Abstract
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. 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. 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. 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. 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. 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. 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.
Highlights
Antibody (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 preparations developed to combat emergent outbreaks such as Ebola
Observed and potential limitations of broadly neutralizing antibodies (bNAbs) noted far in 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 regenerationlimited tissues
Opportunities to improve the utility of HIV Abs address these challenges and build upon each other as the timing/ stage of infection progresses
Summary
Antibody (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. Horwitz et al demonstrated the capacity of nnAbs to modulate the course of HIV infection in humanized mice via Fc-mediated effector functions in two nnAb cases: [1] using anti-HA Abs in humanized mice challenged with a newly developed recombinant indicator HIV strain containing an HA-tag-, (HIVivoHA) or HIVivoHA-infected cells and [2] using a patient-derived nnAb 246D [45] targeting a linear gp epitope in humanized mice challenged with HIV-1YU2 virus or HIV-1YU2-infected cells [44] In both cases, passive transfer of nnAbs mediated modest protection from viral challenge, reduced viral load in established infection, cleared virus-infected cells, and exerted selective pressure for escape mutations that deleted or concealed the targeted epitope, all in an Fc-dependent manner that was diminished or absent in passive transfer of the same nnAbs modified with mutations that abrogated binding to activating Fc-receptors [44]. Engineering strategies to combat the development of viral resistance reviewed previously [28] include [1] structure-based modifications to increase the breadth, potency (both neutralization and effector function), and half-life of individual bNAbs, [2] combinations of
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