Transactivator of transcription (Tat)‑induced neuroinfammation as a key pathway in neuronal Dysfunction: A scoping review

Abstract

The activity of HIV-1 and its viral proteins within the central nervous system (CNS) is responsible for a wide array of neuropathological efects, resulting in a spectrum of neurocognitive defcits defned as HIV-associated neurocognitive disorders (HAND). Amongst the various viral proteins, the transactivator of transcription (Tat) remains detectable even with efective antiretroviral therapy (ART) and suppressed viremia, highlighting the signifcance of this protein in the modern ART era. Tat has been extensively researched in both fundamental and clinical settings due to its role in neuroinfammation, neuronal damage, and neurocognitive impairment amongst people living with HIV (PLHIV). To date, numerous fundamental studies have explored Tat-induced neuroinfammation. However, there is no clear consensus on the most frequently studied infammatory markers or the consistency in the levels of these Tat-induced infammatory marker levels across diferent studies. Therefore, we conducted a scoping review of studies investigating Tat-induced neuroinfammation. We conducted searches in PubMed, Scopus, and Web of Science databases using a search protocol tailored specifcally to adhere to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses for scoping reviews (PRISMA-ScR) guidelines. From the 22 included studies, fndings suggest that the HIV-1 Tat protein amplifes levels of neuroinfammatory markers. Amongst the vast array of infammatory markers explored in the included studies, consistent results point to higher levels of CCL2, IL-6, IL-8, and TNF-α in primary cells and cell lines exposed to or transfected with HIV-1 Tat. These markers are regulated by key infammatory pathways, such as the extracellular signal-regulated kinase (ERK)1/2 mitogen-activated protein kinase (MAPK) pathway, the phosphatidylinositol 3-kinase (PI3K) pathway, the p38 MAPK pathway, and nuclear factor-kB (NF-kB). Furthermore, Tat has been shown to induce neuronal apoptosis, both directly and indirectly. With regards to study designs, utilizing full-length Tat101 at concentrations ranging from 100 to 1000 ng/ml and durations of 24 and 48 h appears optimal for investigating Tat-induced neuroinfammation. In this context, we highlight specifc infammatory markers and pathways that are potentially pivotal in Tat-induced neuroinfammation and subsequent neuronal damage. A deeper investigation into these markers and pathways is crucial to better understand their roles in the development of HAND.