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Effect of antiretroviral prophylaxis on gene expression in PBMCs

ABSTRACT: It is important to understand how, if at all, antiretroviral prophylaxis with tenofovir disoproxil fumarate (TDF) alone or TDF in conjunction with emtricitabine (FTC) affects gene expression. To ask this question, we used peripheral blood mononuclear cells from women enrolled in the Genital Mucosal Substudy (GMS) [1] of the Partners PrEP Study (NCT02621242) [2]. Partners PrEP was a randomized Phase III trial of oral TDF or TDF/FTC compared to placebo, which showed that either active drug was effective at protecting against HIV-1 infection. Samples were taken after 24-36 months of oral treatment with placebo, TDF, or TDF/FTC or two months after discontinuation. Treatment adherence was based on plasma TDF concentrations. Covariates included Nugent scores (for bacterial vaginosis), HSV-2 serology, age, and birth control method. Levels of natural and synthetic hormones (medroxyprogesterone acetate [MPA], estradiol [E2], ethinyl estradiol [EE2], levonorgestrel [LNG], etonogestrel [ENG], progesterone [P4], and norethisterone enanthate [NET-EN]) were measured in the serum. 1. Lund, J. M. et al. HIV-1-Neutralizing IgA Detected in Genital Secretions of Highly HIV-1-Exposed Seronegative Women on Oral Preexposure Prophylaxis. J. Virol. 90, 9855–9861 (2016). 2. Baeten, J. M. et al. Antiretroviral prophylaxis for HIV prevention in heterosexual men and women. N. Engl. J. Med. 367, 399–410 (2012).

ORGANISM(S): Homo sapiens

PROVIDER: GSE139649 | GEO | 2020/07/07

REPOSITORIES: GEO

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Effect of antiretroviral prophylaxis on gene expression in the vagina

Project description:It is important to understand how, if at all, antiretroviral prophylaxis with tenofovir disoproxil fumarate (TDF) alone or TDF in conjunction with emtricitabine (FTC) affects gene expression. To ask this question, we used vaginal biopsies from women enrolled in the Genital Mucosal Substudy (GMS) [1] of the Partners PrEP Study (NCT02621242) [2]. Partners PrEP was a randomized Phase III trial of oral TDF or TDF/FTC compared to placebo, which showed that either active drug was effective at protecting against HIV-1 infection. Samples were taken after 24-36 months of oral treatment with placebo, TDF, or TDF/FTC or two months after discontinuation. Treatment adherence was based on plasma TDF concentrations. Covariates included Nugent scores (for bacterial vaginosis), HSV-2 serology, age, and birth control method. Levels of natural and synthetic hormones (medroxyprogesterone acetate [MPA], estradiol [E2], ethinyl estradiol [EE2], levonorgestrel [LNG], etonogestrel [ENG], progesterone [P4], and norethisterone enanthate [NET-EN]) were measured in the serum. 1. Lund, J. M. et al. HIV-1-Neutralizing IgA Detected in Genital Secretions of Highly HIV-1-Exposed Seronegative Women on Oral Preexposure Prophylaxis. J. Virol. 90, 9855–9861 (2016). 2. Baeten, J. M. et al. Antiretroviral prophylaxis for HIV prevention in heterosexual men and women. N. Engl. J. Med. 367, 399–410 (2012).

2020-07-07 | GSE139654 | GEO

Effect of antiretroviral prophylaxis on gene expression in the ectocervix

Project description:It is important to understand how, if at all, antiretroviral prophylaxis with tenofovir disoproxil fumarate (TDF) alone or TDF in conjunction with emtricitabine (FTC) affects gene expression. To ask this question, we used ectocervical biopsies from women enrolled in the Genital Mucosal Substudy (GMS) [1] of the Partners PrEP Study (NCT02621242) [2]. Partners PrEP was a randomized Phase III trial of oral TDF or TDF/FTC compared to placebo, which showed that either active drug was effective at protecting against HIV-1 infection. Samples were taken after 24-36 months of oral treatment with placebo, TDF, or TDF/FTC or two months after discontinuation. Treatment adherence was based on plasma TDF concentrations. Covariates included Nugent scores (for bacterial vaginosis), HSV-2 serology, age, and birth control method. Levels of natural and synthetic hormones (medroxyprogesterone acetate [MPA], estradiol [E2], ethinyl estradiol [EE2], levonorgestrel [LNG], etonogestrel [ENG], progesterone [P4], and norethisterone enanthate [NET-EN]) were measured in the serum. 1. Lund, J. M. et al. HIV-1-Neutralizing IgA Detected in Genital Secretions of Highly HIV-1-Exposed Seronegative Women on Oral Preexposure Prophylaxis. J. Virol. 90, 9855–9861 (2016). 2. Baeten, J. M. et al. Antiretroviral prophylaxis for HIV prevention in heterosexual men and women. N. Engl. J. Med. 367, 399–410 (2012).

