Immune effector mechanisms that confer protection against HIV acquisition remains poorly understood. Recent data from the Phase III RV144 trial of the prime/boost ALVAC+gp120 protein vaccine, which delivered an overall 31.2% reduction in virus acquisition, suggest potential protective effects of anti-gp120 antibody responses. Specifically, of the six primary immunological parameters evaluated in the RV144 case-control study, high IgG responses to the V2 loop of HIV envelope gp120 significantly correlate with protection from HIV infection. However, it is unclear if anti-V2 antibodies have direct anti-viral functions for blocking HIV infection. V2 and other variable loops of gp120 are thought to be undesirable targets for HIV vaccines, due to their highly variable sequences. While a closer scrutiny of V2 sequences has demonstrated a significant level of AA conservation including a conserved LDV/I motif, which is involved in binding ?4?7 integrin, the gut homing receptor expressed on key CD4 T cell targets for mucosal transmission, anti-V2 antibodies have little or no neutralizing activities against many HIV-1 primary isolates when measured under conventional assay conditions and with target cells expressing no ?4?7. We propose herein to utilize non-conventional in vitro and in vivo approaches to investigate the capacity of anti-V2 antibodies to block HIV transmission. We will first measure the ability of anti-V2 human monoclonal antibodies to block virus infection in vitro by varying incubation time, temperature, target CD4 T cells with or without active ?4?7, cell-free and cell-to-cell transmission. Secondly, we will test human anti-V2 monoclonal antibodies in vivo for the ability to reduce HIV acquisition in passive transfer and virus challenge in humanized mice. Finally, we will evaluate the ability of polyclonal anti-V2 antibodies raised by vaccination to mediate virus blocking in vitro and in vivo. Our results will define the potential contributions of anti-V2 antibody response in preventing HIV acquisition, opening a new venue for future design of HIV vaccines.

Public Health Relevance

A prophylactic vaccine is much needed for controlling the HIV/AIDS pandemic, but its development has faced tremendous challenges. The immune mechanisms needed to protect against this virus are not fully understood. This proposal aims to address how antibodies against the V2 loop of HIV envelope gp120 contribute to protection against HIV transmission.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI102740-02
Application #
8515934
Study Section
Special Emphasis Panel (ZAI1-DR-A (M1))
Program Officer
Li, Yen
Project Start
2012-08-01
Project End
2017-03-31
Budget Start
2013-08-01
Budget End
2015-03-31
Support Year
2
Fiscal Year
2013
Total Cost
$524,558
Indirect Cost
$149,429
Name
New York University
Department
Pathology
Type
Schools of Medicine
DUNS #
121911077
City
New York
State
NY
Country
United States
Zip Code
10016
Upadhyay, Chitra; Mayr, Luzia M; Zhang, Jing et al. (2014) Distinct mechanisms regulate exposure of neutralizing epitopes in the V2 and V3 loops of HIV-1 envelope. J Virol 88:12853-65