Genetic variation and function of the HIV-1 Tat protein

Abstract

Human immunodeficiency virus type 1 (HIV-1) encodes a transactivator of transcription (Tat) protein, which has several functions that promote viral replication, pathogenesis, and disease. Amino acid variation within Tat has been observed to alter the functional properties of Tat and, depending on the HIV-1 subtype, may produce Tat phenotypes differing from viruses representative of each subtype and commonly used in in vivo and in vitro experimentation. The molecular properties of Tat allow for distinctive functional activities to be determined such as the subcellular localization and other intra-and extracellular functional aspects of this important viral protein influenced by variation within the Tat sequence. Once Tat has been transported into the nucleus and becomes engaged in transactivation of the long terminal repeat (LTR), various Tat variants may differ in their capacity to activate viral transcription. Post-translational modification patterns based on these amino acid variations may alter interactions between Tat and host factors, which may positively or negatively affect this process. Additionally, the ability of HIV-1 to utilize or not utilize the transactivation response (TAR) element within the LTR, based on genetic variation and cellular phenotype, adds a layer of complexity to the processes that govern Tatmediated proviral DNA-driven transcription and replication. In contrast, cytoplasmic or extracellular localization of Tat may cause pathogenic effects in the form of altered cell activation, apoptosis, or neurotoxicity. Tat variants have been shown to differentially induce these processes, which may have implications for long-term HIV-1-infected patient care in the antiretroviral therapy era. Future studies concerning genetic variation of Tat with respect to function should focus on variants derived from HIV-1-infected individuals to efficiently guide Tat-targeted therapies and elucidate mechanisms of pathogenesis within the global patient population.

Nonthermal plasma as part of a novel strategy for vaccination

“…Pathogens, like the human immunodeficiency virus type 1 (HIV‐1), almost always succeed in causing disease by disabling immune cells, evading the immune system, and acquiring mutations that provide resistance to antiviral drugs. [ 11–14 ] Control of pathogens that have such mechanisms to evade the host immune system necessitates a pharmacological intervention to prevent the disease. Therefore, each pathogen may present a unique set of challenges to the immune system that must be specifically addressed.…”

Morphine exposure exacerbates HIV-1 Tat driven changes to neuroinflammatory factors in cultured astrocytes

“…therefore, Tat secretion-deficient mutants may alleviate this phenotype within patients [49][50][51][52][53][54][55]. Finally, mutations at a conserved cysteine at amino acid position 31, C31, which is within the cysteine-rich domain, have been shown to abrogate synaptodendritic injury in neurons and normalize levels of amyloid beta production, therefore conferring protection from Tatmediated neurotoxicity [41,[56][57][58].…”

“…Tat is actively secreted to the extracellular space by HIV-1 infected cells; a function which allows Tat to interact with other cells and cell types, potentially modulating cell signaling [45,46,92]. The translocation of Tat across membranes relies on a single tryptophan, W11, which is indispensable for Tat's transactivation function [41]. To explore whether the lack of secretory function of Tat affects cellular accumulation and subsequently βcatenin activation, we utilized mutations at Tat W11, Tat W11F and Tat W11Y, in our studies.…”

“…In particular, the HIV-1 viral protein Tat has been associated with clinical neuropathogenicity in the CNS, specifically through induction of inflammatory processes including astrogliosis [32][33][34][35][36][37][38][39][40]. HIV-1 Tat has classically been described in its function as the viral transactivator for HIV-1 transcription in infected cells [41]. HIV-1 transcription is mediated by Tat binding to the transactivation response (TAR) element, an RNA stem-loop encoded by the HIV-1 long-terminal repeat (LTR) promoter, which results in the recruitment of the host positive transcription elongation factor b (p-TEFb) complex, which phosphorylates RNA pol II, thereby driving HIV-1 transcriptional elongation [41][42][43][44].…”

“…HIV-1 is subject to genetic variation, which may alter the functionality of the encoded viral proteins. In vitro, Tat expressing cells have been demonstrated to readily secrete Tat extracellularly, a function mediated by a tryptophan at amino acid position 11 (W11), as well as residues 49-51 within the basic domain [41,[45][46][47]. Tat variants containing mutations at this position, such as W11F or W11Y, are deficient in both secretion from Tat-producing cells and cytoplasmic translocation in recipient cells [46,48].…”