Neurologic involvement of HIV remains an important concern for patients, physicians, and investigators. Catastrophic decline is rarely seen in patients on combination antiretroviral therapy (cART); however, neurological decline remains a critical clinical challenge. In this issue of the JCI, Spudich and associates investigated the status of HIV in the cerebral spinal fluid (CSF) and revealed ongoing presence of HIV in the nervous system. Surprisingly, even in the face of optimal treatment, including suppressed HIV RNA, almost half of the patients investigated showed cell-associated HIV (CA-HIV) DNA in the CSF. Spudich et al. find that persistence of HIV in CSF cells is associated with lower performance on neurocognitive testing. These findings emphasize the need to consider a viral-associated mechanism as playing a significant and potentially ongoing role in HIV-associated neurocognitive disorder (HAND).