2020-07-07 | GSE139644 | GEO

Effect of antiretroviral prophylaxis on gene expression in peripheral blood mononuclear cells

Project description:It is important to understand how, if at all, antiretroviral prophylaxis with tenofovir disoproxil fumarate (TDF) alone or TDF in conjunction with emtricitabine (FTC) affects gene expression. To ask this question, we used cryopreserved peripheral blood mononuclear cells (PBMC) from women enrolled in the Genital Mucosal Substudy (GMS) [1] of the Partners PrEP Study (NCT02621242) [2]. Partners PrEP was a randomized Phase III trial of oral TDF or TDF/FTC compared to placebo, which showed that either active drug was effective at protecting against HIV-1 infection. Samples were unpaired, with one sample per person, after 24-36 months of oral treatment with placebo, TDF, or TDF/FTC. Treatment adherence was based on plasma TDF concentrations. Covariates included Nugent scores (for bacterial vaginosis), HSV-2 serology, age, and birth control method. Levels of natural and synthetic hormones (medroxyprogesterone acetate [MPA], estradiol [E2], ethinyl estradiol [EE2], levonorgestrel [LNG], etonogestrel [ENG], progesterone [P4], and norethisterone enanthate [NET-EN]) were measured in the serum. 1. Lund, J. M. et al. HIV-1-Neutralizing IgA Detected in Genital Secretions of Highly HIV-1-Exposed Seronegative Women on Oral Preexposure Prophylaxis. J. Virol. 90, 9855–9861 (2016). 2. Baeten, J. M. et al. Antiretroviral prophylaxis for HIV prevention in heterosexual men and women. N. Engl. J. Med. 367, 399–410 (2012).

2020-07-07 | GSE139411 | GEO

Effect of antiretroviral prophylaxis on gene expression in the endocervix

Project description:It is important to understand how, if at all, antiretroviral prophylaxis with tenofovir disoproxil fumarate (TDF) alone or TDF in conjunction with emtricitabine (FTC) affects gene expression. To ask this question, we used cervicovaginal biopsies from women enrolled in the Genital Mucosal Substudy (GMS) [1] of the Partners PrEP Study (NCT02621242) [2]. Partners PrEP was a randomized Phase III trial of oral TDF or TDF/FTC compared to placebo, which showed that either active drug was effective at protecting against HIV-1 infection. Samples were taken after 24-36 months of oral treatment with placebo, TDF, or TDF/FTC or two months after discontinuation. Treatment adherence was based on plasma TDF concentrations. The samples in this series are thought to be endocervical biopsies on the basis of their gene expression. Covariates included Nugent scores (for bacterial vaginosis), HSV-2 serology, age, and birth control method. Levels of natural and synthetic hormones (medroxyprogesterone acetate [MPA], estradiol [E2], ethinyl estradiol [EE2], levonorgestrel [LNG], etonogestrel [ENG], progesterone [P4], and norethisterone enanthate [NET-EN]) were measured in the serum. 1. Lund, J. M. et al. HIV-1-Neutralizing IgA Detected in Genital Secretions of Highly HIV-1-Exposed Seronegative Women on Oral Preexposure Prophylaxis. J. Virol. 90, 9855–9861 (2016). 2. Baeten, J. M. et al. Antiretroviral prophylaxis for HIV prevention in heterosexual men and women. N. Engl. J. Med. 367, 399–410 (2012).

2020-07-07 | GSE139645 | GEO

In vitro exposure of leukocytes to HIV pre-exposure prophylaxis (PrEP) decreases mitochondrial function and alters gene expression profiles.

