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

Abstract

BACKGROUND. Persistence 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. METHODS. Participants 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. RESULTS. Sixty-nine participants (97% male, median age 50 years, CD4 696 cells/mm 3 , 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/10 3 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. CONCLUSION. HIV-infected cells persist in CSF in almost half of individuals on long-term ART, and their detection is associated with poorer neurocognitive performance.

A streamlined clinical metagenomic sequencing protocol for rapid pathogen identification

“…HIV-1 sequences were identi ed in two of these patients with a mapping rate of 4.14 and 1425.45 RPM (Table 3), their serum HIV-1 RNA levels were 3.14E+04 and 7.57E+05 copies/mL, respectively. This con rmed previous reports of cerebral infection of HIV-1 in some AIDS patients [19]. Furthermore, toxoplasma gondii sequences (RPMsample=18024) were identi ed in one of these two samples (sample # 12, Table 3) with a mapping ratio of 61.7 (RPM-r) compared to the blank control (RPM NTC =292, data not shown).…”

Osteopontin/Secreted Phosphoprotein-1 Behaves as a Molecular Brake Regulating the Brain Translocator Protein-Dependent Neuroinflammatory Response to Chronic Viral Infection

“…Ruling out underlying genetic susceptibility to dementia, there are competing ideas, supported by data suggesting that cognitive de cits could be related to a legacy effect (52) or low-level chronic HIV replication in the brain (53), both of which would in ict accumulating damage to neural networks over the span of time. Our mice model in which HIV RNA expression was detected in the brain in only a few cells per ve-micron section represents the latter, low-level chronic infection modeling approximately 48-55 human years.…”

Is successful HIV therapy a Pyrrhic victory for the brain?

“…It is important not to catastrophize the results of this study. Spudich et al report that patients both with and without CSF CA-HIV DNA had median neurocognitive performances in the normal range (4). While the percentage of participants whose performance fell in the impaired range was higher for those with virus in the CSF, the difference in performance was notably modest.…”

“…In this issue, Spudich et al studied a group of 69 patients that represent bestcase outcomes for optimal management of HIV as it has evolved during the post-cART era (4). The subjects initiated treatment during chronic infection through the AIDS Clinical Trials Group studies, and were continuously monitored for a median of 8.6 years of treatment with good evidence for excellent compliance throughout that period (4). Nearly half of the patients possessed cerebral spinal fluid-derived (CSF-derived) cells that contained HIV DNA, and importantly this persistence was associated with inferior neurocognitive performance.…”

“…The most striking finding in Spudich et al -that such a large proportion of patients have cells harboring HIV DNA -raises several critical questions that are important but technically difficult to answer (4). What cell type contains this residual virus remains a key question.…”