Background:  We hypothesize that HIV-associated dementia results from ongoing HIV replication (aggravated by drug resistance), which leads to increased cytokine production and neurologic deterioration. We investigated inter-relationships among clinical HIV status, drug treatment history, adherence, neuropsychological assessment, plasma vs cerebrospinal fluid (CSF) reservoir findings (cytokines, viral load, drug resistance), and nuclear magnetic resonance spectroscopy imaging (NMRS).

Methods:  HIV⁺ subjects and HIV^­ controls with negative toxicology screens; no psychiatric, brain opportunistic infections, central nervous system cancers, or severe liver or kidney disease. All completed neuropsychological assessment and NMRS. Paired plasma/CSF from 41 subjects (25 HIV⁺, 16 HIV^­) were analyzed by 4 Quantikine Human Immunoassays (IL-1β, IFN-γ, TNF-α, and MCP-1) and by Roche U.S. viral load assay (v1.5). HIV pol genotyping was done on plasma/CSF pairs with HIV RNA ≥ 50 copies (c)/mL. We analyzed 3 groups:  8 HIV⁺ with HIV RNA ≥50 copies/mL both plasma and CSF; 17 HIV⁺ lacking HIV RNA ≥50 copies/mL in both plasma and CSF; and 16 HIV^­ controls. ANOVA and nonparametric statistics (c²) were used for group comparisons.

Results:  The 3 groups differed significantly in plasma viral load, plasma MCP-1, plasma TNF-α, and plasma IL-β. IFN-γ was undetectable in plasma and CSF. The 3 groups differed significantly in CSF viral load and CSF MCP-1 levels, but not in CSF TNF-a and CSF IL-1β levels. c² analyses demonstrated significant differences among the 3 groups on neuropsychological assessment:  HIV⁺ with CSF/plasma pairs having HIV RNA ≥50 copies/mL in both compartments displayed worse dementia and at a higher frequency than HIV⁺ lacking RNA ≥50 copies/mL in both compartments and HIV^­ (c² [df = 2] = 32.447; p = 0.000). They did significantly worse on standard tests of psychomotor speed/dexterity (c² [df = 2] = 12.239; p = 0.002), visuospatial functioning (c² [df = 2] = 15.130; p = 0.001), visual memory (c² [df = 2] = 6.770; p = 0.034) and executive functioning (c² [df = 2] = 15.339; p = 0.000). Key HIV drug-resistance mutations were seen in 7 of 8 plasma/CSF pairs with HIV RNA ≥50 copies/mL with 3 of 7 pairs being discordant.

Conclusions:  Subjects with HIV RNA ≥50 copies/mL in both plasma and CSF compartments displayed worse dementia and significantly worse neuropsychological assessment testing results, suggesting this is a clinically relevant level with respect to HIV neuropathogenesis. HIV drug resistance was seen in subjects with HIV RNA ≥50 copies/mL in both compartments, which may aggravate ongoing HIV replication, cytokine production, and neurologic deterioration.