There is now no doubt that cellular immune responses select for new mutant viruses. The two outstanding issues that remain are whether there is any functional significance associated with escape from these responses and furthermore, whether the selected escape mutants can be propagated in populations. The resolution of these two issues will be important in HIV vaccine design and pathogenesis studies. Recent HIV vaccine strategies have targeted cytotoxic T lymphocyte (CTL) and helper T lymphocyte (HTL) responses, which are associated with control of viral replication. However, immunodeficiency viruses evolve rapidly, spawning new mutant viruses If escape variant viruses are stable after transmission to new hosts, cellular immune responses could select for the accumulation of escape variation in populations, complicating AIDS vaccine development. We will examine the functional significance of escape from cellular immune responses and the propagation of these escape mutants in two cohorts of MHC-defined macaques.
In Specific Aim I we will examine the functional significance and propagation of escape mutants in 3 immunodominant CTL epitopes. We have infected 52 macaques with SIVmac239 and have identified 3 rhesus macaques that control virus replication. Surprisingly all three of these macaques express both of the MHC class I molecules Mamu-A*01 and Mamu-B*17. Together, these two molecules bind peptides that elicit 3 high-frequency CTL responses. These three epitopes usually escape after infection. Infection of Mamu- A*01/Mamu-B*17-positive macaques with """"""""pre-escaped"""""""" viruses should abrogate these immunodominant CTL responses, resulting in loss of ability to control viral replication.
In Specific Aim II we will examine the functional significance and propagation of escape mutants in multiple CTL and HTL epitopes. We have identified 6 sibling pairs of MHC-identical rhesus macaques and we have infected one sibling of each pair with SIVmac239 Infection of the MHC-identical siblings with """"""""pre-escaped"""""""" virus at all relevant CTL and HTL epitopes should cause rapid disease progression. Finally, we hypothesize that escaped virus evolving without any selective pressure on the """"""""pre-escaped"""""""" CTL and HTL epitopes will evolve towards higher fitness viruses.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI052056-05
Application #
7220040
Study Section
Special Emphasis Panel (ZRG1-AARR-1 (01))
Program Officer
Embry, Alan C
Project Start
2003-04-01
Project End
2008-06-30
Budget Start
2007-04-01
Budget End
2008-06-30
Support Year
5
Fiscal Year
2007
Total Cost
$639,000
Indirect Cost
Name
University of Wisconsin Madison
Department
Pathology
Type
Schools of Medicine
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
Abdelaal, Hadia M; Kim, Hyeon O; Wagstaff, Reece et al. (2015) Comparison of Vibratome and Compresstome sectioning of fresh primate lymphoid and genital tissues for in situ MHC-tetramer and immunofluorescence staining. Biol Proced Online 17:2
Maness, Nicholas J; Wilson, Nancy A; Reed, Jason S et al. (2010) Robust, vaccine-induced CD8(+) T lymphocyte response against an out-of-frame epitope. J Immunol 184:67-72
Giraldo-Vela, Juan P; Bean, Alex T; Rudersdorf, Richard et al. (2010) Simian immunodeficiency virus-specific CD4+ T cells from successful vaccinees target the SIV Gag capsid. Immunogenetics 62:701-7
Valentine, Laura E; Loffredo, John T; Bean, Alex T et al. (2009) Infection with ""escaped"" virus variants impairs control of simian immunodeficiency virus SIVmac239 replication in Mamu-B*08-positive macaques. J Virol 83:11514-27
Giraldo-Vela, Juan P; Rudersdorf, Richard; Chung, Chungwon et al. (2008) The major histocompatibility complex class II alleles Mamu-DRB1*1003 and -DRB1*0306 are enriched in a cohort of simian immunodeficiency virus-infected rhesus macaque elite controllers. J Virol 82:859-70
Watkins, David I; Burton, Dennis R; Kallas, Esper G et al. (2008) Nonhuman primate models and the failure of the Merck HIV-1 vaccine in humans. Nat Med 14:617-21
Valentine, Laura E; Watkins, David I (2008) Relevance of studying T cell responses in SIV-infected rhesus macaques. Trends Microbiol 16:605-11
Goulder, Philip J R; Watkins, David I (2008) Impact of MHC class I diversity on immune control of immunodeficiency virus replication. Nat Rev Immunol 8:619-30
Watkins, David I (2008) The hope for an HIV vaccine based on induction of CD8+ T lymphocytes--a review. Mem Inst Oswaldo Cruz 103:119-29
Loffredo, John T; Bean, Alex T; Beal, Dominic R et al. (2008) Patterns of CD8+ immunodominance may influence the ability of Mamu-B*08-positive macaques to naturally control simian immunodeficiency virus SIVmac239 replication. J Virol 82:1723-38

Showing the most recent 10 out of 27 publications