15th Conference on Retroviruses and Opportunistic Infections Boston, Massachusetts - February 3-6, 2008

Conf Retrovir Opportunistic Infect 2008 Feb 3-6;15: (abstract no. 18)

John Loffredo ¹, A Bean¹, D Beal¹, E Leon¹, S Piaskowski¹, S Musani², E Rakasz¹, N Wilson¹, D Allison², and D Watkins^1
1Wisconsin Natl Primate Res Ctr, Univ of Wisconsin, Madison, US and ²Univ of Alabama at Birmingham, US

BACKGROUND: Certain major histocompatibility complex (MHC) class I alleles are strongly associated with control of HIV and simian immunodeficiency virus (SIV). We and others hypothesize that CD8+ T cells specific for epitopes restricted by these molecules may be particularly effective. Understanding how CD8+ T cells contribute to control of viral replication should yield important insights for vaccine design. Recently, we identified an Indian rhesus macaque MHC class I allele, Mamu-B*08, associated with elite control and low plasma viremia after infection with SIV_mac239. Interestingly, a preliminary binding motif for Mamu-B*08 appears comparable to that of HLA-B27, an allele associated with human elite controllers. These similarities make SIV_mac239-infected Mamu-B*08+ macaques an ideal system for modeling HIV-infected human elite controllers.

METHODS: We studied the immunopathogenic events of acute phase SIV infection in Mamu-B*08+ macaques in an attempt to further understand CD8-mediated viral control in elite controllers. After challenging 4 Mamu-B*08+ macaques intravenously with SIV_mac239, we followed plasma viral concentrations, peripheral blood CD4+ counts (including total and memory subsets), antigen-specific responses (CD8+ and CD4+), and viral evolution during the first 20 weeks after SIV infection.

RESULTS: Of 4 macaques, 2 became elite controllers with viral set-points significantly below those of 175 macaques that progressed to AIDS (p≤0.0076). Of the 4 macaques, 2 preserved their CD4+ memory T lymphocytes during peak viremia, and all 4 recovered their CD4+ memory T lymphocytes in the chronic phase of infection. Mamu-B*08-restricted CD8+ T cell responses dominated the acute phase and accounted for 23.3% to 59.6% of the total SIV-specific immune responses. Interestingly, the pattern of immunodominance varied from animal to animal, and Mamu-B*08-restricted CD8+ T cell breadth seemed to correlate with successful control of SIV_mac239 replication. The elite controllers mounted strong and broad CD8+ T cell responses against several epitopes in Vif and Nef. Mamu-B*08-specific CD8+ T cells also accounted for the majority of viral variation at 18 weeks post-infection, and escape was detected as early as 10 weeks post-infection. Interestingly, patterns of escape in Nef differed between the elite controllers and the other 2 macaques.

CONCLUSIONS: Natural containment of AIDS virus replication in Mamu-B*08+ macaques may be related to a combination of immunodominance and viral escape from CD8+ T cell responses.

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2008-02-03
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