The persistence of HIV in sanctuary sites in the human body even in the presence of antiretroviral therapy (ART) is a potential barrier to HIV remission and cure. The central nervous system is one of those sanctuary sites and it has unique properties, in terms of cell composition and antiretroviral penetration. Because neurocognitive function can be compromised even in individuals whose HIV is well treated, it is important to understand HIV persistence in the nervous system. In the ACTG HIV Reservoirs Cohort Study (A5321), virally suppressed individuals with HIV taking long-term ART were tested for persistent HIV in their cerebrospinal fluid.

The study included 69 participants with well-treated HIV who had their cerebrospinal fluid and blood collected and underwent neurocognitive assessments, which included tests of memory, learning, motor function, and more. Participants were mostly male (97%) and had been on HIV treatment for a long time (median almost 9 years), with a good response to medications (HIV viral loads all <100, and median CD4 count in the normal range). The team examined genetic material of HIV in the cells from the cerebrospinal fluid, as well as from the portion of the fluid without cells. The study revealed that HIV DNA was detected in almost half of participants and was associated with poorer neurological and cognitive function. This persisted even after adjusting for participants’ age and the severity of immune suppression they had experienced in the past.

The association between HIV genetic material in cerebrospinal fluid with poorer performance on cognitive tests suggests that there may be a link between HIV persistence in the brain compartment and the neurological complications that some people living with HIV experience. Further studies will help determine strategies to reverse this persistence and improve neurological functioning in patients with long-standing HIV.

Spudich S*, Robertson K*, Bosch R, Gandhi RT, Cyktor J, Mar H, Macatangay B, Lalama C, Rinaldo C, Collier A, Godfrey C, Eron J, McMahon D, Jacobs J, Koontz D, Hogg E, Vecchio A, Mellors J.  Persistent HIV-infected cells in cerebrospinal fluid are associated with poorer neurocognitive performance.  Journal of Clinical Investigation 2019, in press.
*Authors contributed equally


There is an ongoing debate in the literature about whether elite controllers require antiretroviral therapy (ART) for secondary benefits, including control for low-level viral replication and reduction of inflammation. ACTG A5308 attempted to resolve this debate by looking at the effect of ART on virologic suppression, the viral reservoir, immune activation, and quality of life in a group of elite controllers enrolled in the ACTG.

A5308 study was a prospective, open-label study of rilpivirine, emtricitabine and tenofovir disoproxil fumarate provided to ART-naïve HIV controllers (n=35) defined as having HIV RNA levels of <500 copies/mL off of therapy. The study found that ART was effective in increasing the proportion of individuals with undetectable residual viremia and decreasing the proportion of CD38+HLA-DR+CD8+ T cells (a marker of immune activation). Researchers also identified a modest but statistically significant improvement in self-reported quality of life. A5308 resolves the question around the value of ART for elite controllers, by demonstrating the clinical benefits of ART in this population.

Li J, Segal FP, Bosch RJ, Lalama CM, Roberts-Toler C, Delagreverie H, Getz R, Garcia-Broncano P, Kinslow J, Tressler R, Van Dam CN, Keefer M, Carrington M,9, Lichterfeld M, Kuritzkes D, Yu XG, Landay 5, Sax PE; ART reduces T cell activation and immune exhaustion markers in HIV controllers. Clin Infect Dis. 2019 May 25. [Epub ahead of print]