An investigation of the HIV Tat C31S and R57S mutation on peripheral immune marker levels in South African participants: A pilot study

Williams, Monray E.; Ruhanya, Vurayai; Paul, Robert; Ipser, Jonathan; Stein, Dan J.; Joska, John A.; Naudé, Petrus J.W.

doi:10.1002/jmv.27720

Cited by 6 publications

(3 citation statements)

References 12 publications

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“…This may also explain why lower levels of neuropathogenesis are seen in PLWH with subtype C when compared to subtype B ( Ruiz et al, 2019 ). We recently observed that the R57S mutation in South Africa participants accounted for lower levels of certain immune markers including C-C motif chemokine ligand 2 and thymidine phosphorylase ( Williams et al, 2022 ) and these markers are related to neurocognitive impairment in PLWH ( Ancuta et al, 2008 ; Cohen et al, 2011 ; Williams et al, 2019 ). Our findings suggest that the R57S mutation found in Tat subtype C may influence lower TAR binding and this may be an initiating step to why we see less severe neuropathophysiological (e.g., dysregulated inflammation) features related to HIV-1C infection ( Ruiz et al, 2019 ).…”

Section: Discussionmentioning

confidence: 99%

Molecular Modeling of Subtype-Specific Tat Protein Signatures to Predict Tat-TAR Interactions That May Be Involved in HIV-Associated Neurocognitive Disorders

Williams

Cloete

2022

Front. Microbiol.

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HIV-1 is responsible for a spectrum of neurocognitive deficits defined as HIV-associated neurocognitive disorders (HAND). The HIV transactivator of transcription (Tat) protein plays a key role in the neuropathophysiology of HAND. The Tat protein functions by transactivation of viral genes through its interaction with the transactivation response (TAR) RNA element. Subtype-specific Tat protein signatures including C31S, R57S and Q63E present in Tat subtype C has previously been linked to a lowered neuropathophysiology compared to Tat subtype B. In this study, we attempted to understand the molecular mechanism by which Tat subtype-specific variation, particularly, C31S, R57S, and Q63E influence the Tat-TAR interaction. We performed molecular modeling to generate accurate three-dimensional protein structures of the HIV-1 Tat subtypes C and B using the Swiss model webserver. Thereafter, we performed a molecular docking of the TAR RNA element to each of the Tat subtypes B and C protein structures using the HDOCK webserver. Our findings indicate that Tat subtype B had a higher affinity for the TAR RNA element compared to Tat subtype C based on a higher docking score of −187.37, a higher binding free energy value of −9834.63 ± 216.17 kJ/mol, and a higher number of protein–nucleotide interactions of 26. Furthermore, Tat subtype B displayed more flexible regions when bound to the TAR element and this flexibility could account for the stronger affinity of Tat subtype B to TAR. From the Tat signatures linked to neuropathogenesis, only R57/R57S are involved in Tat-TAR interaction. Due to the lack of electrostatic interactions observed between Tat subtype C and TAR, weaker affinity is observed, and this may contribute to a lower level of neuropathophysiology observed in subtype C infection.

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Section: Discussionmentioning

confidence: 99%

Molecular Modeling of Subtype-Specific Tat Protein Signatures to Predict Tat-TAR Interactions That May Be Involved in HIV-Associated Neurocognitive Disorders

Williams

Cloete

2022

Front. Microbiol.

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“…Last, we wanted to determine if HIV subtype variation may have influenced the association between inflammatory markers and NCI/HIVE in post‐mortem brain tissue of PLWH, considering the fact that the HIV‐1 subtype variation and subtype‐specific viral protein amino acid substitutions can influence the prevalence of HAND, 91 , 92 , 93 , 94 as well as the levels of inflammatory markers. 95 , 96 …”

Section: Methodsmentioning

confidence: 99%

The relationship between HIV‐1 neuroinflammation, neurocognitive impairment and encephalitis pathology: A systematic review of studies investigating post‐mortem brain tissue

