The enormous sequence diversity of HIV-1 remains a major obstacle to the development of an effective prophylactic vaccine. Human APOBEC3G and 3F proteins are potent inhibitors of Vif-deficient HIV-1. HIV-1 Vif counteracts APOBEC 3G and 3F by inducing their ubiquitination and subsequent degradation by the proteasome. Increased proteasomal processing of APOBEC could lead to presentation of APOBEC-derived peptide epitopes on the surface of HIV-1-infected cells. Because higher levels of APOBEC antigens might be present on the surface of HIV-infected cells, APOBEC epitopes could, therefore, serve as a surrogate marker of HIV-1 infection. Targeting CD8+ T cells to HIV-1-infected cells based on increased APOBEC epitope expression could circumvent the obstacle of HIV-1 sequence diversity. We have generated preliminary data that shows HIV-1 infected elite controllers mount strong T cell responses to epitopes derived from the APOBEC3G sequence. We have also discovered that elite-controlling SIV-infected macaques mount APOBEC specific T cell responses. Based upon these initial observations, we hypothesize that lentiviral infection generates APOBEC-specific CD8+ T cells, which are capable of recognizing and eliminating virally infected cells. Further, a vaccine immunogen using APOBEC sequences could generate APOBEC specific T cells, which could recognize and kill a cell infected with any variant of HIV-1. This novel approach targets infected cells based on their presentation of APOBEC derived peptides, not HIV-1 peptides. The central goal of our R21 is to understand the contribution of APOBEC epitope-specific responses to the total cellular immune response directed at HIV-1 and SIV. These studies will dictate whether we proceed to the R33 stage of the plan. We have two goals for the R33. We want to know whether APOBEC-specific CD8+ T cells arising during retroviral infections can recognize and eliminate virally infected cells. Additionally, we want to determine whether vaccine-induced APOBEC-specific cellular immune responses might provide control of viral replication after SIV infection. We hypothesize that T cells specific for Vif-sensitive APOBEC proteins will suppress viral replication both in vitro and in vivo. This project would provide proof-of-principle data that APOBEC-specific T cells specifically suppress replication of SIV/HIV-1. These studies are, therefore, the first steps towards a novel vaccine approach, which circumvents the obstacle of HIV-1 sequence diversity by targeting a surrogate marker of HIV infection.

Public Health Relevance

The goal of this R21/33 proposal is to determine which APOBEC epitopes are recognized in HIV-1 infected subjects and in SIV infected macaques. An APOBEC vaccine will be tested in a macaque challenge protection model. This information will be used to design a novel "no HIV-1" vaccine against HIV-1/AIDS.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AI093179-02
Application #
8262370
Study Section
HIV/AIDS Vaccines Study Section (VACC)
Program Officer
Warren, Jon T
Project Start
2011-05-04
Project End
2014-04-30
Budget Start
2012-05-01
Budget End
2014-04-30
Support Year
2
Fiscal Year
2012
Total Cost
$236,177
Indirect Cost
$39,653
Name
University of California San Francisco
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Raposo, Rui Andre Saraiva; Abdel-Mohsen, Mohamed; Holditch, Sara J et al. (2013) Increased expression of intrinsic antiviral genes in HLA-B*57-positive individuals. J Leukoc Biol 94:1051-9
Champiat, Stephane; Garrison, Keith E; Raposo, Rui Andre Saraiva et al. (2013) T cells target APOBEC3 proteins in human immunodeficiency virus type 1-infected humans and simian immunodeficiency virus-infected Indian rhesus macaques. J Virol 87:6073-80