Summary: HIV can persist in the nervous system even when standard blood tests show viral suppression. This hidden viral material in cerebrospinal fluid (CSF) cells is linked to ongoing problems with memory and concentration for some people on long-term antiretroviral therapy (ART).
Source: NIH/NIAID
New findings reveal that many people living with HIV who are receiving antiretroviral therapy still have viral genetic material in cells found in their cerebrospinal fluid (CSF), and those with this cellular HIV are more likely to report problems with memory, attention, and other cognitive functions. The study, published online in the Journal of Clinical Investigation, examined 69 adults on long-term ART and found that nearly half had detectable HIV DNA in CSF cells. Among that group, about 30% showed measurable neurocognitive difficulties. These results suggest that, for some patients, HIV may persist in the central nervous system (CNS) despite effective suppression of virus in blood, and that this persistent cellular reservoir may contribute to cognitive symptoms.
Researchers from the University of North Carolina, the University of Pittsburgh, and Yale University analyzed participants enrolled in the AIDS Clinical Trials Group (ACTG) HIV Reservoirs Cohort Study (A5321). The cohort was predominantly male with a median age in the early 50s and represented long-term HIV survivors whose infections had been controlled on ART for a median of approximately nine years.
The team collected cerebrospinal fluid by lumbar puncture, drew blood for parallel testing, and conducted standard neurocognitive assessments for each participant. Using sensitive quantitative PCR methods, investigators measured cell-associated HIV DNA (CA-DNA) and cell-associated HIV RNA (CA-RNA) in both peripheral blood mononuclear cells (PBMCs) and the cell pellets recovered from CSF. They also measured cell-free HIV RNA in CSF supernatant and plasma with single-copy sensitivity and evaluated inflammatory biomarkers.
Key results from the study include:
- Cell-associated HIV DNA was detected in CSF cells in 48% of participants, indicating a substantial prevalence of persistent viral material within the CNS cellular compartment.
- Cell-free HIV RNA in CSF supernatant was uncommon and identified in only about 4% of participants, while CA-RNA was detected in 9%.
- Among participants with detectable CSF CA-DNA, 30% had clinical neurocognitive impairment versus 11% of those without CSF CA-DNA.
- Detection of cell-free CSF HIV RNA correlated with higher plasma HIV RNA, but CSF inflammatory biomarkers did not show a consistent relationship with measures of HIV persistence in this study.
These findings reinforce the idea that cellular HIV reservoirs in the CNS can persist despite years of suppressive ART and may be associated with worse performance on neurocognitive testing, including higher global deficit scores. The authors emphasize that while the association between CSF cell-associated HIV DNA and poorer cognition was statistically significant—even after adjustment for age and historical lowest CD4 count (nadir CD4)—the overall frequency of clinically significant neurocognitive impairment in the cohort was relatively low. Importantly, the study establishes an association but does not demonstrate direct causation between persistent CSF HIV DNA and HIV-associated neurocognitive disorder (HAND).
Interpretation and implications: The detection of HIV-infected cells in CSF highlights a potential barrier to full eradication of HIV from the body and raises questions about the mechanisms that drive neurocognitive symptoms in some people on long-term ART. One hypothesis is that even low-level or latent infection within CNS-resident or trafficking immune cells contributes to localized inflammation or dysfunction, which could affect cognition. However, this study did not find a consistent link between measured inflammatory biomarkers in CSF and viral persistence, indicating that the relationship between CNS viral reservoirs, inflammation, and cognition remains complex and requires further investigation.
Funding: The research was supported by the National Institute of Allergy and Infectious Diseases (NIAID) and the National Institute of Mental Health (NIMH), both components of the National Institutes of Health.
Source:
NIH/NIAID
Media Contacts:
Judith Lavelle – NIH/NIAID
Image Source:
The image is in the public domain.
Original Research: Open access
“Persistent HIV-infected Cells in Cerebrospinal Fluid are Associated with Poorer Neurocognitive Performance”. S Spudich et al. Journal of Clinical Investigation. DOI: 10.1172/JCI127413
Abstract (summary)
Background. Persistence of HIV in sanctuary sites despite antiretroviral therapy (ART) presents a barrier to HIV remission and may affect neurocognitive function. This study assessed HIV persistence in cerebrospinal fluid (CSF) and explored associations with inflammation and neurocognitive performance during long-term ART.
Methods. Participants enrolled in the ACTG HIV Reservoirs Cohort Study underwent concurrent lumbar puncture, blood sampling, and neurocognitive assessment. Cell-associated HIV DNA and RNA were quantified in PBMCs and CSF cell pellets, while cell-free HIV RNA in CSF supernatant and plasma was measured with single-copy sensitivity. Inflammatory biomarkers were measured by enzyme immunoassay.
Results. Among 69 participants (97% male; median age 50; median CD4 696 cells/mm3; median ART duration 8.6 years), 48% had detectable CSF cell-associated HIV DNA (median 2.1 copies per 103 cells). Cell-free CSF HIV RNA was detected in 4%, and CA-RNA in 9%. Detection of CSF CA-DNA was associated with worse neurocognitive outcomes, including higher global deficit scores, even after adjusting for age and nadir CD4 count. CSF inflammatory biomarkers did not correlate with measures of HIV persistence.
Conclusion. HIV-infected cells persist in CSF in nearly half of individuals on long-term ART, and their detection is associated with poorer neurocognitive performance. These results underscore the importance of further research into CNS reservoirs as obstacles to HIV remission and potential contributors to cognitive symptoms in treated individuals.