Persistent HIV-infected cells in cerebrospinal fluid are associated with poorer neurocognitive performance

Abstract

BACKGROUNDPersistence of HIV in sanctuary sites despite antiretroviral therapy (ART) presents a barrier to HIV remission and may affect neurocognitive function. We assessed HIV persistence in cerebrospinal fluid (CSF) and associations with inflammation and neurocognitive performance during long-term ART.METHODSParticipants enrolled in the AIDS Clinical Trials Group (ACTG) HIV Reservoirs Cohort Study (A5321) underwent concurrent lumbar puncture, phlebotomy, and neurocognitive assessment. Cell-associated HIV DNA and HIV RNA (CA-DNA, CA-RNA) were measured by quantitative PCR (qPCR). in peripheral blood mononuclear cells (PBMCs) and in cell pellets from CSF. In CSF supernatant and blood plasma, cell-free HIV RNA was quantified by qPCR with single copy sensitivity, and inflammatory biomarkers were measured by enzyme immunoassay.RESULTSSixty-nine participants (97% male, median age 50 years, CD4 696 cells/mm3, plasma HIV RNA <100 copies/mL) were assessed after a median 8.6 years of ART. In CSF, cell-free RNA was detected in 4%, CA-RNA in 9%, and CA-DNA in 48% of participants (median level 2.1 copies/103 cells). Detection of cell-free CSF HIV RNA was associated with higher plasma HIV RNA (P = 0.007). CSF inflammatory biomarkers did not correlate with HIV persistence measures. Detection of CSF CA-DNA HIV was associated with worse neurocognitive outcomes including global deficit score (P = 0.005), even after adjusting for age and nadir CD4 count.CONCLUSIONHIV-infected cells persist in CSF in almost half of individuals on long-term ART, and their detection is associated with poorer neurocognitive performance.FUNDINGThis observational study, AIDS Clinical Trials Group (ACTG) HIV Reservoirs Cohort Study (A5321), was supported by the National Institutes of Health (NIAID and NIMH).

Keywords: AIDS/HIV; Cellular immune response; Immunology.

Figure 1. HIV persistence measures in CSF during ART.

In CSF of individuals on sustained ART started in chronic infection, cell-free HIV RNA was detected in 4% (95% CI: 1%–12%), CA-HIV RNA was detected in 9% (95% CI: 3%–18%), and CA-HIV DNA was detected in 48% (95% CI: 36%–60%). The boxes indicate percentage positive (A). Detection of CA-HIV DNA in CSF cells did not significantly associate with pre-ART CD4 count (B), HIV RNA level (C), CD4/CD8 ratio (D), or years on ART (E), where the boxes indicate median values.

Figure 2. Soluble inflammatory biomarkers in CSF.

CSF sCD163 (A) and CXCL-10 (B) were elevated in CSF in HIV⁺ compared with HIV- participants. Age at CSF collection associated with levels of multiple biomarkers including sCD163 (C), and lower pre-ART CD4/CD8 ratio predicted higher CSF neopterin (D). Segment inside the box indicates median, box edges represent 25th and 75th percentiles and whiskers 10th and 90th percentiles.

Figure 3. Association between detection of CSF CA-HIV DNA and neuropsychological performance.

GDS, global deficit score. Segment inside the box indicates median, box edges represent 25th and 75th percentiles.