AIDS patients are afflicted with a variety of neurologic disorders. While many of these are due to focal opportunistic infections and neoplasms, approximately 20-30% of AIDS patients develop a subacute encephalitis of presumed viral etiology1-3. Given the high viremia and frequent recovery of human immunodeficiency virus (HIV) from the cerebrospinal fluid, it is not readily apparent why only a subset of patients develop HIV encephalopathy and others do not. Some investigators have explained this discrepancy on the assumption that neurologic damage is mediated only by a specific """"""""neurotropic"""""""" strain of HIV4. While several studies document different biological properties of nervous system isolates of HIV, as of yet, attempts to show unique nucleic acid sequences specific to """"""""neurotropic"""""""" strain of HIV have been unrewarding. Other investigators have suggested that some defect in host immunity is responsible for progression to nervous system disease. To support this host-specific predisposition, a recent study has shown a strong correlation between the HLA haplotype A1 B8 DR3 and a rapid decline in T4 cells and development of HIV-related symptoms5. In studies of HTLV-1 associated myelopathy, the presence of nervous system disease has been shown to be tightly associated with the individual's HLA haplotype6. In endemic regions, large proportions of the population are infected by HTLV-1, but only a small subset develop the myelopathy. Fully 70% of those who develop the myelopathy belong to 4 haplotypes. The immune mechanisms explaining this remarkable association is unknown. We propose to examine the relationship between; presence or absence of HIV encephalopathy, and specific aspects of the host immune responsiveness. Our hypothesis is that there is some factor in the host humoral or cellular responsiveness, that predisposes a particular subset of AIDS patients to develop HIV encephalopathy. The proposed study will capitalize on the unique opportunity to prospectively evaluate the immune responsiveness in a group of 410 HIV seropositive individuals and 90 HIV seronegative individuals undergoing intensive neuropsychiatric testing in a currently funded program project. We will compare the presence or absence of neuropsychiatric and neuropsychiatric and neuropathologic disease with: 1.) HLA phenotype, 2.) T-cell proliferative response to specific viral peptides, and 3.) intrathecal and sera humoral responses to specific viral peptides. To further delineate the pathogenesis of HIV mediated nervous system damage, we will evaluate the role of immune cytokines in mediating nervous system damage. Together these data will help define the role of host immune responsiveness in determining nervous system damage during retroviral infection.
| Harrold, Sharon M; Wang, Guoji; McMahon, Deborah K et al. (2002) Recovery of replication-competent HIV type 1-infected circulating monocytes from individuals receiving antiretroviral therapy. AIDS Res Hum Retroviruses 18:427-34 |
| Bissel, Stephanie J; Wang, Guoji; Ghosh, Mimi et al. (2002) Macrophages relate presynaptic and postsynaptic damage in simian immunodeficiency virus encephalitis. Am J Pathol 160:927-41 |
| Jordan-Sciutto, Kelly L; Wang, Guoji; Murphey-Corb, Michael et al. (2002) Cell cycle proteins exhibit altered expression patterns in lentiviral-associated encephalitis. J Neurosci 22:2185-95 |
| Jordan-Sciutto, K L; Wang, G; Murphy-Corb, M et al. (2000) Induction of cell-cycle regulators in simian immunodeficiency virus encephalitis. Am J Pathol 157:497-507 |
| Wiley, C A; Achim, C L; Christopherson, C et al. (1999) HIV mediates a productive infection of the brain. AIDS 13:2055-9 |
| Wang, G; Achim, C L; Hamilton, R L et al. (1999) Tyramide signal amplification method in multiple-label immunofluorescence confocal microscopy. Methods 18:459-64 |
| Sanders, V J; Pittman, C A; White, M G et al. (1998) Chemokines and receptors in HIV encephalitis. AIDS 12:1021-6 |
| Wiley, C A; Soontornniyomkij, V; Radhakrishnan, L et al. (1998) Distribution of brain HIV load in AIDS. Brain Pathol 8:277-84 |
| Reddy, R T; Achim, C L; Sirko, D A et al. (1996) Sequence analysis of the V3 loop in brain and spleen of patients with HIV encephalitis. AIDS Res Hum Retroviruses 12:477-82 |
| Achim, C L; Wiley, C A (1996) Inflammation in AIDS and the role of the macrophage in brain pathology. Curr Opin Neurol 9:221-5 |
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