Recent data have argued for a role for immune system activation in HIV pathogenesis. At least two of the Aims in this proposal will address this issue directly in an in vivo model of HIV disease, SIV infection of the rhesus macaque. We propose to ask two questions regarding the relationship between activation, apoptosis, and disease progression: 1) Will an immature immune system support viral replication and progression to disease? That is, does disease progression require the presence of an immune system that is capable of activation? and 2) What is the effect of adding an activating stimulus to a system of ongoing HIV (or SIV) infection? In many of the in vivo and in vitro studies of apoptosis in AIDS, cellular activation leads to induction of apoptosis in a susceptible cell population. This work will go on to test a mechanism of viral persistence in the face of triggering of apoptosis by cellular activation, and to assess the role of mucosal Langerhans cells in induction of apoptosis in acute and chronic infection.
The Specific Aims are to: 1. Determine the effect of immune activation on viral load and apoptosis in SIV-infected macaques. 2. Determine viral load, apoptosis, and disease progression after in utero infection, before and after the development of immune responsiveness. 3. Determine viral load and apoptosis in neonatal and adult animals infected with SIV or SIVdelta 3 by oral or intravenous infection. 4. Compare susceptibility of T cell lines to activation-induced apoptosis after infection with an HIV env-minus construct. 5. Determine infection and apoptosis of resting or activated T cells exposed to acutely infected Langerhans cells; compare infection with HIV-1 or SIVmac251 with isogenic strains deleted in nef or vpr. The proposed work is highly significant because it will yield new insights into lentiviral pathogenesis in fetal, neonatal, and adult infection.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
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AIDS and Related Research Study Section 3 (ARRC)
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National Jewish Health
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