This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.We developed an animal model of controlled lentiviral infection by infecting rhesus macaques (RMs) with SIVagm. We showed that acute SIVagm infection in RMs is characterized by: (i) high levels of viral replication, with high peak viral loads (VLs) of 108-109 SIVagm copies/ml of plasma, and (ii) dramatic mucosal CD4+ T-cell depletion, both of which are similar to pathogenic HIV-1/SIV infections of humans and RMs. Surprisingly, during the post-acute phase of infection there is complete control of SIVagm replication defined as: (i) undetectable VLs from day 72 post-inoculation (p.i.) to at least four years p.i.; (ii) negative nested-PCRs for multiple SIVagm genes in PBMCs, lymph nodes (LNs) and intestine; (iii) seroreversion; (iv) progressive recovery of mucosal CD4+ T-cells, (after day 200), with complete recovery of this T-cell subset by four years p.i.; (v) normal levels of T-cell immune activation, proliferation and apoptosis and (vi) no disease progression. Cloning and sequencing of the envelopes of SIVagm isolated from RMs and AGMs demonstrated similar rates of substitutions, therefore excluding a possible role of partial host restriction for SIVagm control in RMs Experimental CD8 cell depletion in controlled SIVagm infections of RMs resulted in transient increases in VLs. To understand the mechanisms of virus control, RMs were inoculated with SIVagm; VLs, CD4+ T-cell dynamics, T-cell immune activation, proliferation and apoptosis were monitored. Animals were euthanized at sequential time points during the acute and chronic phases of infection, and timing and extent of RMs tissue infection with SIVagm, as well as 'sanctuary silencing' (control of virus replication) are currently investigated by nested PCRs targeting SIVagm structural genes performed on both DNA and RNA extracted from lymphoid and non-lymphoid tissues. In situ hybridization (ISH) will also be performed to characterize SIVagm distribution in vivo during the acute and post-acute infection.
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