However, heterologous administration of particularly potent and broad antibodies prior to exposure or to acutely infected individuals has demonstrated therapeutic utility in humanized mice ( 3– 7), macaques ( 8– 13), and humans ( 14– 19). Within infected individuals, viral populations consistently outpace host immune responses in a coevolutionary race to gain functionally favorable mutations contributing to immune evasion or viral neutralization/suppression, respectively. Endogenous antibodies raised within the context of HIV infection have similarly demonstrated antiviral activity ( 1), but typically arise too late in the natural history of infection to prevent disease progression ( 2). While the clinical use of HIV Abs has never been closer, remaining studies to precisely define, model, and understand the complex roles and dynamics of HIV Abs and viral evolution in the context of the human immune system and anatomical compartmentalization will be critical to both optimize their clinical use in combination with existing agents and define further strategies with which to enhance their clinical safety and efficacy.Īntibody (Ab)-based therapies have a robust history of therapeutic utility in the setting of infectious diseases, first serving as serum therapy in the 1800s to treat diphtheria and most recently, as monoclonal antibody (mAb) preparations developed to combat emergent outbreaks such as Ebola. In the setting of chronic infection, bNAbs may better mediate viral remission or “cure” in combination with antiretroviral therapy and/or latency reversing agents, by targeting additional markers of tissue reservoirs or infected cell types, or by serving as targeting moieties in engineered cell therapy. After exposure and/or in the setting of acute infection, bNAb use to prevent/reduce viral reservoir establishment and spread may be enhanced by increasing the potency with which autologous adaptive immune responses are stimulated, clearing acutely infected cells, and preventing cell–cell transmission of virus. Before exposure, bNAbs’ ability to serve as prophylaxis by neutralization may be improved by increasing serum half-life to necessitate less frequent administration, delivering genes for durable in vivo expression, and targeting bNAbs to sites of exposure. Here, we review opportunities to improve the clinical utility of HIV Abs to address these challenges and further accomplish functional targets for anti-HIV Ab therapy at various stages of exposure/infection. Observed and potential limitations of bNAbs from these recent studies include the selection of resistant viral populations, immunogenicity resulting in the development of antidrug (Ab) responses, and the potentially toxic elimination of reservoir cells in regeneration-limited tissues. Preclinical and early human clinical studies of broadly neutralizing antibodies (bNAbs) to prevent and treat HIV infection support the clinical utility and potential of bNAbs for prevention, postexposure prophylaxis, and treatment of acute and chronic infection.
2Thayer School of Engineering, Dartmouth College, Hanover, NH, United States.
1Department of Microbiology and Immunology, Geisel School of Medicine, Lebanon, NH, United States.
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