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

Asia, Levanco K; Vuren, Esmé Jansen van; Williams, Monray E.

doi:10.1111/eci.13943

Cited by 5 publications

(5 citation statements)

References 91 publications

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“…For this review, we applied a criterion for identifying ‘noteworthy’ markers as done previously. 17 , 25 For a marker (gene transcript/protein) to be noteworthy it had to be (1) investigated by three or more (>2) independent studies and (2) >50% of the studies investigating the marker had to report a consistent direction in their association with NCI/HIVE. In other words, if >50% of studies that investigated a particular marker found it to have the same direction in association with CI/HIVE, it was considered a noteworthy marker for future investigation.…”

Section: Resultsmentioning

confidence: 99%

“…Therefore, we considered the frequency a marker was investigated when contextualising the findings. For this review, we applied a criterion for identifying ‘noteworthy’ markers as done previously 17,25 . For a marker (gene transcript/protein) to be noteworthy it had to be (1) investigated by three or more (>2) independent studies and (2) >50% of the studies investigating the marker had to report a consistent direction in their association with NCI/HIVE.…”

Section: Resultsmentioning

confidence: 99%

“…Here we have amended the JBI quality questions from the Checklist for Analytical Cross‐Sectional Studies 23 by implementing a Likert‐type scale to provide a quantitative measure of study quality. 16 , 24 , 25 , 26 , 27 For all included studies, we have collated the JBI quality questions which assess those factors, which may significantly affect the findings of the included studies (i.e., level of neuroinflammation and neurocognitive function). These included the questions: Confounders: Did the study report on potential confounders (e.g., substance misuse, comorbid conditions (e.g., Hepatitis C (HCV)), neurological conditions and psychiatric disorders), a relevant exclusionary criterion and were these controlled for upon statistical analysis?…”

Section: Methodsmentioning

confidence: 99%

“…For this review, we applied a criterion for identifying 'noteworthy' markers as done previously. 17,25 For a marker (gene transcript/protein) to be noteworthy it had to be (1) investigated by three or more (>2) independent studies and (2) >50%…”

Section: Markers Associated With Nci/hive In Plwhmentioning

confidence: 99%

“…Here we have amended the JBI quality questions from the Checklist for Analytical Cross-Sectional Studies 23 by implementing a Likert-type scale to provide a quantitative measure of study quality. 16,[24][25][26][27] For all included studies, we have collated the JBI quality questions which assess those factors, which may significantly affect the findings of the included studies (i.e., level of neuroinflammation and neurocognitive function). These included the questions:…”

Section: Quality Assessmentmentioning

confidence: 99%

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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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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Markers Associated With Nci/hive In Plwhmentioning

confidence: 99%

Section: Quality Assessmentmentioning

confidence: 99%

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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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Transactivator of Transcription (Tat)-Induced Neuroinflammation as a Key Pathway in Neuronal Dysfunction: A Scoping Review

Muvenda,

Williams,

Williams

2024

Mol Neurobiol

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The activity of HIV-1 and its viral proteins within the central nervous system (CNS) is responsible for a wide array of neuropathological effects, resulting in a spectrum of neurocognitive deficits defined as HIV-associated neurocognitive disorders (HAND). Amongst the various viral proteins, the transactivator of transcription (Tat) remains detectable even with effective antiretroviral therapy (ART) and suppressed viremia, highlighting the significance of this protein in the modern ART era. Tat has been extensively researched in both fundamental and clinical settings due to its role in neuroinflammation, neuronal damage, and neurocognitive impairment amongst people living with HIV (PLHIV). To date, numerous fundamental studies have explored Tat-induced neuroinflammation. However, there is no clear consensus on the most frequently studied inflammatory markers or the consistency in the levels of these Tat-induced inflammatory marker levels across different studies. Therefore, we conducted a scoping review of studies investigating Tat-induced neuroinflammation. We conducted searches in PubMed, Scopus, and Web of Science databases using a search protocol tailored specifically to adhere to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses for scoping reviews (PRISMA-ScR) guidelines. From the 22 included studies, findings suggest that the HIV-1 Tat protein amplifies levels of neuroinflammatory markers. Amongst the vast array of inflammatory 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 inflammatory 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 neuroinflammation. In this context, we highlight specific inflammatory markers and pathways that are potentially pivotal in Tat-induced neuroinflammation and subsequent neuronal damage. A deeper investigation into these markers and pathways is crucial to better understand their roles in the development of HAND.

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A Pilot Investigation of the Association Between Vpr Amino Acid Substitutions and Peripheral Immune Marker Levels in People With Human Immunodeficiency Virus: Implications for Neurocognitive Impairment

Asia,

Van Vuren,

Kruger

et al. 2024

Open Forum Infectious Diseases

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Background Subtype-specific amino acid variations in viral proteins of HIV-1 influence disease progression. Furthermore, Vpr sequence variation correlates with chronic inflammation, a central mechanism in HIV-1 (neuro)pathogenesis. Nevertheless, no clinical study has investigated the link between Vpr sequence variation and peripheral inflammation in people living with HIV. The aim of this pilot study was to ascertain whether specific Vpr amino acid variants were associated with immune markers in people living with HIV. Methods We included a unique cohort of forty-eight treatment-naïve South African people living with HIV to determine the association between blood-derived Vpr sequence variation and peripheral immune marker levels using Sanger sequencing and ELISA analysis, respectively. Results Our findings indicate that among the many neuropathogenic Vpr amino acid variants and immune markers examined, after applying Bonferroni corrections (p = .05/3) and adjusting for sex and locality, suPAR was nearing significance for higher levels in participants with the G41 amino acid variant compared to those with the S41 variant (p = .035), after. Further, amino acid variations at position 41 (between G41 and S41) exhibited a significant association with suPAR (adj R2 = .089, β = .386; 95% CI .125 to 3.251; p = .035). Conclusions These findings suggest that Vpr amino acid sequence variations might contribute to dysregulated inflammation, which could explain the observed association between specific Vpr variants and HIV-1 (neuro)pathogenesis found in prior research. These Vpr variants merit further investigation to fully understand their roles in HIV-1 pathogenesis and neuropathogenesis.

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

Cited by 5 publications

References 91 publications

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

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

Transactivator of Transcription (Tat)-Induced Neuroinflammation as a Key Pathway in Neuronal Dysfunction: A Scoping Review

A Pilot Investigation of the Association Between Vpr Amino Acid Substitutions and Peripheral Immune Marker Levels in People With Human Immunodeficiency Virus: Implications for Neurocognitive Impairment

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