AEGiS-9CROI: Blockade of T-Cell Co-Stimulation during Acute SIV Infection in Rhesus Macaques Blunts SIV-Specific Cellular Immune Responses but Does not Protect Them from AIDS

9th Conference on Retroviruses and Opportunistic Infections

Seattle, Washington - February 24 -February 28, 2002

Blockade of T-Cell Co-Stimulation during Acute SIV Infection in Rhesus Macaques Blunts SIV-Specific Cellular Immune Responses but Does not Protect Them from AIDS

Conf Retroviruses Opportunistic Infect 2002 Feb 24-28;9:abstract no. 24
Garber D, Silvestri G, Fedanov A, Kozyr N, Barry A, Ibegbu C, Carter A, Anderson D, Wang X, Mittler R, McClure H, Larsen C, Altman J, Staprans S, Feinberg MB; Emory Vaccine Res. Ctr., Atlanta, GA

BACKGROUND: SIV infection of rhesus macaques results in immune system activation and in progression to simian AIDS. In contrast, sooty mangabey monkeys, a natural reservoir of SIV, exhibit little immune activation or CTL responses to SIV, despite high levels of cytopathic viral replication. Further, sooty mangabeys do not develop AIDS. We hypothesized that blocking the host immune response during primary SIV infection of macaques, thereby simulating the low immune response in sooty mangabeys, may make the macaques tolerant of SIV antigens and result in decreased virus-induced immunopathogenesis.

METHODS: Blockade of CD28-CD80/CD86 and CD40-CD40L co-stimulatory pathways was achieved in Mamu-A01 macaques (treated group) by intravenous infusions of CTLA4-Ig and anti-CD40L mAb during primary infection with SIVmac239.

RESULTS: The co-stimulatory blockade was found to significantly reduce both the generation and function of SIV-specific CD8+ T cells during acute and chronic SIV infection. In addition, costimulatory blockade in SIV-infected macaques dramatically inhibited proliferation of CD4⁺ T cells and formation of lymph node germinal centers, and it substantially delayed time to seroconversion. While treated animals exhibited a transient 50-fold increase in plasma viremia as compared to untreated macaques, no correlation was observed between set point SIV viremia and the magnitude of anti-SIV CD8+ T-cell responses. In contrast, good inverse correlations between anti-SIV antibody titer and SIV plasma viral load were observed in both treated and untreated macaques at their respective times of SIV seroconversion. Accelerated progression to AIDS, with extensive opportunistic infections, was observed in 3 of 4 treated animals and 1 of 4 control macaques. Accelerated depletion of peripheral CD4⁺ T cells was not observed in treated macaques, despite overall higher levels of SIV replication in this group. In addition to the direct effects of SIV infection on disease progression, blockade of T-cell responses against opportunistic pathogens initially encountered during acute SIV infection may also have contributed to the accelerated progression to AIDS observed in treated macaques.

CONCLUSION: The classic CD8+ T-cell-mediated immunopathology model for AIDS, which posits that abrogation of an antiviral T-cell response against a noncytopathic immunodeficiency virus should reduce immunopathology, is not consistent with our results.

Keywords: AEGiS, SIV, Simian Acquired Immunodeficiency Syndrome, Macaca mulatta, Cercocebus atys, T-Lymphocytes, Macaca, CD4-Positive T-Lymphocytes, CD8-Positive T-Lymphocytes, Viremia, Viral Load, T-Lymphocytes, Helper-Inducer, T-Lymphocyte Subsets, Greece, Animal, therapy

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Copyright © 2002 - Foundation for Retrovirology and Human Health. Reproduction of this abstract (other than one copy for personal reference) must be cleared through the Foundation for Retrovirology and Human Health. Licensed (AIDSLINE) from National Library of Medicine.