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Background:  Activated monocytes play a critical role in the pathogenesis of HIV-related brain disease. We have shown that activated CD14⁺/CD16⁺ monocytes are enriched in cerebrospinal fluid (CSF) in HIV infection, especially in patients on successful ART. In the era of ART, clinical dementia has become very rare, thus, the enrichment of activated monocytes in CSF of virologically suppressed patients on ART is unexpected. To investigate predictors of monocyte activation in CSF, multiple clinical parameters of our sample of 76 HIV⁺ patients were tested in a multivariate analysis. We hypothesize that ART-treated, especially protease-inhibitor (PI)-treated individuals have higher baseline plasma lipids, and that changes in plasma lipids due to ART lead to monocyte activation and subsequent trafficking into tissues, among them CSF.

Methods:  We performed a multivariate analysis to test for predictors of activated monocytes in CSF in our HIV⁺ sample. Further, lipid profiles of total cholesterol, LDL-cholesterol, HDL-cholesterol, and triglycerides were performed on frozen plasma from the day of the monocyte activation assessment. Oxidized LDL was measured using an Ox-LDL-ELISA-kit (murine monoclonal antibody 4E6).

Results:  In patients off ART, the best predictor of monocyte activation in CSF was CSF viral load; on ART, the best predictor was use of PI. PI users (n = 27) had higher monocyte activation percentages in CSF than uninfected controls (n = 8, p = 0.0009), patients off treatment (n = 38, p = 0.004), and patients on non-PI-containing regimens (n = 11, p = 0.02). In blood, there was a trend toward lower monocyte activation profiles in PI-users compared with uninfected controls (p = 0.065). Among HIV⁺ patients, PI users had the highest levels of total cholesterol (p = 0.0033 vs off), calculated LDL (p = 0.04 vs off), and oxidized LDL (p = 0.035 vs off) and patients off ART had the lowest levels. In 10 patients on PI who had a follow-up visit ≥ 1 year later, activated monocytes were still high, and there was a trend linking the change in plasma LDL and the change in % of activated monocytes in CSF over time (p = 0.16, r² = 0.23).

Conclusions:  PI-use might lead to changes in plasma LDL without overt lipidemia that can activate monocytes, leading to trafficking of activated monocytes into tissues, among them CSF. Alternatively, monocyte trafficking to the CSF, and possibly CNS, may be an immune response to HIV-infection in brain tissue that persists despite ART.

Keywords: monocyte activation; protease inhibitors; cerebrospinal fluid