“Hidden” HIV in Cerebrospinal Fluid Cells May Lead to Cognitive Problems

Researchers find even after a negative HIV RNA test outcome, some patients may still have viral DNA in their cerebrospinal fluid that could potentially lead to cognitive difficulties in the long-term.


Even when a standard HIV RNA test is negative, some patients may still have viral DNA in their cerebrospinal fluid (CSF)—and that could be a predictor of later memory and concentration problems, say researchers who conducted a National Institute of Health (NIH)-funded study of patients on long-term antiretroviral therapy (ART).

The 69 participants, enrolled in the AIDS Clinical Trials Group HIV Reservoirs Cohort Study, had infections controlled with ART for a median of 9 years. Calling it a “striking observation,” the researchers found nearly half of the patients had viral DNA in CSF cells, although the standard viral load tests of the cell-free CSF fluid were positive in only 4% of the patients.

Of the 30 patients with persistent HIV, 9 (30%) experienced neurocognitive difficulties in a 7-domain neuropsychological test battery. Among 35 participants with no detectable HIV DNA in CSF, 4 (11%) were clinically impaired.

The low rates of detectable HIV RNA in the cell-free CSF fraction and within CSF cell pellets suggest low levels of HIV transcription within cells and infrequent release into the extracellular space during systemically suppressive ART, the researchers say.

The brain is one of the first targets of the virus, and CNS manifestations are common. Neurocognitive impairment in HIV-positive patients is probably related to multiple factors, including HIV infection, age, neuroinflammation, and comorbid conditions, including substance abuse, the researchers say. There also may be a “legacy effect,” in which processes associated with long-term exposure to HIV before ART leads to irreversible neurologic injury and more extensive infection of CSF cells. Lack of an association with inflammatory biomarkers in this study suggested that current inflammation does not lead to present neurocognitive dysfunction, the researchers say, but does not rule out prior inflammation as the underlying cause of neuronal injury.

Still, given that brain tissue in living individuals is “inaccessible” (as the researchers put it), CSF offers a window into neuropathogenesis of HIV. Studies have found a range between 15% and 55% of participants develop an HIV-associated neurocognitive disorder (HAND). The new findings may support a role of persistent HIV-infected cells, but the researchers emphasize that the association does not confirm that HIV DNA causes HAND. However, they add, persistent HIV in “sanctuary sites” despite ART presents a barrier to curing the infection. Their study, they say, indicates that examination of CSF cells is important in assessing residual HIV in compartments during ART.

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