PLoS Pathog 17(12):Įditor: Guido Silvestri, Emory University, UNITED STATES (2021) Cerebrospinal fluid CD4+ T cell infection in humans and macaques during acute HIV-1 and SHIV infection. Our study provides new insights to the early events of viral entry and replication in the CNS with implications for subsequent viral persistence and neuronal injury.Ĭitation: Sharma V, Creegan M, Tokarev A, Hsu D, Slike BM, Sacdalan C, et al. In addition, infected T cells were present at similar frequencies in the CNS and other anatomic compartments, suggesting equilibration of T cell infection levels across these sites and potential for establishment of long-term reservoirs in the CNS. We found HIV-1 replication in T cells in the cerebrospinal fluid during this early window. Here, we use novel techniques to probe cells for viral infection during the first few weeks of infection in the CNS of humans and animals to determine the source of this virus. The appearance of HIV-1 in the cerebrospinal fluid during the earliest stages of infection suggests that these processes may begin very early. How HIV-1 causes neurocognitive dysfunction is currently unclear, though it is widely believed that viral replication within the central nervous system (CNS) prior to therapy triggers these detrimental processes. Despite the advent of successful viremia suppression by anti-retroviral therapy, increased life expectancies and co-morbidities have led to higher prevalence of milder forms of neurocognitive dysfunction. Neurological pathologies are associated with HIV-1 infection and remain common in the ongoing AIDS epidemic. Thus, early initiation of antiretroviral therapy may not be able to prevent establishment of CNS viral reservoirs and sources of long-term inflammation, important targets for HIV-1 cure and therapeutic strategies. These studies provide direct evidence of HIV-1 replication in CD4+ T cells and broad immune activation in peripheral blood and the CNS during acute infection, likely contributing to early neuroinflammation and reservoir seeding. In addition, surface markers of activation were increased on CSF T cells and monocytes and correlated with CSF soluble markers of inflammation. Infection levels were similar between CSF and peripheral blood (and lymph nodes in macaques), indicating comparable T cell infection across these compartments. Replication-inactive CD4+ T cell infection, indicated by unspliced viral RNA in the absence of spliced viral RNA, was even more prevalent, present in CSF of >50% macaques and human CSF at ~10-fold higher frequency than productive infection. Active viral transcription (spliced viral RNA) was present in CSF CD4+ T cells as early as four weeks post-SHIV infection, and among all acute HIV-1 specimens (N = 6 Fiebig III/IV).
We measured viral RNA+ cells in CSF from acutely infected macaques longitudinally and people living with early stages of acute HIV-1. The origins of HIV-1 detected in the CNS compartment are unknown, including whether cells within the cerebrospinal fluid (CSF) produce virus.
HIV-1 replication within the central nervous system (CNS) impairs neurocognitive function and has the potential to establish persistent, compartmentalized viral reservoirs.