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.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG5 (03))
Program Officer
Kerza-Kwiatecki, a P
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California San Francisco
Schools of Medicine
San Francisco
United States
Zip Code
Sturdevant, Christa Buckheit; Joseph, Sarah B; Schnell, Gretja et al. (2015) Compartmentalized replication of R5 T cell-tropic HIV-1 in the central nervous system early in the course of infection. PLoS Pathog 11:e1004720
Yilmaz, Aylin; Yiannoutsos, Constantin T; Fuchs, Dietmar et al. (2013) Cerebrospinal fluid neopterin decay characteristics after initiation of antiretroviral therapy. J Neuroinflammation 10:62
Peluso, Michael J; Ferretti, Francesca; Peterson, Julia et al. (2012) Cerebrospinal fluid HIV escape associated with progressive neurologic dysfunction in patients on antiretroviral therapy with well controlled plasma viral load. AIDS 26:1765-74
Schnell, Gretja; Joseph, Sarah; Spudich, Serena et al. (2011) HIV-1 replication in the central nervous system occurs in two distinct cell types. PLoS Pathog 7:e1002286
Spudich, Serena; Gisslen, Magnus; Hagberg, Lars et al. (2011) Central nervous system immune activation characterizes primary human immunodeficiency virus 1 infection even in participants with minimal cerebrospinal fluid viral burden. J Infect Dis 204:753-60
Probasco, John C; Deeks, Steven G; Lee, Evelyn et al. (2010) Cerebrospinal fluid in HIV-1 systemic viral controllers: absence of HIV-1 RNA and intrathecal inflammation. AIDS 24:1001-5
Schnell, Gretja; Price, Richard W; Swanstrom, Ronald et al. (2010) Compartmentalization and clonal amplification of HIV-1 variants in the cerebrospinal fluid during primary infection. J Virol 84:2395-407
Schnell, Gretja; Spudich, Serena; Harrington, Patrick et al. (2009) Compartmentalized human immunodeficiency virus type 1 originates from long-lived cells in some subjects with HIV-1-associated dementia. PLoS Pathog 5:e1000395
Harrington, Patrick R; Schnell, Gretja; Letendre, Scott L et al. (2009) Cross-sectional characterization of HIV-1 env compartmentalization in cerebrospinal fluid over the full disease course. AIDS 23:907-15
Hunt, Peter W; Brenchley, Jason; Sinclair, Elizabeth et al. (2008) Relationship between T cell activation and CD4+ T cell count in HIV-seropositive individuals with undetectable plasma HIV RNA levels in the absence of therapy. J Infect Dis 197:126-33

Showing the most recent 10 out of 38 publications