Exploring the Potential of Monoclonal Antibody Therapeutics for HIV-1 Eradication

Abstract

The HIV field has seen an increased interest in novel cure strategies. In particular, new latency reversal agents are in development to reverse latency to flush the virus out of its hiding place. Combining these efforts with immunotherapeutic approaches may not only drive the virus out of latency, but allow for the rapid elimination of these infected cells in a ''shock and kill'' approach. Beyond cell-based approaches, growing interest lies in the potential use of functionally enhanced ''killer'' monoclonal therapeutics to purge the reservoir. Here we discuss prospects for a monoclonal therapeutic-based ''shock and kill'' strategy that may lead to the permanent elimination of replication-competent virus, making a functional cure a reality for all patients afflicted with HIV worldwide.

Natural killer cells in HIV-1 infection and therapy

“…Furthermore, those few patients able to produce bNAbs do not really benefit from their anti-viral activities because of low Ab titers in the plasma or the high variability and complexity of HIV-1 strains. Recently, a modern technology based on single cell cloning has made it possible to isolate, expand and characterize a 2 nd generation of bNAbs [133–136]. These bNAbs show a wide range of affinities towards different sites on the HIV-1 envelope and are now being manufactured and tested in several clinical trials.…”

“…In particular, we can now measure the ability of each of these monoclonal Abs (mAbs) obtained from millions of HIV-1-specific B cells purified from HIV-1 infected patients to inhibit viral replication. In regard to NK cell biology, bNAbs can be used to promote the killing of HIV-1 infected cells via ADCC [136–138] as the ability of these bNAbs to prevent HIV-1 infection has been extensively reported [139, 140]. Whether therapeutic approaches using ADCC will work in HIV-1 infection is still being debated and requires additional investigation and clinical trials.…”

Engineering broadly neutralizing antibodies for HIV prevention and therapy

“…The only example of complete viral eradication thus far has been the Berlin patient, a formerly HIV-infected individual with acute myelogenous leukemia who underwent bone marrow/stem cell transplantation from a donor lacking expression of viral coreceptor CCR5 [132]. Less drastic approaches that preserve autologous immunity may instead implement mAbs to target viral reservoirs: 1) “kick and kill” strategies employ a combination of viral inducers to activate viral reservoirs and bNAbs to eliminate newly activated cells [131, 133], and 2) gene delivery strategies induce long-lasting expression and production of mAbs to continuously protect against newly activated reservoir cells and virion release [134]. For these strategies, understanding the dynamics of viral Env epitope expression on the surface of latently infected cells will be critical: current studies suggest that early in infection prior to virion release, cells will more likely express trimeric Env proteins [135] whereas later in the virus infection cycle, cells will more likely express monomeric gp140 and gp41 stumps as the dissociated remnants of viral Env [133].…”

“…Thus, neutralizing Abs may be best suited for acutely infected and recently reactivated cells and non-neutralizing Abs recognizing gp41 epitopes for latent, chronically infected cells. Furthermore, viral reservoirs may exist in multiple tissues [136], and concerns regarding compartmental differences in innate immune cell populations and access to immunologically privileged sites [133] may require the addition of nonnative functions to bNAbs to fully eradicate reservoirs.…”

Short Communication: Exploring Antibody Potential as Prophylactic/Therapeutic Strategies for Prevention of Early Mucosal HIV-1 Infection

“…These multiple antibody activities should be taken into consideration for the design of vaccine strategies to prevent early virus dissemination at mucosal frontlines, to contribute to protection against sexual transmission of HIV-1, and to create the next generation of antibody-based therapeutic agents. [35][36][37] …”