DESCRIPTION (provided by applicant): The simian immunodeficiency virus (SIV) animal model presents a unique and significant opportunity for assessing novel antiviral strategies for human immunodeficiency virus (HIV)/AIDS in humans. Careful elucidation of HIV accessory gene functions in vivo in an animal model will be crucial to the design and development of targeted intervention strategies useful for treatment of human immunodeficiency virus-1 (HIV-1) infection of humans. The accessory gene vif is present in genomes of all known lentiviruses, with the exception of equine infective anemia virus (EIAV), and has been shown to be required for efficient viral replication both in vivo and in vitro for multiple animal lentiviruses. Mechanisms by which Vif functions to facilitate viral infectivity for both HIV-1 and SIV have only recently been elucidated. Vif inhibits virion incorporation of a cellular cytidine deaminase, APOBEC3G, by targeting this cellular protein for proteosomal degradation. If incorporated into virions, APOBEC3G severely restricts reverse transcription of viral RNA by inducing C to U mutations in newly synthesized negative strand viral DNA. These findings based on in vitro experiments further demonstrate the requirement of Vif for efficient lentivirus replication and distinguish this viral factor as a potential target for antiviral therapies. Our recent studies indicate that rhesus macaques inoculated with a proviral SIV vif mutant exhibit strong virus-specific cellular immune responses along with low level antiviral antibody responses. Taken together, these findings imply that replication of a wf-deleted virus is persistent in the host, although at extremely low levels. Furthermore, these observations strongly support the hypothesis of the presence of a reservoir or a specific population of target cells permissive for SIV vif-negative virus infection in vivo. This proposal intends to use infection of rhesus macaques with a SIV vif deletion mutant to identify target cell populations permissive for SIV-vif infection in vivo and to examine such populations for expression of APOBEC3A-H genes, as well as APOBEC3F and APOBEC3G protein expression. Moreover, this proposal includes an in depth analysis of APOBEC3A-H expression in specific SIV/HIV target cell populations within multiple lymphoid tissues in vivo. Given the potential significance of W-APOBEC3 interactions as a target for antiviral therapies, a clear understanding of the expression of the APOBEC3 family of proteins in the host, is critical, particularly for characterizing cell populations where APOBEC3(A-H) may be low or absent and which may support HIV-1 replication in the face of Vif-targeted antiviral therapies. Accordingly, findings from these proposed experiments may have significant impact on the design and expectation of antiviral therapeutics that target Vif and Vif interactions with cellular factors (i. e., APOBEC3 family of proteins).
|Effective start/end date||7/1/06 → 6/30/08|
- National Institutes of Health: $184,490.00
- National Institutes of Health: $113,625.00
- Immunology and Microbiology(all)