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329 AIDS Pathogenesis Elucidated by Divergent Host Responses during SIV Infection of Natural and Non-Natural Hosts
S. Staprans*, G. Silvestri, L. Perry, N. Kozyr, A. Fedanov, D. Garber, H. McClure, and M. Feinberg
Emory Univ., Atlanta, GA, USA
Background: Sooty mangabeys (SMs), the natural reservoir host of SIVSMM, maintain normal CD4 T-cell counts and avoid AIDS despite high-level SIV replication. Subdued antiviral immune responses may avoid the bystander damage seen in pathogenic HIV infections.
Methods: To study divergent host responses to infection we infected SMs and non-natural rhesus macaque (RM) hosts with a diverse, uncloned SIVSMM quasispecies. Changes in peripheral blood lymphocyte subsets were monitored by flow cytometry up to twice weekly for the first 2 weeks post infection and monthly thereafter. Plasma SIV replication dynamics and viral evolution were monitored in parallel.
Results: Uncloned SIVSMM causes high level viremia in both SMs and RMs. Infection of SMs is not marked by the massive T-cell expansion seen in the non-natural RM host. The magnitude of initial SIV replication correlates with the magnitude of CD4 T-cell activation, with the non-natural RM host manifesting 10-fold higher peak viremia than is observed in SMs. Thereafter, SMs manifest a limited decline in post peak SIVSMM viremia, while RMs manifest a larger decline. Even though virus suppression is greater in RMs than in SMs, CD4 and CD8 T-cell proliferation remain elevated in the non-natural RM host and only RMs loose CD4 T cells. In RMs, Env V1-V2 sequence analysis shows early selection for a restricted subset of variants present in the inoculum, whereas Env diversity is not restricted in the natural SM host (p = 0.02). Higher nonsynonymous substitution rates in RMs compared to SMs provide additional evidence for selection on viral populations (p < 0.001).
Conclusions: (1) Zoonotic transmission of SIV may be facilitated by the ability of the diverse SIVSMM quasispecies to readily replicate in a new non-natural host, (2) SIVSMM virulence doesn’t require viral passaging; rather, (3) high level chronic immune activation in non-natural hosts may lead to immunopathogenesis.
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