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157 Implications of Variation in SHIV/SIV Challenge Strains Used in Preclinical HIV Vaccine Trials
M. Feinberg1, J. Cohen2, A. Barry1, N. Kozyr1, D. Garber1, G. Silvestri1, H. McClure1, H. Robinson1, and S. Staprans*1
1Emory Univ., Atlanta, GA, USA and 2NIH, Bethesda, MD, USA
Background: Little is known about the mechanisms underlying the differential primary HIV replication dynamics that determine set point viremia and how vaccines may impact these dynamics.
Methods: We assess how early SIV/SHIV replication dynamics are influenced by the infecting virus strain, number of activated CD4 T cells, virus-suppressing immune responses, and vaccine-induced alterations in lymphocyte responses.
Results: The commonly used, highly passaged, pathogenic SHIV89.6P and SIVmac251/239 establish uniformly high viremia. In contrast, SIVSMM-E660 or unpassaged SIVSMM manifest variable viremia, resembling the variation seen in HIV-infected humans. Strain differences in set point viremia are presaged by different early replication dynamics. SHIV89.6P and SIVmac251/239 manifest robust and invariant initial viral growth; in these models, the kinetics of the post-peak virus decline predicts set point viremia. In contrast, SIVSMM-E660 and naturally occurring SIVSMM quasispecies manifest variable initial viral replication dynamics, the magnitude of which predicts set point viremia. It is not known which challenge-strain best recapitulates primary HIV replication dynamics in humans. The multi-protein SHIV DNA prime/MVA boost vaccine has modest effects on initial SHIV replication dynamics; vaccine effects are most apparent during the post-peak decline in viremia, when substantial virus suppression occurs. An ideal vaccine would significantly restrict initial virus replication. A VZV-SIV Env-only vaccine actually increased CD4 T-cell proliferation following SIVSMM-E660 challenge, resulting in increased viremia. This links early differences in CD4 T-cell activation to variation in SIVSMM-E660 replication and suggests that antiviral memory CD4 T-cell responses, in the absence of strong CD8 T-cell responses, could lead to enhanced challenge virus replication and accelerated disease.
Conclusions: These studies highlight the need to understand how well the various SIV/macaque models serve as preclinical vaccine test models, and suggest that studies of primary HIV/SIV replication dynamics should incorporate target-cell availability and how vaccines alter this parameter.
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