HIV persists in the central nervous system (CNS), and a subset of PWH develop neurocognitive issues despite virally suppression. With a diverse set of infected cells comprising the CNS reservoir, along with the impact of both acute and chronic infection on local inflammation and blood brain barrier integrity, the CNS presents an important and unique challenge, not only for ongoing management, but importantly for cure strategies.
Studies have demonstrated the CNS reservoir resides predominantly in resident microglia, the role of astrocytes, resident and circulating T cells is less clear. HIV genomes in the CNS are transcriptionally/translationally active despite viral suppression with transcriptional products and viral proteins detected. As reported for peripheral reservoirs, defective proviral genomes predominate in the CNS in both virally suppressed and viremic PWH. The function of these defective genomes remains unclear, but likely contribute to ongoing neuroinflammation. The frequency of infected cells within the brain is reported to be very low, however, in the cerebrospinal fluid (CSF), levels of cell free virus and HIV+ T cells have been associated with adverse neurological outcomes in PWH. The source of cell free CSF virus remains unclear.
With the advent of cure strategies involving activation of virus either by removal of ART or by the administration of latency reversal agents (LRAs) the ability of these strategies to access and impact the CNS is critical. Some LRAs can cross the blood brain barrier (BBB) with little toxicity observed and are capable of activating brain derived HIV in vitro, however, the impact of activating the brain reservoir on local inflammation is less clear. The restrictive nature of BBB may impact other current strategies including immunotherapy and gene therapy approaches; therefore, effectiveness and adverse CNS effects needs consideration.
Currently, the development of cure strategies focuses primarily on effectiveness and impacts on the peripheral blood and tissue reservoirs. Clinical trials in both non-human primates (NHPs) and PWH have largely failed to include consideration and analysis of impacts on the CNS. It is critical that future cure strategies consider the CNS and include PWH with a greater predisposition for poor HIV associated neurological outcomes.
In this presentation we will discuss the nature and impact of the CNS reservoir, its role in ongoing neuropathology and the potential impact of cure strategies.