There are two major reasons for study of HIV-1 infection of the central nervous system (CNS). First, direct brain infection by HIV-1 appears to drive the brain injury manifesting clinically as the AIDS dementia complex (ADC). Second, and of potentially broader importance, because of restricted entry of antiretroviral drugs the CNS, including both the brain parenchyma and the cerebrospinal fluid (subarachnoid and ventricular) space, may serve as a sequestered compartment that allows viral persistence and independent development of viral mutants. This issue is emerging as of particular importance with the development of potent antiviral therapies and the prospect of long-term suppression and even eradication of the HIV-1. Using a multidisciplinary approach, we propose to exploit the cerebrospinal fluid (CSF) as a parallel compartment to the brain in order to examine changes in compartmentalized infection over time. We propose a series of studies that test the overall hypothesis that there are two types of CSF infections: 1) transitory infection in which virus- infected cells that traffic into the CSF space from the blood support only temporally limited local infection and must be constantly renewed by fresh infected cells from the blood to sustain an equilibrium level of virus, and 2) autonomous infection which is self-sustaining and independent of the infection in the blood. The first is characteristic of the early phase of infection ( clinical latency ) and the second of very late infection and severe ADC, with mixed infection occurring between these phases. This and subsidiary hypotheses will be tested in the context of a series of clinical treatment studies that use antiviral therapies as experimental probes. These trials will include subjects in different phases of systemic HIV-1 infection, ranging from very early seroconversion-associated infection to late symptomatic infection (AIDS) and in subjects with varying ADC severity. The studies will compare CSF infection to that of plasma with respect to: a) the kinetics of decrement in viral RNA concentration after therapy, b) genetics (sequence relatedness, genes governing chemokine receptor utilization and mutations associated with antiviral drug resistance), and c) changes in neurological status and immune marker activation in the CSF. Antiviral effects will be correlated with the kinetics of drug entry into the CSF.
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