The main research objectives of this proposal are to (1) identify early cellular targets of SIV in hematopoietic tissues and (2) to determine the role of SIV-infected cells on the development of hematopathologic changes in bone marrow of rhesus macaques during the primary stage of infection. These results will further characterize the SIV model of AIDS in rhesus macaques and be of key importance in studying unanswered questions relevant to hematopoietic disturbances in human AIDS.
The specific aims are: PHASE 1 (Year 10) Specific Aim 1: To obtain didactic training in molecular biology and retrovirology as well as hands-on research training in molecular methods so that the pathogenesis studies in Specific Aim 2 may be accomplished. PHASE 2 (Years 2-4) Specific Aim 2. To determine the association between SIV infection of bone marrow macrophages and T cells and the development of bone marrow pathology in the primary phase of SIV infection in rhesus macaques in a prospective study.
Specific aim 2 a. To correlate levels of hematopoietic growth factor (HGF) and cytokine expression in blood and bone marrow with (i) presence of SIV nucleic acid expression nd identification of cellular targets in bone marrow, (ii) pathologic changes in bone marrow in early infection and (iii) peripheral blood abnormalities and clinical disease. HGF and cytokine expression in early infection will be compared to that in macaques at the terminal stage of disease.
Specific aim 2 b. To elucidate the role of HGF and cytokine released from SIV-infected bone marrow macrophages and lymphocytes in the pathogenesis of hematopoietic abnormalities in SIV-infected rhesus macaques. (1) Alterations in HGF expression or synthesis will be evaluated by in situ hybridization, ELISA immunoassays, immunohistochemistry, quantitative DNA and RNA polymerase chain reaction (PCR) and Northern Blot techniques.
Specific aim 2 c. To elucidate the role SIV viral products (GP120, tat protein) shed from virally infected cells may play in the modulation of HGF expression or synthesis by macrophages or T cells. These studies will characterize the in vivo pathogenetic mechanism(s) responsible for hematologic abnormalities in AIDS as well as foster the development of the applicant toward a research career.
| Mandell, C P; Reyes, R A; Cho, K et al. (1999) SIV/HIV Nef recombinant virus (SHIVnef) produces simian AIDS in rhesus macaques. Virology 265:235-51 |
