Approximately one quarter of AIDS patients develop HIV-associated dementia complex (HIVD). We are studying the pathogenesis of neurologic damage associated with HIV encephalitis, a known pathologic substrate of HIVD. Most hypotheses of the pathogenesis of neurologic damage in HIV encephalitis focus on neurotoxic HIV proteins or immune factors. We and others concluded that many cytokines (in particular monokines) are present within CNS tissues showing HIV encephalitis, but it has been difficult to ferret out their relative importance. Using new quantitative techniques to measure tissue viral-load we observed a tight association between HIV DNA and RNA load. Coupling these findings with our previous observations of viral protein expression, HIV encephalitis would appear to be limited to productive infection of CNS macrophages. The absence of significant proviral load prior to the development of HIV encephalitis leads us to hypothesize that neurologic disease results from either, increased trafficking of HIV-infected monocyte elements into the CNS, loss of immune control of macrophage infection within the CNS, or a CNS microenvironment that promotes HIV replication. To test these hypotheses, in the first 2 specific aims we will examine; the relationship between immunologic and neurologic status and peripheral blood monocyte infection and activation in vivo, infectability in vitro, and changes in the capacity of a subject's cell-mediated immune system to control macrophage infection. In addition to viral entry and immune surveillance, there may be some other attributes of the CNS microenvironment that promote HIV infection. In the third specific aim we will examine the role of immunosuppressive and immuno-enhancing chemokines/cytokines in regulation of macrophage viral production in the CNS. In the fourth specific aim we will bank RNA from peripheral blood, CSF and, brain tissue, to decipher whether a neurotropic strain of HIV evolves within an individual or whether HIV encephalitis is the result of macrophage-tropic strains present from early in infection. The proposed experimentation will help explain why HIV homes for, and propagates within, the nervous system. These data will help design means of identifying subjects at risk for the development of CNS disease and help design therapies for arresting HIV encephalitis.
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