HIV-1 curing is one of the top priorities for AIDS interventions. The recent isolation of many potent and broadly neutralizing antibodies (bNAbs) against HIV envelope glycoproteins (Env) offers great opportunities for exploring their potential as passively administered agents to treat established infections. The protective efficacy of bNAbs is primarily mediated by their extremely high capacity to inhibit virus infectivity and cell-cell virus spread (neutralization), as well as their ability to facilitate the killing of infected cells that express the cognate Env antigens on the cell surface through antibody-dependent cell-mediated cytotoxicity (ADCC) and to form antibody-virus immune complexes leading to viral clearance. Unfortunately, the outcome of the most recent clinical trials with bNAb as therapeutic agent demonstrated that the antigenically diverse and persistently evolving HIV-1 Env can rapidly acquire mutations that evade bNAbs administered as single agents. While simultaneously targeting distinct cognate epitopes by physically combining multiple bNAbs can result in virtually 100% virus coverage, the use of a ?single? agent consisting of these multiple functional binding moieties is preferred for both regulatory and manufacturing purposes, in addition to the potential of augmented potency resulting from the increased avidity through bi- or multi- valence Env binding and possible synergistic effect between bNAbs. In addition, a recent study demonstrated in non-human primate model that in conjunction with bNAb therapy, CD8+ cytolytic T cells can effectively control virus rebound after the cessation of anti-viral therapy. Therefore, it is timely to engineer therapeutic agent that can effectively bridge the infected cells and the cytolytic T cells to mediate the killing of infected cells. Furthermore, previous studies established that modifications in the antibody Fc regions that increase their abilities to mediate cytotoxicity and extend their half-lives. However, such modifications have not been well applied to bNAbs for HIV treatment. This study aims to fill in the tremendous knowledge gap in the field by investigations with the following specific aims: 1) To generate HIV Env bNAbs with multiple epitope binding moieties possessing improved potency, avidity and breadth by structure-based design; 2) To engineer bNAbs that will efficiently recruit CD8+ cytolytic T cells to latently infected CD4+ T cells and kill the infected cells; and 3) To improve Fc region effector function (ADCC). The overall outcome of this study will advance our basic understanding of protective immunity against persistent virus infection and contribute to the development of safe and effective intervention strategies for HIV remission and eradication.

Public Health Relevance

This study proposes to engineer antibodies consisting of multi-functional binding moieties targeting the HIV-1 envelope glycoproteins (Env) with anti-viral potency and breadth superior to conventional Env-specific neutralizing antibodies, to augment the antibody capacity in mediating cytotoxic killing of HIV infected cells for eliminating HIV-infected cells in vivo. The outcomes of this study will contribute to the development and delivery of broadly effective HIV-1 immunotherapeutic agents.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI136756-03
Application #
10054157
Study Section
AIDS Immunology and Pathogenesis Study Section (AIP)
Program Officer
Smiley, Stephen T
Project Start
2018-11-09
Project End
2023-10-31
Budget Start
2020-11-01
Budget End
2021-10-31
Support Year
3
Fiscal Year
2021
Total Cost
Indirect Cost
Name
University of Maryland Baltimore
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
188435911
City
Baltimore
State
MD
Country
United States
Zip Code
21201