Approximately 2,500,000 people were infected with human immunodeficiency virus (HIV) in 2007, underscoring the urgency of developing an effective prophylactic vaccine. The first vaccine designed to elicit CD8+ T cell responses and advance into late-stage clinical trials failed. There is thus considerable debate whether CD8+ T cells alone can protect from acquisition of HIV or reduce the severity of HIV infection. We hypothesize that CD8+ T cells directed against a single viral target, or epitope, can blunt early viral replication if present in sufficient numbers at the time of infection. In this proposal we will test this hypothesis by identifying CD8+ T cells that combat SIV and characterizing their ability to suppress viral replication in vitro. We have identified a population of macaques susceptible to simian immunodeficiency virus (SIV), the genetic cousin of HIV that tolerates infusions of CD8+ T cells derived from other macaques. If we successfully identify a suppressive CD8+ T cell specificity in the first two years of this proposal, then we will transfer massive numbers of these cells into SIV-naive macaques immediately before SIV challenge. If successful, these experiments will prove that CD8+ T cells alone can protect against SIV and support continued development of CD8+ T cell vaccines.

Public Health Relevance

There is no definitive evidence that CD8+ T cells alone can reduce the severity of SIV infection, a primary objective of current vaccines. In this proposal we will identify a potent CD8+ T cell response that suppresses viral replication in vitro, expand these cells to massive numbers, and in- fuse the expanded T cells into macaques immediately before SIV challenge. For the first time we will be able to determine whether adoptively transferred CD8+ T cells alone can control SIV.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants Phase II (R33)
Project #
5R33AI082880-05
Application #
8469385
Study Section
AIDS Immunology and Pathogenesis Study Section (AIP)
Program Officer
Warren, Jon T
Project Start
2009-04-01
Project End
2014-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
5
Fiscal Year
2013
Total Cost
$373,106
Indirect Cost
$123,537
Name
University of Wisconsin Madison
Department
Pathology
Type
Schools of Medicine
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
Mohns, Mariel S; Greene, Justin M; Cain, Brian T et al. (2015) Expansion of Simian Immunodeficiency Virus (SIV)-Specific CD8 T Cell Lines from SIV-Naive Mauritian Cynomolgus Macaques for Adoptive Transfer. J Virol 89:9748-57
Greene, Justin M; Weiler, Andrea M; Reynolds, Matthew R et al. (2014) Rapid, repeated, low-dose challenges with SIVmac239 infect animals in a condensed challenge window. Retrovirology 11:66
Cain, Brian T; Pham, Ngoc H; Budde, Melisa L et al. (2013) T cell response specificity and magnitude against SIVmac239 are not concordant in major histocompatibility complex-matched animals. Retrovirology 10:116
Greene, Justin M; Lhost, Jennifer J; Hines, Paul J et al. (2013) Adoptive transfer of lymphocytes isolated from simian immunodeficiency virus SIVmac239Δnef-vaccinated macaques does not affect acute-phase viral loads but may reduce chronic-phase viral loads in major histocompatibility complex-matched recipients. J Virol 87:7382-92
Greene, Justin M; Chin, Emily N; Budde, Melisa L et al. (2012) Ex vivo SIV-specific CD8 T cell responses in heterozygous animals are primarily directed against peptides presented by a single MHC haplotype. PLoS One 7:e43690
Hughes, Austin L; Becker, Ericka A; Lauck, Michael et al. (2012) SIV genome-wide pyrosequencing provides a comprehensive and unbiased view of variation within and outside CD8 T lymphocyte epitopes. PLoS One 7:e47818
Burwitz, Benjamin J; Sacha, Jonah B; Reed, Jason S et al. (2011) Pyrosequencing reveals restricted patterns of CD8+ T cell escape-associated compensatory mutations in simian immunodeficiency virus. J Virol 85:13088-96