Evidence of a Source of HIV Type 1 within the Central Nervous System by Ultraintensive Sampling of Cerebrospinal Fluid and Plasma

Abstract

Defining the source of HIV-1 RNA in cerebrospinal fluid (CSF) will facilitate studies of treatment efficacy in the brain. Four antiretroviral drug-naive adults underwent two 48-hr ultraintensive CSF sampling procedures, once at baseline and again beginning on day 4 after initiating three-drug therapy with stavudine, lamivudine, and nelfinavir. At baseline, constant CSF HIV-1 RNA concentrations were maintained by daily entry of at least 10(4) to 10(6) HIV-1 RNA copies into CSF. Change from baseline to day 5 ranged from -0.38 to -1.18 log(10) HIV-1 RNA copies/ml in CSF, and from -0.80 to -1.33 log(10) HIV-1 RNA copies/ml in plasma, with no correlation between CSF and plasma changes. There was no evidence of genotypic or phenotypic viral resistance in either CSF or plasma. With regard to pharmacokinetics, mean CSF-to-plasma area-under-the-curve (AUC) ratios were 38.9% for stavudine and 15.3% for lamivudine. Nelfinavir and its active M8 metabolite could not be accurately quantified in CSF, although plasma M8 peak level and AUC(0-8hr) correlated with CSF HIV-1 RNA decline. This study supports the utility of ultraintensive CSF sampling for studying HIV-1 pathogenesis and therapy in the CNS, and provides strong evidence that HIV-1 RNA in CSF arises, at least in part, from a source other than plasma.

Compartmentalized Human Immunodeficiency Virus Type 1 Present in Cerebrospinal Fluid Is Produced by Short-Lived Cells

“…The study subjects, plasma/CSF sampling, and medication for this study have been previously described (13). Briefly, blood plasma and CSF samples were obtained at the Vanderbilt Clinical Research Center (Nashville, Tenn.) from four asymptomatic, treatment-naïve, HIV-1-infected patients with Ͼ200 CD4 ϩ T cells/mm 3 .…”

“…Several studies have validated the use of CSF as a surrogate source of virus from the brain, and CSF viral loads often predict the neurological outcome of HIV-1 infection (8,9,24,46,49). However, although CSF is an integral component of the CNS, in the context of HIV-1 infection it more accurately serves as an intermediate compartment between the brain and the periphery (7,10,13). Unique HIV-1 lineages evolve over time in the brain and peripheral blood, which is most likely a reflection of different selective pressures on viral replication in each compartment, whereas viral populations in the CSF appear to be genetically related to those in both the brain and the periphery (3,48,51).…”

Comparison of Roche MONITOR and Organon Teknika NucliSens Assays To Quantify Human Immunodeficiency Virus Type 1 RNA in Cerebrospinal Fluid

“…We previously established that baseline HIV-1 RNA levels in CSF were constant over 48-h intervals in these patients (11). Mean variance did not differ significantly between MONITOR (0.036 log 10 copies/ml) and NucliSens (0.019 log 10 copies/ml) assays (P ϭ 0.20).…”

“…Ultraintensive sampling of CSF via indwelling lumbar catheters was performed as described elsewhere (11). Briefly, lumbar CSF was sampled continuously for 48 h at baseline.…”

HIV-1 Pathogenesis: The Virus

“…It is not known which cell type supports the evolution and replication of macrophage-tropic viruses in the central nervous system (CNS). In addition to detecting these viruses in brain tissue at autopsy, it has now been possible to link the slow decay of virus in the CSF during therapy (Ellis et al 2000;Haas et al 2000;Cinque et al 2001;Schnell et al 2009), which is distinct from the rapid decay seen in the blood Wei et al 1995), with the presence of macrophage-tropic virus in the CSF, thus indicating replication in a long-lived cell (Schnell et al 2011).…”