TNF-Block Genotypes Influence Susceptibility to HIV-Associated Sensory Neuropathy in Indonesians and South Africans

Gaff, Jessica; Octaviana, Fitri; Pillay, Prinisha; Mbenda, Huguette Gaelle Ngassa; Ariyanto, Ibnu; Gan, June Anne; Cherry, Catherine L.; Kamerman, Peter R.; Laws, Simon M.; Price, Patricia

doi:10.3390/ijms21020380

Cited by 4 publications

(3 citation statements)

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“…9 Genetic polymorphisms, e.g., in CAMKK2 and TNF, have been associated with the development of HIV-SN after treatment with staduvine. 10,11 In this study we analyzed the effect of HIV infection on neuropathy and mtDNA integrity in skin biopsies in a cohort of PWH. Using an assay that allows measurement of mutation burden across the mitochondrial genome, we have analyzed the frequency of mutations in this cohort and have correlated the degree of mutation deletion with demographic factors and objective measurements of neuropathy.…”

Section: Trial Registration Informationmentioning

confidence: 99%

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Large Mitochondrial DNA Deletions in HIV Sensory Neuropathy

et al. 2021

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Objective:The primary objective of this study was to evaluate the correlation of large mitochondrial DNA deletions in skin samples of people with human immunodeficiency virus (PWH) with measures of neuropathy and prior exposure to therapy. We hypothesized that deletions would be associated with neuropathy. As secondary objectives we determined the correlation of deletion burden with demographic data and neuropathy measures.Methods:In this retrospective cohort study we measured the accumulation of large mtDNA deletions in skin biopsies from PWH recruited as part of the AIDS Clinical Trials Group (ACTG). Our cohort includes individuals with and without sensory neuropathy, as well as individuals with normal or abnormal skin biopsies. Skin biopsies, sural and peroneal nerve conduction studies, Total Neuropathy Score and deletion burden scores were measured along with baseline demographic data such as age, CD+4 cell count, viral counts and prior dNRTI exposures.Results:Sixty-seven PWH were enrolled in the study. The mean age of the cohort (n=67) was 44 years (SD 6.8, range 32-65 years) and 9 were female. The mean CD4+ T-cell count was 168 cells/mm3 (SD 97, range 1 – 416) and mean viral load was 51129 copies/mL (SD 114586, range 147 – 657775). We determined that there was a correlation between the total mtDNA deletion and intra-epidermal nerve fiber density (IENFD) (r=-0.344, p=0.04) and sural nerve amplitude (r=-0.359, p=0.004).Conclusions:IENFD and sural nerve amplitude both statistically correlate with mitochondrial mutation burden in PWH, specifically in those with HIV-associated sensory neuropathy (HIV-SN) as assessed by skin biopsy.

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Section: Trial Registration Informationmentioning

confidence: 99%

“…9 Genetic polymorphisms, e.g., in CAMKK2 and TNF , have been associated with the development of HIV-SN after treatment with staduvine. 10,11…”

Section: Trial Registration Informationmentioning

confidence: 99%

Large Mitochondrial DNA Deletions in HIV Sensory Neuropathy

et al. 2021

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“…It was possible to predict virological and immunological therapy failure/effectiveness based on the descriptors generated from a nucleotide sequence in combination with other descriptors, reflecting laboratory data and the clinical status of the patient, such as CD4 + count and viral load. Application of the computational models developed to predict HIV drug resistance, HIV treatment history, and virological and immunological therapy failure/effectiveness could be helpful in the optimization and personalization of antiretroviral therapy, which could be particularly important taking into account the toxicity and adverse effects [34][35][36] of drugs comprising ART schemes.…”

Section: Predicting Treatment Failure and Treatment Effectivenessmentioning

confidence: 99%

A Computational Approach for the Prediction of Treatment History and the Effectiveness or Failure of Antiretroviral Therapy

