Our laboratory has recently made an interesting series of observations that may have important implications for HIV vaccine design. Surprisingly, we have discovered that CD8+ T cells recognized Gag-derived epitopes by two hours post-infection: before integration, viral protein synthesis, and Nef-mediated MHC-I down-regulation. Additionally, CD8+ T cells recognized Tat and Nef-derived epitopes as early as 12-13 hrs post-infection. In contrast, epitopes derived from Env did not appear on the cell surface until eighteen hours post-infection, close to the onset of progeny virus production. We have also shown that Nef down-regulates MHC class I at 12-13 hrs post-infection. Thus, our preliminary data suggest that a CD8+ T cell-based HIV vaccine should stimulate responses against Gag, Tat and Nef. Conversely, Env-specific CD8+ T cells may not be effective because epitopes derived from this highly variable glycoprotein are expressed too late in the viral replication cycle well after Nef has down-regulated MHC-I. We hypothesize that vaccine induced CD8+ T cell responses directed against epitopes that are present on the cell surface soon after infection and prior to Nef-mediated MHC-I down regulation will control replication of the highly pathogenic SIVmac239 isolate. We will test this hypothesis in two related specific aims.
Our Specific Aims (SA) are, therefore, to: I. Determine the exact timing after infection of when CD8+ T cell epitopes from each of the viral proteins are present on the surface of infected cells. II. We will use the information generated in SAI to design a DNA, Ad5 vaccine regimen. We will deliver proteins that encode epitopes present on the cell surface soon after infection as both whole ORFs and as minigenes. Delivery of these constructs as minigenes should broaden the immune response and facilitate control of SIVmac239 replication. We are very excited about our new findings in the rhesus macaque implicating Gag-specific CDS positive T cell responses in control of viral replication. While entire ORFs have been used in human vaccine modalities, dividing these larger ORFs into smaller pieces to avoid immunodominance has never been rigorously tested. The novelty of this proposal, therefore, lies in the intriguing, as yet unexplored possibility that subdominant epitopes in Gag and other viral proteins encoding epitopes expressed on the cell surface soon after infection could represent novel immunogens in our vaccine strategies for HIV. We feel that this proposal represents a highly significant and innovative approach to address the HIV epidemic.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI076114-05
Application #
8092568
Study Section
AIDS Immunology and Pathogenesis Study Section (AIP)
Program Officer
Warren, Jon T
Project Start
2007-07-15
Project End
2013-06-30
Budget Start
2011-07-01
Budget End
2013-06-30
Support Year
5
Fiscal Year
2011
Total Cost
$530,913
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
Martins, Mauricio A; Wilson, Nancy A; Piaskowski, Shari M et al. (2014) Vaccination with Gag, Vif, and Nef gene fragments affords partial control of viral replication after mucosal challenge with SIVmac239. J Virol 88:7493-516
Martins, Mauricio A; Bonaldo, Myrna C; Rudersdorf, Richard A et al. (2013) Immunogenicity of seven new recombinant yellow fever viruses 17D expressing fragments of SIVmac239 Gag, Nef, and Vif in Indian rhesus macaques. PLoS One 8:e54434
Mudd, Philip A; Martins, Mauricio A; Ericsen, Adam J et al. (2012) Vaccine-induced CD8+ T cells control AIDS virus replication. Nature 491:129-33
Vojnov, Lara; Martins, Mauricio A; Bean, Alexander T et al. (2012) The majority of freshly sorted simian immunodeficiency virus (SIV)-specific CD8(+) T cells cannot suppress viral replication in SIV-infected macrophages. J Virol 86:4682-7
Mudd, Philip A; Ericsen, Adam J; Burwitz, Benjamin J et al. (2012) Escape from CD8(+) T cell responses in Mamu-B*00801(+) macaques differentiates progressors from elite controllers. J Immunol 188:3364-70
Mudd, Philip A; Ericsen, Adam J; Price, Andrew A et al. (2011) Reduction of CD4+ T cells in vivo does not affect virus load in macaque elite controllers. J Virol 85:7454-9
Mudd, Philip A; Watkins, David I (2011) Understanding animal models of elite control: windows on effective immune responses against immunodeficiency viruses. Curr Opin HIV AIDS 6:197-201
Reynolds, Matthew R; Sacha, Jonah B; Weiler, Andrea M et al. (2011) The TRIM5{alpha} genotype of rhesus macaques affects acquisition of simian immunodeficiency virus SIVsmE660 infection after repeated limiting-dose intrarectal challenge. J Virol 85:9637-40
Vojnov, Lara; Bean, Alexander T; Peterson, Eric J et al. (2011) DNA/Ad5 vaccination with SIV epitopes induced epitope-specific CD4? T cells, but few subdominant epitope-specific CD8? T cells. Vaccine 29:7483-90
Mudd, Philip A; Ericsen, Adam J; Walsh, Andrew D et al. (2011) CD8+ T cell escape mutations in simian immunodeficiency virus SIVmac239 cause fitness defects in vivo, and many revert after transmission. J Virol 85:12804-10

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