Probes for HIV

Combination antiretroviral therapy (ART) can suppress plasma HIV-RNA to < 50 copies/mL, decrease HIV transmission, reduce mortality, and improve quality of life for people living with HIV. ART cannot, however, eliminate HIV from an infected individual. The primary barrier to cure HIV infection is the multiple reservoir sites, including adipose tissue, bone marrow, central nervous system, liver, lungs, male and female reproductive system, secondary lymph nodes, and gut-associated lymphoid tissue, established 1 to 2 weeks after acquisition of HIV. Additional challenges include understanding the mechanism(s) by which HIV is maintained at low or undetectable levels and developing treatments that will eradicate or produce a sustained suppression of virus without ART. To date, the most extensive clinical investigations of cure strategies have been the shock-and-kill approach using histone deacetylase inhibitors (HDACis) to induce reactivation of latent HIV. Despite evidence for HIV latency reversal, HDACis alone have not decreased the size of the latent reservoir. Clinical pharmacologic explanations for these results include a low inhibitory quotient (i.e., low potency) within the reservoir sites and intrinsic (e.g., sex differences and reservoir size) and extrinsic (physiochemical and pharmacokinetic drug characteristics) factors. We offer an outline of desired clinical pharmacologic attributes for therapeutics intended for clinical HIV cure research and call for research teams to have early and ongoing involvement of clinical pharmacologists. We believe such a collective effort will provide a solid scientific basis and hope for reaching the goal of a cure for HIV infection.

The chronic infection established by the human immunodeficiency virus 1 (HIV-1) produces serious CD4+ T cell immunodeficiency despite the decrease in HIV-1 ribonucleic acid (RNA) levels and the raised life expectancy of people living with HIV-1 (PLWH) through treatment with combined antiretroviral therapies (cART). HIV-1 enters the central nervous system (CNS), where perivascular macrophages and microglia are infected. Serious neurodegenerative symptoms related to HIV-associated neurocognitive disorders (HAND) are produced by infection of the CNS. Despite advances in the treatment of this infection, HAND significantly contribute to morbidity and mortality globally. The pathogenesis and the role of inflammation in HAND are still incompletely understood. Principally, growing evidence shows that the CNS is an anatomical reservoir for viral infection and replication, and that its compartmentalization can trigger the evolution of neurological damage and thus make virus eradication more difficult. In this review, important concepts for understanding HAND and neuropathogenesis as well as the viral proteins involved in the CNS as an anatomical reservoir for HIV infection are discussed. In addition, an overview of the recent advancements towards therapeutic strategies for the treatment of HAND is presented. Further neurological research is needed to address neurodegenerative difficulties in people living with HIV, specifically regarding CNS viral reservoirs and their effects on eradication.

HIV-1 infection within the central nervous system (CNS) includes evolution of the virus, damaging inflammatory cascades, and the involvement of multiple cell types; however, our understanding of how Env tropism and inflammation can influence CNS infectivity is incomplete. In this study, we utilize macrophage-tropic and T cell-tropic HIV-1 Env proteins to establish accurate infection profiles for multiple CNS cells under basal and interferon alpha (IFN-α) or lipopolysaccharide (LPS)-induced inflammatory states. We found that macrophage-tropic viruses confer entry advantages in primary myeloid cells, including monocyte-derived macrophage, microglia, and induced pluripotent stem cell (iPSC)-derived microglia. However, neither macrophage-tropic or T cell-tropic HIV-1 Env proteins could mediate infection of astrocytes or neurons, and infection was not potentiated by induction of an inflammatory state in these cells. Additionally, we found that IFN-α and LPS restricted replication in myeloid cells, and IFN-α treatment prior to infection with vesicular stomatitis virus G protein (VSV G) Envs resulted in a conserved antiviral response across all CNS cell types. Further, using RNA sequencing (RNA-seq), we found that only myeloid cells express HIV-1 entry receptor/coreceptor transcripts at a significant level and that these transcripts in select cell types responded only modestly to inflammatory signals. We profiled the transcriptional response of multiple CNS cells to inflammation and found 57 IFN-induced genes that were differentially expressed across all cell types. Taken together, these data focus attention on the cells in the CNS that are truly permissive to HIV-1, further highlight the role of HIV-1 Env evolution in mediating infection in the CNS, and point to limitations in using model cell types versus primary cells to explore features of virus-host interaction. IMPORTANCE The major feature of HIV-1 pathogenesis is the induction of an immunodeficient state in the face of an enhanced state of inflammation. However, for many of those infected, there can be an impact on the central nervous system (CNS) resulting in a wide range of neurocognitive defects. Here, we use a highly sensitive and quantitative assay for viral infectivity to explore primary and model cell types of the brain for their susceptibility to infection using viral entry proteins derived from the CNS. In addition, we examine the ability of an inflammatory state to alter infectivity of these cells. We find that myeloid cells are the only cell types in the CNS that can be infected and that induction of an inflammatory state negatively impacts viral infection across all cell types.