HIV Tat potentiates cell toxicity in a T cell model for sulphamethoxazole-induced adverse drug reactions

Adeyanju, Kemi; Krizova, Adriana; Gilbert, Philippe Alexandre; Dekaban, Gregory A.; Rieder, Michael J.

doi:10.1007/s11262-009-0344-3

Cited by 5 publications

(22 citation statements)

References 48 publications

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“…ADRs to SMX in patients undergoing antiretroviral therapy arise increasingly as HIV-1 infection progresses to AIDS suggesting that HIV-1 is a key contributing factor. Previously, our research has shown that the HIV-1 Tat protein is such a factor as Tat expression correlates with increased sensitivity to SMX-HA, the reactive metabolite of SMX [8,21]. In this study we sought to determine the region of the Tat protein mediating this effect.…”

Section: Discussionmentioning

confidence: 98%

“…We have previously demonstrated SMX-HA induced cell death via apoptosis in a cultured T cell line expressing the first exon of the HIV-1 Tat protein [21]. Here we determine the mechanism by which SMX -HA enhances Tat's ability to promote apoptosis using the full-length form of Tat.…”

Section: Introductionmentioning

confidence: 87%

“…The full-length Tat gene (Tat101), with or without stop codons, and Tat deletion mutants (Tat86, Tat72, Tat48 and Tat∆(49-59)) were cloned into the plasmid pEGFP-N1 (Clontech Inc.), resulting in Tat101, Tat101GFP, Tat86GFP, Tat72GFP, Tat48GFP and Tat∆GFP fusion gene, respectively. The fusion genes were then subcloned into pBIG2i as previously described [21]. The results were the following plasmid constructs; pBIG Tat101, pBIG Tat101GFP, pBIG Tat86GFP, pBIG Tat72GFP, pBIG Tat48GFP and pBIG Tat∆GFP.…”

Section: Construction Of Plasmids and Cell Linesmentioning

confidence: 99%

“…As a control, the GFP gene from pEGFP-N1 was also cloned into pBIG2i to create pBIG GFP. The pBIG Tat constructs or pBIG GFP were transfected into Jurkat E6.1 T cells by nucleofection (Lonza, Amaxa Nucleofector) according to the manufacturer's instructions and stable cell lines were generated as previously described [21]. Cos-7 cells were also transfected with the pBIG TatGFP constructs for confocal microscopy studies.…”

Section: Construction Of Plasmids and Cell Linesmentioning

confidence: 99%

“…We began by constructing and expressing full length Tat and Tat deletion mutants ( Figure 1) fused to EGFP as previously described [21]. Briefly, the full-length HIV-1 Tat protein (Tat101) was PCR amplified and subcloned onto the N-terminal end of an EGFP plasmid to create the fusion protein Tat101GFP.…”

Section: Tatgfp Constructsmentioning

confidence: 99%

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Cytoplasmic Distribution of HIV-1 Tat Sensitizes Jurkat T cells to Sulphamethoxazole-Hydroxylamine Induced Toxicity

Adeyanju¹,

Dekaban²,

Rieder³

2016

HIV Curr Res

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Section: Discussionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 87%

Section: Construction Of Plasmids and Cell Linesmentioning

confidence: 99%

Section: Construction Of Plasmids and Cell Linesmentioning

confidence: 99%

Section: Tatgfp Constructsmentioning

confidence: 99%

See 3 more Smart Citations

Cytoplasmic Distribution of HIV-1 Tat Sensitizes Jurkat T cells to Sulphamethoxazole-Hydroxylamine Induced Toxicity

Adeyanju¹,

Dekaban²,

Rieder³

2016

HIV Curr Res

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Cytoplasmic Distribution of HIV-1 Tat Sensitizes Jurkat T Cells to Sulphamethoxazole-hydroxylamine Induced Toxicity

