Of Mice, Macaques, and Men: Broadly Neutralizing Antibody Immunotherapy for HIV-1

Abstract

Neutralizing antibodies targeting the HIV-1 envelope protein have been a major focus for HIV therapy. Early studies with anti-HIV-1 neutralizing monoclonal antibodies (mAbs) administered to infected individuals showed some promise as they resulted in transient reductions in plasma viremia in some recipients. However, resistant viral variants rapidly emerged. A major development during the past 6 to 7 years has been the isolation and characterization of highly potent and broadly neutralizing mAbs (bNAbs) from infected individuals known as “elite neutralizers”. These “next generation” bNAbs have been tested in animal model systems and shown to effectively control virus replication, particularly following combination immunotherapy. The success of these preclinical animal studies has led to human clinical trials using an individual bNAb for therapy. This review examines recent findings from animal models and human clinical trials and discusses the future use of bNAbs for HIV-1 treatment.

Broadly resistant HIV-1 against CD4-binding site neutralizing antibodies

“…Although their prevalence remains uncertain, their existence implies that they can successfully compete with other wildtype clones and be transmitted to uninfected individuals. In this regard, combination therapy with bnAbs targeting more than one vulnerable site on the envelope would be a more efficacious approach than monotherapy [1,9,10,61]. Similar lessons have already been learned in the development of antiretroviral drugs, where combination therapyis required for protection against resistance and to achieve sustained suppression of viral replication [62,63].Ultimately, treatment strategies that integrate antiretroviral drugs and bnAbs are more likely to maximize the potential of both classes.…”

“…Recent scientific advances have identified a growing number of broadly neutralizing antibodies (bnAbs) against human immunodeficiency virus type I (HIV-1), providing promising candidates for HIV-1 prevention and treatment [1][2][3][4][5]. Compared with bnAbs isolated in earlier studies, these bnAbs demonstrated broader and more potent activity against global HIV-1 panels and displayed impressive safety and efficacy profiles for therapeutic applications in a number of animal models and human clinical trials [1,[6][7][8][9][10][11]. These results also offer the opportunity to tailor these antibodies and maximize their prevention and treatment potential.…”

“…Resistance is largely attributed to mutated residues within the epitopes or steric hindrance imposed by the bulky side-chain or glycan shield of the mutated residues, and is largely correlated with reduced binding avidity of the antibody to the quaternary trimeric envelope protein expressed on the PLOS Pathogens | https://doi.surface of the transfected cells. Treatment strategies based on the CD4bs bnAbs therefore must overcome such resistance to achieve optimal clinical outcomes.Recent scientific advances have identified a growing number of broadly neutralizing antibodies (bnAbs) against human immunodeficiency virus type I (HIV-1), providing promising candidates for HIV-1 prevention and treatment [1][2][3][4][5]. Compared with bnAbs isolated in earlier studies, these bnAbs demonstrated broader and more potent activity against global HIV-1 panels and displayed impressive safety and efficacy profiles for therapeutic applications in a number of animal models and human clinical trials [1,[6][7][8][9][10][11].…”

Early exposure to broadly neutralizing antibodies may trigger a dynamical switch from progressive disease to lasting control of SHIV infection

“…The recent success of passive immunization with bNAbs in eliciting functional cure of HIV-1 infection can potentially revolutionize HIV-1 care (11,15,(29)(30)(31)(32). In this study, using mathematical modelling and analysis of in vivo data, we elucidated the pleiotropic effects of bNAbs responsible for inducing lasting viremic control following a short, early passive immunization course, and suggest strategies to use bNAbs for achieving functional cure in acute as well as chronic HIV-1 infection.…”

“…We constructed a mathematical model that considered the within-host dynamics of populations of target CD4 + T cells, productively and latently infected cells, free virions, antigen presenting cells (APCs), effector CTLs, and administered bNAbs ( Figure 1). Based on the known effects of bNAbs (12)(13)(14)(15)(16), we let bNAbs 1) enhance the clearance of free virions and 2) increase antigen uptake by APCs, both in a dose-dependent manner. CTLs were stimulated by APCs and could become exhausted by sustained antigenic stimulation.…”