Williams,

Naudé

2024

Reviews in Medical Virology

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The activities of HIV‐1 in the central nervous system (CNS) are responsible for a dysregulated neuroinflammatory response and the subsequent development of HIV‐associated neurocognitive disorders (HAND). The use of post‐mortem human brain tissue is pivotal for studying the neuroimmune mechanisms of CNS HIV infection. To date, numerous studies have investigated HIV‐1‐induced neuroinflammation in post‐mortem brain tissue. However, from the commonly investigated studies in this line of research, it is not clear which neuroinflammatory markers are consistently associated with HIV neurocognitive impairment (NCI) and neuropathology (i.e., HIV‐encephalitis, HIVE). Therefore, we conducted a systematic review of the association between neuroinflammation and NCI/HIVE from studies investigating post‐mortem brain tissue. Our aim was to synthesise the published data to date to provide commentary on the most noteworthy markers that are associated with NCI/HIVE. PubMed, Scopus, and Web of Science databases were searched using a search protocol designed specifically for this study. Sixty‐one studies were included that investigated the levels of inflammatory markers based on their gene and protein expression in association with NCI/HIVE. The findings revealed that the (1) transcript expressions of IL‐1β and TNF‐α were consistently associated with NCI/HIVE, whereas CCL2 and IL‐6 were commonly not associated with NCI/HIVE, (2) protein expressions of CD14, CD16, CD68, Iba‐1, IL‐1β and TNF‐α were consistently associated with NCI/HIVE, while CD45, GFAP, HLA‐DR, IL‐1 and IL‐6 were commonly not associated with NCI/HIVE, and (3) gene and protein expressions of CNS IL‐1β and TNF‐α were consistently associated with NCI/HIVE, while IL‐6 was consistently not associated with NCI/HIVE. These markers highlight the commonly investigated markers in this line of research and elucidates the neuroinflammatory mechanisms in the HIV‐1 brain that are involved in the pathophysiology of NCI/HIVE. These markers and related pathways should be investigated for the development of improved diagnostics, prognostics, and therapeutics of HAND.

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“…The sequence variation in the HIV-1 viral proteins influences the pathophysiology of HIV-1. 31,[45][46][47][48][49][50][51] When comparing the Vpr protein sequences between HIV-1 subtypes, several variances are noted (Figure 1) and certain amino acid substitutions have been associated with the pathophysiology of HIV-1. 50,52 This may be due to a change in the structural characteristics of the Vpr protein (Figure 2).…”

Section: Introductionmentioning

confidence: 99%

The influence of viral protein R amino acid substitutions on clinical outcomes in people living with HIV: A systematic review

Asia

Vuren

Williams

2023

Eur J Clin Investigation

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Background:The HIV viral protein R (Vpr) is a multifunction protein involved in the pathophysiology of HIV-1. Recent evidence has suggested that Vpr amino acid substitutions influence the pathophysiology of HIV-1 and clinical outcomes in people living with HIV (PLWH). Several studies have linked Vpr amino acid substitutions to clinical outcomes in PLWH; however, there is no clear consensus as to which amino acids or amino acid substitutions are most important in the pathophysiology and clinical outcomes in PLWH. We, therefore, conducted a systematic review of studies investigating Vpr amino acid substitutions and clinical outcomes in PLWH.Methods: PubMed, Scopus and Web of Science databases were searched according to PRISMA guidelines using a search protocol designed specifically for this study.Results: A total of 22 studies were included for data extraction, comprising 14 cross-sectional and 8 longitudinal studies. Results indicated that Vpr amino acid substitutions were associated with specific clinical outcomes, including disease progressions, neurological outcomes and treatment status. Studies consistently showed that the Vpr substitution 63T was associated with slower disease progression, whereas 77H and 85P were associated with no significant contribution to disease progression. Conclusions:Vpr-specific amino acid substitutions may be contributors to clinical outcomes in PLWH, and future studies should consider investigating the Vpr amino acid substitutions highlighted in this review.

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An investigation of the HIV Tat C31S and R57S mutation on peripheral immune marker levels in South African participants: A pilot study

Cited by 6 publications

References 12 publications

Molecular Modeling of Subtype-Specific Tat Protein Signatures to Predict Tat-TAR Interactions That May Be Involved in HIV-Associated Neurocognitive Disorders

Molecular Modeling of Subtype-Specific Tat Protein Signatures to Predict Tat-TAR Interactions That May Be Involved in HIV-Associated Neurocognitive Disorders

The relationship between HIV‐1 neuroinflammation, neurocognitive impairment and encephalitis pathology: A systematic review of studies investigating post‐mortem brain tissue

The influence of viral protein R amino acid substitutions on clinical outcomes in people living with HIV: A systematic review

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