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LB2 Use of T-Cell Costimulatory Blockade during Acute SIV Infection of Rhesus Macaques to Define the Relative Importance of Cellular and Humoral Immune Responses in Control of Viremia and Disease Progression
D. A. Garber1, G. Silvestri1, A. Fedanov1, R. Regos1, A. Barry1, N. Kozyr1, C. P. Larsen1, H. McClure1, D. Montefiori2, J. D. Altman1, S. Staprans1, and M. B. Feinberg*1
1Emory Vaccine Res. Ctr., Atlanta, GA, USA and 2Duke Univ., Durham, NC, USA
Background: The immune effector mechanisms responsible for containment of primary infection and establishment of “set point” levels of virus replication are not completely understood.
Methods: To investigate the role of SIV-specific CD4+ and CD8+ T-cell responses and the humoral antibody responses in immune control of SIV infection, Mamu-A01 rhesus macaques were infected with SIVmac239 in the presence of agents that block key pathways for costimulation of T cells and antigen-presenting cells (CTLA4-Ig that blocks CD28/CD80-86 interactions plus anti-CD40L mAb that blocks CD40/CD40L interactions) or in their absence. In this way, we sought to block primary immune responses to SIV but leave memory responses to other antigens unperturbed and leave global T cell populations intact. Viremia, cellular immune responses, and humoral responses were intensively monitored at successive times post-infection.
Results: Costimulatory blockade effectively blocks the CD4 response during primary infection and abrogates anti-SIV antibody production for a prolonged period. SIV-specific CD8 T-cell responses are attenuated significantly, during both primary and chronic infection. Peaks of initial viremia were actually higher in the control group, and transient containment of viremia was observed in both groups, despite widely varying CD8+ T-cell responses. Although treated animals exhibited a transient 50-fold increase in plasma viremia compared with untreated controls, no correlation was observed between “set point” SIV viremia and the magnitude of SIV-specific CD8+ T-cell responses. In contrast, good inverse correlations were observed between anti-SIV antibody titers and SIV plasma RNA levels, and in the timing and magnitude of virus load reductions. Accelerated progression to AIDS was observed in three-fourths of treated animals and one-fourth of controls.
Conclusions: (1) The role of the CD8+ T-cell response in the control of primary and established SIV infection may have been overestimated in earlier studies; and (2) the role of the humoral immune response in the control of primary and established SIV infection may have been underestimated by earlier studies.
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