Highly active antiretroviral therapy (HAART) for HIV-1 infection effectively reduces systemic virus burden and improves immune function in most compliant patients. Nevertheless, HIV-1-associated dementia and other nervous system disorders persist. Viral reservoirs in long-lived macrophages and brain cells are not sensitive to HAART and the brain is inaccessible to certain drugs. This application is designed to investigate the effects of antiviral drugs on HIV-1 replication and pathogenesis in the brain experimentally using a new model of HIV-1 infection of immunocompetent mice by the chimeric virus, EcoHIV/NDK. This virus encodes all the proteins of HIV-1, except gp120, and thus preserves sensitivity to HAART agents. We recently reported that zalcitabine and abacavir block EcoHIV/NDK infection of mice and show in this application that nevirapine and the protease inhibitor saquinavir significantly reduce virus spread in mice. Access to a large number of infected animals and monitoring of virus in multiple tissues using real-time PCR permit quantitative test of drug efficacy, and through assay of cellular transcripts, brain cell dysfunction in our model. In this developmental program we propose to 1) test the efficacy of antiretroviral drugs for prophylaxis of acute peripheral and central nervous system infection of adult and young mice by EcoHIV/NDK and 2) test the efficacy of antiretroviral drugs for reduction of established EcoHIV/NDK infection in peripheral tissues and brain and consequential neuropathogenesis in young mice. Virus burden in lymphocytes, macrophages, and the brain and activation of brain cell gene expression will be determined by real-time PCR and microglial activation will be assessed by immunocytochemistry. This program directly investigates whether drugs with poor access to the brain can prevent establishment of a nervous system reservoir of HIV-1 and brain disease, whether virus resident in the brain is sensitive to HAART agents, and to what extent inhibition of ongoing virus replication depletes viral reservoirs in brain cells, macrophages, and bone marrow and ameliorates brain disease. This developmental program is proposed to guide future translational studies in this animal model to screen or develop new agents for their ability to prevent HIV-1-associated neuropathogenesis.
HIV-1 infection causes immunodeficiency and often nervous system disorders resulting in memory lapses, confusion, and poorly controlled movements. This application proposes to use mice experimentally infected by HIV-1 and antiviral drugs now used in human beings to determine whether they block infection and disease in the mouse brain. In addition, the application will test if drugs given to mice after infection actually eliminate virus from the brain, giving promise for the ability of antiviral drugs to control the nervous system disease seen in infected human beings.
