Human Immunodeficiency Virus Type-1 (HIV-1) Transcriptional Regulation, Latency and Therapy in the Central Nervous System

Abstract

The central nervous system (CNS) is highly compartmentalized and serves as a specific site of human immunodeficiency virus (HIV) infection. Therefore, an understanding of the cellular populations that are infected by HIV or that harbor latent HIV proviruses is imperative in the attempts to address cure strategies, taking into account that HIV infection and latency in the CNS may differ considerably from those in the periphery. HIV replication in the CNS is reported to persist despite prolonged combination antiretroviral therapy due to the inability of the current antiretroviral drugs to penetrate and cross the blood–brain barrier. Consequently, as a result of sustained HIV replication in the CNS even in the face of combination antiretroviral therapy, there is a high incidence of HIV-associated neurocognitive disorders (HAND). This article, therefore, provides a comprehensive review of HIV transcriptional regulation, latency, and therapy in the CNS.

Bcl-2 Antagonist Obatoclax Reactivates Latent HIV-1 via the NF-κB Pathway and Induces Latent Reservoir Cell Apoptosis in Latently Infected Cells

“…HIV-1 Tat mainly acts on RNA element TAR on HIV-1 transcription elongation. − Obatoclax stimulates transcription initiation and elongation in ACH2 cells (mutation in TAR) (Figure A). Numerous works of literature confirm that NF-κB is a key transcriptional regulatory factor for the initiation and extension of HIV-1 transcription, and it affects HIV-1 Tat-mediated transcription without TAR. , Here, we further assessed whether the effect of obatoclax on HIV-1 reactivation was related to its effect on the NF-κB pathway. Generally, NF-κB remains sequestered in the cytoplasm by its inhibitor protein IκB in its inactive state.…”

Cocaine sensitizes the CD4+ T cells for HIV infection by co-stimulating NFAT and AP-1

“…Consequently, even shorter interruptions of ART result in severe damage to brain and immune functions in patients with HIV using illicit drugs compared to non-drug-using HIV-infected individuals. 17 , 56 , 57 , 58 , 59 Cocaine, one of the most abused drugs in the world, is an important cofactor in spreading HIV by enhancing both HIV transmission and replication, in addition to making cells suitable to support HIV infection. 22 , 57 , 58 Notably, in ART naive patients, use of illicit drugs accelerates AIDS progression.…”

New Insights into HIV Life Cycle, Th1/Th2 Shift during HIV Infection and Preferential Virus Infection of Th2 Cells: Implications of Early HIV Treatment Initiation and Care

“…The resultant complex formed is made up of multiple proteins comprising TBP and TAF, referred to as TFIID, which, along with three SP1 binding sites, constitutes the minimal transcription complex that can induce basal HIV LTR promoter transcription. However, for efficient HIV LTR promoter-mediated transcription, it requires the TFIID interaction with upstream enhancer binding factors such as NF-κB, AP-1 or NFAT [75,[82][83][84][85][86][87][88][89][90]. Transcription factor II H (TFIIH) exhibits kinase activity (CDK7) required for promoter clearance by phosphorylating the C-terminal domain (CTD) of RNAP II, whose recruitment to the HIV LTR promoter is reported to be the major determinant in HIV transcription, especially HIV-1 transcription initiation [80,91,92].…”