We will pursue a radically different approach to HIV vaccine design. Treatment of HIV-infected patients with single antiretroviral drugs often results in the emergence of variant, drug-resistant viruses. We have recently shown that cellular immune responses place similar selective pressure on the virus. We will design candidate vaccines by identifying those regions of the virus under intense selective pressure during acute SIV infection. We will sequence the entire virus at 4 and 16 weeks post-infection to determine cellular immune responses that are important in controlling early viral replication. Our hypothesis is that vaccine-induction of cytotoxic T lymphocyte (CTL) that exert selective pressure on the virus will reduce initial virus replication in macaques challenged with SIV. To address this hypothesis we first need to know which of the CTL responses control virus replication.
In Specific Aim I we will sequence the entire SIV viral genome from 12 macaques at 2, 4 and 16 weeks post-infection with a molecularly cloned virus to identify regions of the virus, which have escaped. We will use an overlapping set of peptides spanning the entire SIVmac239 genome to map cellular immune responsesin these infected animals using ELISPOT assays.
In Specific Aim II we will then vaccinate macaqueswith the regions of the virus that have escaped recognition by the immune response. We already have preliminary data suggesting that virus isolated 4 weeks post-infection has """"""""escaped"""""""" from a strong CTL response. This suggests that the CTL responsible for selecting the escape variants had destroyed all cells actively producing the wild-type virus. We will, therefore, use epitopes in the wild-type virus that escape during acute infection to induce robust CTL. We predict that these vaccine-induced CTL responses will reduce the initial viremia, and prevent escape mutant generation, thereby facilitating the development of strong host immune responses. The results of this proposal utilizing rhesus macaques challenged with SIV will have direct relevance to the rational design of a vaccine for HIV. If vaccination with regions of the virus that escape during the acute phase reduce initial viremia in macaques, then we can use analogous regions in HIV in vaccination regimens. Indeed, a CTL epitope-based vaccine is already in Phase I trials in Oxford and Kenya under the direction of Dr. McMichael. Thus, results from our studies will be important in the eventual design of this vaccine.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI049120-03
Application #
6632389
Study Section
Special Emphasis Panel (ZRG1-VACC (01))
Program Officer
D'Souza, Patricia D
Project Start
2001-03-15
Project End
2005-02-28
Budget Start
2003-03-01
Budget End
2004-02-29
Support Year
3
Fiscal Year
2003
Total Cost
$931,391
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
Reynolds, Matthew R; Weiler, Andrea M; Piaskowski, Shari M et al. (2012) A trivalent recombinant Ad5 gag/pol/nef vaccine fails to protect rhesus macaques from infection or control virus replication after a limiting-dose heterologous SIV challenge. Vaccine 30:4465-75
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; 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
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
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
Reed, Jason S; Sidney, John; Piaskowski, Shari M et al. (2011) The role of MHC class I allele Mamu-A*07 during SIV(mac)239 infection. Immunogenetics 63:789-807
Vojnov, Lara; Martins, Mauricio A; Almeida, Jorge R et al. (2011) GagCM9-specific CD8+ T cells expressing limited public TCR clonotypes do not suppress SIV replication in vivo. PLoS One 6:e23515

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