversal and, subsequently, to determine if the level of viral protein induction on a reactivated cell is sufficient to enable immune-mediated clearance. Classical measures of the HIV reservoir leverage nucleic acid readouts to estimate the burden of disease or viral transcription, but they often overestimate reservoir size due to the presence of defective proviruses.…”

“…As highlighted above, several current immunological strategies are aimed at engaging the immune system to clear HIV + -expressing cells (5,17,18,32,33). We hypothesized that in vivo and ex vivo treatment with latency-reversing agents could result in sufficient viral protein expression to enable redirected CD8 + cell killing and that changes in viral levels could be assessed directly by measuring a reduction in HIV gag p24.…”

“…Worth noting, the induction of viral protein expression is a prerequisite for several investigational immune-mediated "kill" strategies (3)(4)(5). Broadly neutralizing antibodies are already being used in clinical trials, and other strategies involving the use of other forms of antibodies that target viral protein are currently being developed, highlighting the need for approaches that can demonstrate low-level detection of viral antigens and report on the efficacy of such therapeutic approaches (5,17,18).…”