Project description:The use of antiretroviral therapy (ART) as pre-exposure prophylaxis (PrEP) is an effective strategy for preventing HIV acquisition. The cellular consequences of PrEP exposure, however, have not been sufficiently explored to determine potential effects on health in individuals without HIV. Peripheral blood mononuclear cells (PBMCs) from people without HIV were exposed to tenofovir disoproxil fumarate (TDF) or emtricitabine (FTC) overnight. Mitochondrial mass and function were measured by flow cytometry and Agilent XFp analyzer. Monocyte-derived macrophages (MDMs) were differentiated in 20% autologous serum for 5 days in the presence or absence of TDF or FTC, and surface markers, lipid uptake, and efferocytosis were measured by flow cytometry. MDM gene expression was measured using RNAseq. Serum lipids were measured using mass spectrometry. PBMCs exposed to TDF or FTC had decreased maximal oxygen consumption rate (OCR) and reduced mitochondrial mass. Exposure to PrEP also increased reactive oxygen species (ROS) production from monocyte subsets. Compared to MDMs cultured in medium alone, cells differentiated in the presence of TDF (829 genes) or FTC (888) genes had significant changes in gene expression. Further, PrEP-exposed MDMs had decreased mitochondrial mass, and displayed increased lipid uptake and reduced efferocytosis. Plasma biomarkers and lipid levels were also altered in vivo in individuals receiving a PrEP regimen. Exposure of leukocytes to TDF or FTC resulted in decreased mitochondrial function, and altered functional and transcriptional profiles. These findings may have important implications for the metabolic and immunologic consequences of PrEP in populations at risk for HIV acquisition.

2021-10-01 | GSE159339 | GEO

Effect of pre-exposure prophylaxis with tenofovir disoproxil fumarate and emtricitabine on gene expression in the blood

Project description:Pre-exposure prophylaxis (PrEP) with tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC) effectively prevents infection with HIV-1. We sought to determine how use of these medications affects gene expression. We performed a small, prospective trial (https://clinicaltrials.gov/ct2/show/NCT02621242) of eight men initiating PrEP with TDF/FTC. We obtained blood before treatment initiation and after two months of daily use. We isolated RNA from whole blood (PAXgene tubes). Gene expression was measured from all eight men at both time points.

2020-07-07 | GSE139607 | GEO

Effect of pre-exposure prophylaxis with tenofovir disoproxil fumarate and emtricitabine on gene expression in the rectum

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2020-07-07 | GSE139610 | GEO

Effect of pre-exposure prophylaxis with tenofovir disoproxil fumarate and emtricitabine on gene expression in PBMC

Project description:Pre-exposure prophylaxis (PrEP) with tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC) effectively prevents infection with HIV-1. We sought to determine how use of these medications affects gene expression. We performed a small, prospective trial (https://clinicaltrials.gov/ct2/show/NCT02621242) of eight men initiating PrEP with TDF/FTC. We obtained blood before treatment initiation and after two months of daily use. We isolated RNA from cryopreserved peripheral blood mononuclear cells (PBMC). Gene expression was measured from all eight men at both time points.

2020-07-07 | GSE139609 | GEO

Effect of pre-exposure prophylaxis with tenofovir disoproxil fumarate and emtricitabine on gene expression in the duodenum

Project description:Pre-exposure prophylaxis (PrEP) with tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC) effectively prevents infection with HIV-1. We sought to determine how use of these medications affects gene expression. We performed a small, prospective trial (https://clinicaltrials.gov/ct2/show/NCT02621242) of eight men initiating PrEP with TDF/FTC. We obtained duodenal biopsies before treatment initiation and after two months of daily use. We isolated RNA from duodenal biopsies preserved with RNAlater. Gene expression was measured from all eight men at both time points.

2020-07-07 | GSE139608 | GEO

A Phase 2 Randomized Sequence Open Label Expanded Safety and Acceptability Study of Oral Emtricitabine/Tenofovir Disoproxil Fumarate Tablet and Rectally-Applied Tenofovir Reduced-Glycerin 1% Gel

Project description:Human immunodeficiency virus (HIV) disproportionately affects men who have sex with men (MSM) and transgender women (TGW). Safe and acceptable topical HIV prevention methods that target the rectum are needed. MTN-017 was a phase 2, 3-period, randomized sequence, open-label, expanded safety and acceptability crossover study comparing rectally applied reduced-glycerin (RG) 1% tenofovir (TFV) and oral emtricitabine/TFV disoproxil fumarate (FTC/TDF). In each 8-week study period participants were randomized to RG-TFV rectal gel daily, or RG-TFV rectal gel before and after receptive anal intercourse (RAI; or at least twice weekly in the event of no RAI), or daily oral FTC/TDF. MSM and TGW (n = 195) were enrolled from 8 sites in the United States, Thailand, Peru, and South Africa with mean age of 31.1 years (range 18-64). The clinical results were reported here https://www.ncbi.nlm.nih.gov/pubmed/27986684. For the gene expression study, rectal biopsies were obtained from a subset of participants (n = 36) in the United States (Pittsburgh) and Thailand (Bangkok). Biopsies were provided at baseline and after each study period.

2020-07-07 | GSE138723 | GEO

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