This Competitive Revision Application requests funds to expand the scope of the parent grant by adding a new objective, Aim 5, dedicated to behavioral/cognitive evaluations of HIV-1 infected mice. Our research is based on the hypothesis that there are core changes in brain physiology arising from long- lived HIV-1 infected cells that persist through existing therapies. Unabated production of viral proteins by these cells can cause cumulative inflammatory, antiviral, and oxidative stress reactions that affect neuronal function. We test this hypothesis in the parent grant in four Specific Aims to: 1) establish genome-wide brain gene expression profiles representative of patients with milder forms of HIV CNS disease;2) identify biological pathways and biomarkers in the human brain characteristic of continuing mild HIV CNS disease in the presence of antiretroviral treatment;3) validate selected markers of mild HIV CNS disease in brains of mice infected with chimeric, neuroinvasive HIV-1, EcoHIV, which causes mild neuropathological changes in mice similar to MND;4) using this mouse model of MND, test the hypothesis that mild, chronic HIV CNS disease depends upon low level virus transcription unaffected by existing antiretroviral treatment. We have made significant progress in Aims 1-3. We found that EcoHIV infected mice develop mild cognitive impairments that last at least two months after infection and do not involve extensive neuropathology or viral encephalitis, similar to MND in human patients. With symptomatic cognitive impairment easily measured in mice, EcoHIV infection of mice now provides a more faithful representation of HIV-1 CNS disease in people. Behavioral testing in mice was not part of the parent grant (See Aims above). Here we propose to use the mechanism of the Competitive Revision Application to establish a behavioral component in the parent application. Because of its limited funding period, our application proposes primarily to establish and optimize behavioral testing methods, including investment in the required equipment and additional personnel. The behavioral testing will then be employed for the duration of the supplement for evaluation of MND markers that we have already identified. The following objectives are proposed, grouped under a new Specific Aim 5: A) To purchase equipment and test and select optimal behavioral tests measuring learning and short- and long-term memory for scoring behavioral/cognitive deficits induced by EcoHIV infection in mice;B) To determine the time course of the behavioral impairment relative to the course of peripheral EcoHIV infection and host immune status;C) To begin to examine brain pathology and expression of cellular markers of HIV-1 neuropathogenesis accompanying development of neurocognitive impairments in mice. We believe that the proposed behavioral component will significantly enrich the parent program by allowing experimental evaluation of HIV-1 neurocognitive disease, from identifying virus-induced genome- wide changes in the brain to verifying their importance in clinically relevant behavioral tests.
This application is proposed to supplement ongoing studies on the human and mouse gene products that associate with brain disease during HIV-1 infection. We have found that HIV-1 infected mice also develop problems in learning and memory and this study will systemically evaluate these behavioral problems in correlation to the ongoing studies on changes in brain cell gene expression in these animals.
