Potential models for HIV neuroinvasion and infection of the central nervous system (CNS). (a) HIV-infected monocytes with an activated phenotype may transport HIV into the nervous system via migration across the blood–brain barrier. (b) Infected monocytes likely differentiate into perivascular tissue macrophages and proceed to produce HIV within the CNS. This macrophage infection and replication allows for release of free virions and may facilitate infection of microglial cells. (c) Cell-to-cell fusion involving cells that express CD4 and HIV coreceptors results in formation of multinucleated giant cells within the brain, a hallmark of HIV-related brain pathology. (d) Infected CD4⁺ T lymphocytes may also serve as a mechanism of entry of HIV into the brain. There is varied evidence regarding the relative contribution of CD4⁺ T lymphocytes versus cells of the monocyte/macrophage in initiating and sustaining HIV infection within the CNS. (e) Although astrocytes might harbor HIV and also contribute to HIV-related brain disease through mechanisms of astrogliosis induced by local chemokines and cytokines, astrocytes infection is not thought to support ongoing replication within the CNS. (Adapted from Gonzalez-Scarano et al. 2005; with permission, from Macmillan Publishers Ltd. © 2005.)

Heterduplex tracking assay (HTA) was used to compare V1/V2 and V4/V5 env populations in blood plasma (BP) and CSF from subjects with distinct stages of HIV infection and neurological status (PI, primary infection; NI, not impaired; MCMD/I, minor cognitive and motor disorder; HAD, HIV-associated dementia). The % difference for BP/CSF HTA band patterns was determined for each patient and the data compiled. A higher percentage difference indicates more discordant BP/CSF viral genetic populations for the particular region of env analyzed. The mean of V1/V2 and V4/V5 percent difference results was determined for each patient to reflect global env compartmentalization between BP and CSF, and results were compiled for comparison between the different disease categories. p values shown were determined by Wilcoxon rank-sum test. (Adapted from Harrington et al. 2009; with permission, from Wolters Kluwer Health © 2009.)

Baseline levels of markers of HIV infection and inflammation in a primary infection cohort are shown according to estimated days after transmission at blood and CSF sampling. Simple linear regression between the number of days post-estimated HIV transmission and (A) blood plasma HIV RNA levels, (B) CSF HIV RNA levels, (C) CSF WBC counts, and (D) CSF neopterin levels. Regression lines (solid) and 95% confidence intervals (dotted) are indicated; upper limit of normal values for CSF WBC and CSF neopterin are indicated on each graph by a dotted horizontal line. (Adapted from Spudich et al. 2011; with permission, from Oxford University Press © 2011.)