HIV-1 compartmentalization in the central nervous system during cryptococcal meningitis: Analysis of viral, fungal, and host factors

Opportunistic infections in the central nervous system (CNS), such as cryptococcal meningitis (CM) have profound consequences for people living with HIV-1 (PWH), including blood-brain barrier impairment and neuroinflammation. To investigate how CM may shape the HIV-1 populations in the CNS, we characterized viral variants in the blood and cerebrospinal fluid (CSF) compartments in PWH with active CM. Thirty-nine participants with CM had paired plasma and CSF viral load measurements prior to the start of anti-retroviral therapy (pre-ART), with overall significantly higher HIV-1 viral loads in plasma compared to the CSF. Among those with CSF pleocytosis, CSF viral loads were relatively higher and CCR5 coreceptor-utilizing HIV-1 were more frequently detected. To investigate whether these differences were due to sustained HIV-1 replication in the CNS that generated genetically distinct viral lineages in the CSF (i.e., viral compartmentalization), we characterized pre-ART HIV-1 env populations in a subgroup of eighteen PWH with CSF HIV-1 RNA levels > blood (N = 9) and CSF RNA levels < blood (N = 9). Compartmentalization between CSF and plasma viral populations was detected in participants from both groups and was associated with higher interleukin-2 (IL-2) levels in CSF. In some cases, HIV-1 populations in CSF were compartmentalized from plasma, were exclusively macrophage-tropic and reached levels exceeding 105 copies/ml CSF. In other cases, HIV-1 infected cells trafficking across the plasma and CSF compartments seemed the most likely source of virus in the CSF. Post-ART analysis in one participant demonstrated emergence of distinct HIV-1 populations. This study demonstrates that opportunistic infections may have diverse effects in shaping HIV-1 viral populations.