Background:  Compartmentalization of HIV in central nervous system (CNS) can lead to HIV-associated neurocognitive disorders (HAND), either for persistent HIV replication in CNS or for HIV-related CNS immune activation. We correlate the change of CNS viral parameters and immune activation in naïve HIV-infected patients with advanced disease with or without HAND after ART introduction.

Methods:  HIV-infected patients with CD4 <200/µL starting ART with zidovudine (ZDV)/lamivudine (3TC) and lopinavir/ritonavir (LPV/r). Neurocognitive tests were performed at baseline. HIV RNA, pro-inflammatory cytokines (interleukin [IL] -6, IL-10, interferon [INF] -γ, tumor necrosis factor [TNF] -α, tumor growth factor [TGF] -β1, TGF-β2) and chemokines (macrophage inhibitory protein [MIP] -1α, MIP-1β, MCP-1) were measured on plasma and cerebrospinal fluid (CSF) at baseline and T3 by enzyme-linked immunosorbent assay. Wilcoxon log rank sum test was used.

Results:  At baseline HAND was diagnosed in 5 of 10 patients. Baseline CSF HIV RNA levels were not different between patients with normal and impaired tests (3.26 log₁₀ vs 3.36 log₁₀ copies/mL). Conversely when cytokine and chemokine expression was compared between the 2 groups, 10-fold higher median CSF IL-6 (3.5 vs 0.3 pg/mL) and MIP-1β levels (2.1 vs 1.1 pg/mL) were found in patients with HAND as compared to patients with normal cognitive function. All patients receiving ART showed significant decrease in plasma and CSF HIV RNA levels. However all the patients displayed a significant discrepancy in the HIV RNA in plasma and CSF D levels between T0 and T3 (1.5 log₁₀ copies/mL vs 0.0 log₁₀ copies/mL, respectively), indicating a slower HIV decrease in CSF than in plasma. Despite the significant drop in HIV RNA both in plasma and in CSF no significant change in cytokine and chemokine expression were observed in CSF from T0 to T3 either in patients with HAND or in patients without CNS involvement. In particular, despite effective ART, IL-6 and MIP-1β remained persistently higher in patients presenting HAND.

Conclusions:  HIV RNA decrease at a different rate in plasma and in CSF, which supports the hypothesis of compartmentalization of HIV replication in advanced disease. CSF HIV RNA levels did not seem to be primarily associated with impaired neurocognitive function. Conversely, pro-inflammatory cytokines levels were strictly associated to the development of cognitive disorders. Moreover, irrespective of HIV RNA control in CSF cytokine and chemokine CSF expression was not modified by ART. Both findings suggest a major role of pro-inflammatory cytokines in the pathogenetic mechanisms of HAND development in advanced HIV infected patients.