Neuropathology of HAND With Suppressive Antiretroviral Therapy: Encephalitis and Neurodegeneration Reconsidered

HIV-1 infiltrates the central nervous system (CNS) during the initial infection and thereafter plays a persistent role in producing CNS dysfunction as the disease progresses. HIV-associated neurocognitive disorders (HAND) are highly prevalent in HIV-infected patient populations, including currently infected patients with good access to suppressive antiretroviral therapy (cART). cART decreased the severity of CNS dysfunction dramatically and, in doing so, upended the neuropathological foundation of HAND pathophysiology. It is clear that the working concept of pathophysiology prior to cART, which was driven by inflammation, encephalitis, and neurodegeneration, needs to be replaced. The NeuroAIDS field is reluctant to take that important step. This review explores the fact that the neuropathological concept that drove the field before the era of cART no longer seems to fit with what is commonly observed in patients treated successfully with cART. The field clings to the pre-cART idea that HAND is sequentially driven by virus replication in CNS, brain inflammation (encephalitis), and neurodegeneration. Neurovirological, clinicopathological, and gene expression correlations in cART-treated patients, however, provide little strong support for it. Introducing cART into clinical practice decreased HIVE, inflammation, and degeneration but did not cure HAND. Brain gene array data suggest that the neurovascular unit is a critical target in virally suppressed patients with HAND. The NeuroAIDS field needs an infusion of new ideas to steer research toward issues of the highest relevance to virally suppressed patients. With no suitable replacement immediately within reach, devaluating formative ideas is understandably difficult to accept. The cliniconeuropathological correlation in virally suppressed patients needs to be better defined.