Background
HIV-1 can be detected in cerebrospinal fluid (CSF) throughout untreated infection but it is unknown how often this is due to local replication in the CNS. In people with HIV-associated dementia (HAD), local replication can generate genetically distinct viral populations in the CNS (compartmentalized) with the unique ability to efficiently infect myeloid lineage cells (macrophage- or M-tropic; see panel A). Little is known about the frequency of compartmentalized and/or M-tropic HIV-1 in the CNS of people with HIV (PWH) who are neuroasymptomatic or have less severe symptoms.
Methods
Partial HIV-1 env genes were sequenced from viral RNA in plasma and CSF samples collected from a cross-sectional cohort of ART-naïve PWH (N=109). For a subset of PWH (N=45), full-length env genes were also generated and analyzed for the ability to efficiently enter cells expressing a low CD4 density (M tropism); distinguishing them from T-tropic HIV-1 which requires high CD4. Phylogenetic analyses identified compartmentalized viral populations in CSF and a modified CSF viral load was calculated to represent the amount of virus produced by replication in the CNS (CSF compartmentalized viral load, CCVL). Inflammatory biomarkers were measured in plasma and CSF. Standardized questionnaires were used to determine if PWH were neurosymptomatic (NS) or neuroasymptomatic.
Results
In PWH who were NS (53%), CSF HIV-1 RNA was higher (p<0.01), but plasma HIV-1 RNA, CD4+ T cell count, nadir CD4+ T cell count, and CSF WBC count were similar. CSF compartmentalization was more common in PWH who were NS (44% vs 16%, p<0.01), but was detected in both groups (panel B). Overall, compartmentalization (48% vs 18%, p<0.01) and M tropism (85% vs 38%, p=0.02) were more frequent when blood CD4+ T cells were <200/ml. M tropism was only detected with compartmentalization (62% vs 0%, p<0.01). Increasing CCVL was correlated with greater CSF neopterin, NFL, IP10, MMP9, sCD14 and sCD163 (p<0.05).
Conclusions
In this ART-naive cohort, compartmentalized HIV-1 replication in the CNS was more common in participants who were neurosymptomatic, but also occurred in the absence of symptoms and in PWH lacking severe immunosuppression. Compartmentalized viral replication in either myeloid-lineage or T cells in the CNS associates with active brain injury and inflammation. Longitudinal studies are needed to determine whether neuroasymptomatic individuals with viral replication in the CNS are at risk of developing neurologic symptoms over time.