HIV Compartmentalization in the CNS and Its Impact in Treatment Outcomes and Cure Strategies

Abstract

Purpose of review: This review focuses on the cerebrospinal fluid (CSF) findings in connection to the central nervous system (CNS) reservoir in treatment-naïve and virally suppressed PLWH, followed by the findings in CSF HIV-1 escape and analytical treatment interruption studies.

Recent findings: Compared to chronic infection, initiating antiretroviral therapy (ART) during acute HIV-1 infection results in more homogeneous longitudinal benefits in the CNS. Viral variants in CSF HIV-1 escape are independently linked to infected cells from the systemic reservoir and in the CNS, highlighting the phenomenon as a consequence of different mechanisms. HIV-infected cells persist in CSF in nearly half of the individuals on stable ART and are associated with worse neurocognitive performance. Future studies should probe into the origin of the HIV-infected cells in the CSF. Examining the capacity for viral replication would provide new insight into the CNS reservoir and identify strategies to eradicate it or compensate for the insufficiency of ART.

Keywords: Antiretroviral therapy; Central nervous system; Compartmentalization; HIV cure; HIV reservoir.

Figure 1.. Outcomes of CSF Studies in Connection with the Timing of ART Initiation

This schematic diagram illustrates neurologic and virologic observations in people living with HIV (PLWH) before and after antiretroviral therapy (ART). Elevation of markers of neuronal injury in the cerebrospinal fluid (CSF) is observed in a subset of untreated PLWH during the first year of HIV infection and becomes more frequent towards chronic infection. In addition, compartmentalization of R5 T-cell tropic HIV-1 can be observed in the CSF during the first year of infection, whereas the emergence of macrophage-tropic HIV-1 in CSF occurs during more advanced infection. To date, early initiation of ART is associated with less intrathecal inflammation, lower levels of anti-HIV antibodies and neuronal injury marker in the CSF, and reduced risk of CSF viral escape as compared to treatment initiated in later stage infection. A number of conditions (boxes in blue) may impact neurological outcomes, including infection with multiple transmitted/founder HIV-1 variants and an altered ratio of HIV-1 RNA between CSF pre-ART, and levels of anti-HIV antibodies and detection of HIV-infected cells in the CSF post-ART.