Antiretroviral drug transporters and metabolic enzymes in human testicular tissue: potential contribution to HIV-1 sanctuary site

Huang, Yiying; Hoque, Md. Tozammel; Jenabian, Mohammad-Ali; Vyboh, Kishanda; Whyte, Sana-Kay; Sheehan, Nancy L.; Brassard, P.; Bélanger, Maud; Chomont, Nicolas; Fletcher, Courtney V.; Routy, Jean‐Pierre; Bendayan, Reina

doi:10.1093/jac/dkw046

Cited by 49 publications

(58 citation statements)

References 55 publications

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“…HIV sequence diversity was measured as the APD at the indicated time points. Divergence was measured using a test for panmixia, with a P value of less than 0.001 considered significant after correcting for multiple comparisons (8), and by measuring the root-to-tip distances of sequences on phylogenetic trees (longer branches over time indicate viral evolution). A 1-sample t test was used to determine if there was a significant change in APD on ART, and a 2-tailed F test was used to determine whether the root-to-tip slopes were significantly different from 0.…”

Section: Resultsmentioning

confidence: 99%

“…There has been continued debate about whether the HIV reservoir is maintained through the persistence and proliferation of cells infected before the initiation of ART (1)(2)(3)(4)(5), or from ongoing viral replication in potential ART sanctuary sites, such as lymph nodes (LNs) (6)(7)(8)(9)(10), with subsequent trafficking of recently infected cells into the blood (10,11). If ongoing replication in tissues maintains the HIV reservoir, then preventing infection of new cells by developing antiretrovirals that better penetrate sanctuary sites such as LNs would be a high priority.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

No evidence of HIV replication in children on antiretroviral therapy

Zyl

Katusiime

Wiegand

et al. 2017

Journal of Clinical Investigation

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

No evidence of HIV replication in children on antiretroviral therapy

Zyl

Katusiime

Wiegand

et al. 2017

Journal of Clinical Investigation

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“…Several groups have published data generated using both methods[28] , [12], however the utility of Western blot data is limited due to narrow dynamic range and often possible antibody cross reactivity. Further, relative gene expression data should be interpreted with caution, as the high sensitivity may lead to false positives.…”

Section: Discussionmentioning

confidence: 99%

“…Several groups, including our own, have published studies evaluating the expression and localization of drug transporters in tissues relevant for HIV prevention[10], [11] and, more recently, cure[12]. However, there has been no consensus in the field on the optimal way to measure transporter expression.…”

Section: Introductionmentioning

confidence: 99%

Multimodal analysis of drug transporter expression in gastrointestinal tissue

Thompson

Fallon²,

Mathews³

et al. 2017

Aids

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Objectives Drug transporters affect ART tissue disposition, but quantitative measures of drug transporter protein expression across pre-clinical species are not available. Our objective was to use proteomics to obtain absolute transporter concentrations and assess agreement with corresponding gene and immunometric protein data. Design In order to make interspecies comparisons, two humanized mouse (hu-HSC-Rag (n=41); BLT (n=13)) and one primate (rhesus macaque, (NHP, n=12)) models were dosed to steady-state with combination ART. Ileum and rectum were collected at necropsy and snap frozen for analysis. Methods Tissues were analyzed for gene (qPCR) and protein (LC-MS proteomics and Western blot) expression and localization (immunohistochemistry) of ART efflux and uptake transporters. Drug concentrations were measured by LC-MS/MS. Multivariable regression was used to determine the ability of transporter data to predict tissue ART penetration. Results Analytical methods did not agree, with different trends observed for gene and protein expression. For example, qPCR analysis showed a 2-fold increase in permeability glycoprotein (Pgp) expression in NHPs versus mice, however proteomics showed a 200-fold difference in the opposite direction. Proteomics results were supported by IHC staining showing extensive efflux transporter localization on the luminal surface of these tissues. ART tissue concentration was variable between species, and multivariable regression showed poor predictive power of transporter data. Conclusions Lack of agreement between analytical techniques suggests that resources should be focused on generating downstream measures of protein expression to predict drug exposure. Taken together, these data inform the use of pre-clinical models for studying ART distribution and the design of targeted therapies for HIV eradication.

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“…Their results showed that key ABC (ATP‐binding cassette) drug transporters, solute carrier transporters and cytochrome P450 metabolic enzymes (CYP3A4 and CYP2D6) previously shown to interact with many commonly used antiretroviral drugs are expressed at the mRNA and protein level in the testes of both subject groups and localize primarily at the blood‐testis barrier, with no significant differences between HIV and non HIV infected groups. They found that emtricitabine, lamivudine and tenofovir displayed favourable tissue penetration, reaching concentrations comparable to plasma levels and concluded that the testis can restrict the distribution of certain antiretroviral drugs and potentially contribute to HIV‐1 persistence .…”

Section: The Issue Of Inflammation and Immune Activationmentioning

confidence: 99%

Two‐drug vs. three‐drug combinations for HIV‐1: Do we have enough data to make the switch?

et al. 2019

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Three‐drug combination antiretroviral therapy (ART) became available in 1996, dramatically improving the prognosis of people living with HIV. The clinical benefits of ART are due to the sustained viral load suppression and CD4 T cell gains. Major drawbacks of the first ART regimens were adverse events, and high pill burden, which led to the reduction of drug adherence resulting in frequent treatment discontinuations and the development of drug resistance. Due to increased viral potency of new antiretroviral drugs consideration of a two‐drug combination therapy repositioning occurred in an effort to reduce adverse events, drug‐drug interactions and cost, while maintaining a sustained antiviral effect. Various combinations of two‐drug regimens have been studied, and non‐inferiority compared to a three‐drug regimen has been shown only for some of them. In addition, a two‐drug combination regimen may not be suitable for every patient, especially those who are pregnant, those with tuberculosis or coexisting HBV infection. Furthermore no information has been generated concerning the secondary transmission of HIV from patients who have undetectable plasma viral load on two‐drug regimens. Additional studies of two‐drug combinations are also necessary to evaluate the debated existence of low viral replication in tissues and on immune activation. While there is no urgent need to routinely switch patients to two‐drug combination therapy, due to the availability of drug combinations without significant toxicities, dual regimens represent a suitable option that deserve long‐term evaluation before being introduced to clinical practice.

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Antiretroviral drug transporters and metabolic enzymes in human testicular tissue: potential contribution to HIV-1 sanctuary site

Abstract: Our data suggest the testes are a complex pharmacological compartment that can restrict the distribution of certain antiretroviral drugs and potentially contribute to HIV-1 persistence.

Cited by 49 publications

References 55 publications

No evidence of HIV replication in children on antiretroviral therapy

No evidence of HIV replication in children on antiretroviral therapy

Multimodal analysis of drug transporter expression in gastrointestinal tissue

Two‐drug vs. three‐drug combinations for HIV‐1: Do we have enough data to make the switch?

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