Adeyanju

Dekaban

Rieder

2017

Journal of Pharmacological and Toxicological Methods

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Background: One medication commonly used by HIV-1-infected individuals is the antimicrobial sulphamethoxazole (SMX), which is used in the treatment and prophylaxis of pneumocystis pneumonia. However, SMX is responsible for a very high incidence of hypersensitivity adverse drug reactions (ADRs) in the HIV-1 population. While the pathophysiology of ADRs in general is unknown, sulphamethoxazole-mediated ADRs have been linked to its reactive metabolite sulphamethoxazole-hydroxylamine (SMX-HA). Our previous work has shown that increased expression of the HIV-1 Tat protein in T cells correlated with increased apoptosis after incubation with SMX-HA. In this study we sought to determine the region of the Tat protein responsible for this effect and the mechanism by which Tat contributed to SMX-HA mediated apoptosis. Methods: We established Jurkat T and Cos 7 cell lines that stably expressed full-length Tat (Tat101) and deletion mutants (Tat86, Tat72, Tat48 and Tat∆). These cell lines were then incubated with SMX-HA and assayed for cell viability and production of reactive oxygen species (ROS). We further used confocal microscopy to assess the intracellular distribution of the Tat proteins and to determine if changes in the expression and/or localization of key cytoskeleton proteins contributed to Tat-mediated apoptosis after SMX-HA treatment. Results: Deletion of regions of Tat that lead to increased cytoplasmic accumulation significantly contributed to increased cell death in the presence of SMX-HA. The increased cell death did not require induction of ROS. Quantitative analysis also showed that the Tat-expressing cell lines had significantly lower levels of β-actin and α-tubulin present both before and after treatment with SMX-HA. Increased cytoplasmic localization of Tat correlated with greater disturbances in the distribution of actin filaments. Conclusion: The presence of cytoplasmic Tat in T and epithelial cell lines increases their sensitivity to SMX-HA induced cell death, an effect mediated by the first 48 amino acids of TAT.

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An Adverse Drug Reaction to Trimethoprim-Sulfamethoxazole Revealing Primary HIV: A Case Report and Literature Review

Meyer

Behm

Brown

et al. 2015

Case Reports in Infectious Diseases

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Adverse drug reactions (ADRs) to antibiotics complicate the management of any infection, particularly opportunistic infections in advanced HIV as some ADRs are potentiated by HIV. Trimethoprim-sulfamethoxazole (TMP-SMX) causes ADRs in 40–80% of HIV infected individuals, compared to 3–5% in the general population. The incidence and severity of ADRs among HIV infected individuals appear to increase as they progress from latent infection to AIDS. We present a single case report of a 55-year-old African American male found to have an otherwise asymptomatic acute HIV infection who developed an ADR to TMP-SMX, despite having previously tolerating the medication. The proposed mechanisms for the increased incidence of sulfa hypersensitivity reactions among HIV infected individuals focus on either (1) HIV-induced changes in the immune function driven by falling levels of CD4 cells or (2) other HIV-specific factors correlated with rising viral load. To our knowledge this is the first reported case of new sulfa hypersensitivity in primary HIV and may provide clinical evidence to support the correlation between viral load and ADRs to TMP-SMX without a severely diminished CD4 count, though further research is necessary. This case also demonstrates a rare and easily overlooked presentation of HIV that may aid in early diagnosis.

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HIV Tat potentiates cell toxicity in a T cell model for sulphamethoxazole-induced adverse drug reactions

Cited by 5 publications

References 48 publications

Cytoplasmic Distribution of HIV-1 Tat Sensitizes Jurkat T cells to Sulphamethoxazole-Hydroxylamine Induced Toxicity

Cytoplasmic Distribution of HIV-1 Tat Sensitizes Jurkat T cells to Sulphamethoxazole-Hydroxylamine Induced Toxicity

Cytoplasmic Distribution of HIV-1 Tat Sensitizes Jurkat T Cells to Sulphamethoxazole-hydroxylamine Induced Toxicity

An Adverse Drug Reaction to Trimethoprim-Sulfamethoxazole Revealing Primary HIV: A Case Report and Literature Review

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