Tarasova

Biziukova

Kireev

et al. 2020

IJMS

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Human Immunodeficiency Virus Type 1 (HIV-1) infection is associated with high mortality if no therapy is provided. Currently, the treatment of an HIV-1 positive patient requires that several drugs should be taken simultaneously. The resistance of the virus to an antiretroviral drug may lead to treatment failure. Our approach focuses on predicting the exposure of a particular viral variant to an antiretroviral drug or drug combination. It also aims at the prediction of drug treatment success or failure. We utilized nucleotide sequences of HIV-1 encoding protease and reverse transcriptase to perform such types of prediction. The PASS (Prediction of Activity Spectra for Substances) algorithm based on the naive Bayesian classifier was used to make a prediction. We calculated the probability of whether a sequence belonged (P1) or did not belong (P0) to the class associated with exposure of the viral sequence to the set of drugs that can be associated with resistance to the set of drugs. The accuracy calculated as the average Area Under the ROC (Receiver Operating Characteristic) Curve (AUC/ROC) for classifying exposure of the sequence to the HIV-1 protease inhibitors was 0.81 (±0.07), and for HIV-1 reverse transcriptase, it was 0.83 (±0.07). To predict cases of treatment effectiveness or failure, we used P1 and P0 values, obtained in PASS, along with the binary vector constructed based on short nucleotide descriptors and the applied random forest classifier. Average AUC/ROC prediction accuracy for the prediction of treatment effectiveness or failure for the combinations of HIV-1 protease inhibitors was 0.82 (±0.06) and of HIV-1 reverse transcriptase was 0.76 (±0.09).

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Expression in skin biopsies supports genetic evidence linking CAMKK2, P2X7R and P2X4R with HIV-associated sensory neuropathy

et al. 2023

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HIV-associated sensory neuropathy (HIV-SN) affects 14–38% of HIV+ individuals stable on therapy with no neurotoxic drugs. Polymorphisms in CAMKK2, P2X7R and P2X4R associated with altered risk of HIV-SN in Indonesian and South African patients. The role of CaMKK2 in neuronal repair makes this an attractive candidate, but a direct role for any protein is predicated on expression in affected tissues. Here, we describe expression of CaMKK2, P2X7R and P2X4R proteins in skin biopsies from the lower legs of HIV+ Indonesians with and without HIV-SN, and healthy controls (HC). HIV-SN was diagnosed using the Brief Peripheral Neuropathy Screen. Biopsies were stained to detect protein gene product 9.5 on nerve fibres and CaMKK2, P2X7R or P2X4R, and were examined using 3-colour sequential scanning confocal microscopy. Intraepidermal nerve fibre densities (IENFD) were lower in HIV+ donors than HC and correlated directly with nadir CD4 T-cell counts (r = 0.69, p = 0.004). However, IENFD counts were similar in HIV-SN+ and HIV-SN− donors (p = 0.19) and so did not define neuropathy. CaMKK2+ cells were located close to dermal and epidermal nerve fibres and were rare in HC and HIV-SN− donors, consistent with a role for the protein in nerve damage and/or repair. P2X7R was expressed by cells in blood vessels of HIV-SN− donors, but rarely in HC or HIV-SN+ donors. P2X4R expression by cells in the epidermal basal layer appeared greatest in HIV-SN+ donors. Overall, the differential expression of CaMKK2, P2X7R and P2X4R supports the genetic evidence of a role for these proteins in HIV-SN.

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TNF-Block Genotypes Influence Susceptibility to HIV-Associated Sensory Neuropathy in Indonesians and South Africans

Cited by 4 publications

References 36 publications

Large Mitochondrial DNA Deletions in HIV Sensory Neuropathy

Large Mitochondrial DNA Deletions in HIV Sensory Neuropathy

A Computational Approach for the Prediction of Treatment History and the Effectiveness or Failure of Antiretroviral Therapy

Expression in skin biopsies supports genetic evidence linking CAMKK2, P2X7R and P2X4R with HIV-associated sensory neuropathy

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