HIV Viral DNA Cells Persist in Cerebrospinal Fluid Despite Long-Term ART

Nearly half of participants in a national long-term antiretroviral therapy (ART) study continued to have HIV reservoirs present in their cerebrospinal fluid (CSF) after nearly a decade of treatment, contributing to worse neurocognitive outcomes, a study has found.

Investigators from the University of Pittsburgh School of Medicine, Yale University, and the University of North Carolina conducted a trial examining CSF samples from people living with HIV who had been on ART for an average of 9 years to determine where the virus lurks in the body despite ongoing treatment. The results were published recently in The Journal of Clinical Investigation.

A cohort of 69 individuals (97% male, median age 50 years, CD4 696 cells/mm³, plasma HIV RNA <100 copies/mL) enrolled in the AIDS Clinical Trials Group HIV Reservoirs Cohort Study who had initiated ART during chronic infection and whose viral loads had been suppressed for a median 8.6 years were included in the study. Participants underwent concurrent lumbar puncture, phlebotomy, and neurocognitive assessment, and investigators measured cell-associated HIV DNA and HIV RNA (CA-DNA, CA-RNA) via quantitative polymerase chain reaction (qPCR) within peripheral blood mononuclear cells and in cell pellets in CSF.

Investigators detected HIV DNA in CSF cell pellets in 48% of participants (95% CI: 36%—60%), compared with CSF CA-RNA in just 9% of participants (95% CI: 3%–18%) and detectable HIV RNA in 3–5 mL cell-free CSF fluid in only 4% of participants (95% CI: 1%–12%).

“The striking observation that almost half of participants harbored HIV-infected cells in the CSF demonstrates that the [central nervous system] compartment is a site of viral persistence despite many years of viremia suppression on ART,” the research team wrote in the study. “[W]e identified a significant association between detectable HIV DNA in CSF cells and neurocognitive performance, revealing potential clinical relevance of this viral measure in the CNS. It is possible that persistent HIV in the [central nervous system] may drive neurocognitive injury, though the mechanisms of this are unknown.”

John W. Mellors, MD, chief of the Division of Infectious Diseases at the University of Pittsburgh, and an investigator on the study, said the team was surprised by the findings and detailed next steps for this line of research.

“We did not expect 1) to find HIV in cells in fluid around the brain in almost 50% of individuals after long-term treatment and 2) for the cells to be associated with poorer neurocognitive function,” Mellors told Contagion®. Next steps will involve “determining the types of cells that carry HIV in the spinal fluid, whether the HIV is infectious, and teasing apart the relationship between infected cells and neurocognitive dysfunction.”

Clinicians treating people living with HIV should “beware [that] HIV may be causing brain dysfunction in their patients despite best available therapy,” Mellors said.