Progestin‐based contraception regimens modulate expression of putative <scp>HIV</scp> risk factors in the vaginal epithelium of pig‐tailed Macaques

Bosinger, Steven E.; Tharp, Gregory K.; Patel, Nirav; Zhao, Chunxia; Payne, Tamika L.; Ostergaard, Sharon Dietz; Butler, Katherine; Ellis, Shanon; Johnson, Ryan; Kersh, Ellen N.; McNicholl, Janet M.; Vishwanathan, Sundaram A.

doi:10.1111/aji.13029

Cited by 4 publications

(4 citation statements)

References 32 publications

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“…Furthermore, there was a trend toward suppression of type I IFN stimulated genes in the Net-En arm compared to the other study arms. These results are somewhat consistent with our prior findings in which DMPA administration to pig-tailed macaques elicited a significant reduction in ISGs in cervical biopsies ( 30 ); however, the impact of Net-En on the ISG response observed in this study was milder. This may be partially due to DMPA being at an effectively elevated dose in our NHP studies due to more frequent injection ( 29 , 30 ).…”

Section: Discussionsupporting

confidence: 93%

“…These results are somewhat consistent with our prior findings in which DMPA administration to pig-tailed macaques elicited a significant reduction in ISGs in cervical biopsies ( 30 ); however, the impact of Net-En on the ISG response observed in this study was milder. This may be partially due to DMPA being at an effectively elevated dose in our NHP studies due to more frequent injection ( 29 , 30 ). Yet, differences in the metabolism and pharmacokinetics of Net-En vs. DMPA may also contribute to these differences in the ISG response.…”

Section: Discussionsupporting

confidence: 93%

“…We next performed gene set enrichment analysis (GSEA) using various well-defined gene-set/pathway collection databases from the Molecular Signatures Database ( https://www.gsea-msigdb.org/gsea/msigdb ) ( 48 , 60 – 64 ) and for custom in-house gene-sets that include Serpins, Integrins, and immune response genes ( 30 , 65 – 69 ) ( Figure 2G , Supplementary Tables 10 , 11 ). In concordance with the cluster analysis, pathways associated with response to cellular stress and external stimuli, including inflammatory, apoptotic, and DNA repair pathways, were enriched in the CCVR arm compared to both the Net-En and COC arms ( Figure 2G , Supplementary Figure 6 ).…”

Section: Resultsmentioning

confidence: 99%

“…Data from the CAPRISA004 trial found that women using the injectable norethisterone-enanthate (Net-En) had reduced levels of cervicovaginal growth factors compared to women who did not use any HCs, suggesting a similar effect to that of DMPA-IM ( 27 ). In nonhuman primates (NHPs), DMPA treatment has been associated with a decrease in the vaginal epithelial thickness ( 28 – 30 ), more so than estrogen-containing combined oral contraceptives (COCs) ( 30 , 31 ). Physiological levels of medroxyprogesterone acetate (MPA) reduced epithelial barrier integrity in the genital tract epithelial cells in vitro ( 32 – 34 ), whereas estradiol treatment led to enhanced barrier function ( 33 , 34 ).…”

Section: Introductionmentioning

confidence: 99%

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Systems Analysis Reveals Contraceptive-Induced Alteration of Cervicovaginal Gene Expression in a Randomized Trial

Balle

Gupta²,

Tharp³

et al. 2022

Front. Reprod. Health

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Hormonal contraceptives (HCs) are vital in managing the reproductive health of women. However, HC usage has been linked to perturbations in cervicovaginal immunity and increased risk of sexually transmitted infections. Here, we evaluated the impact of three HCs on the cervicovaginal environment using high-throughput transcriptomics. From 2015 to 2017, 130 adolescent females aged 15–19 years were enrolled into a substudy of UChoose, a single-site, open-label randomized, crossover trial (NCT02404038) and randomized to injectable norethisterone–enanthate (Net-En), combined oral contraceptives (COC), or etonorgesterol/ethinyl–estradiol–combined contraceptive vaginal ring (CCVR). Cervicovaginal samples were collected after 16 weeks of randomized HC use and analyzed by RNA-Seq, 16S rRNA gene sequencing, and Luminex analysis. Participants in the CCVR arm had a significant elevation of transcriptional networks driven by IL-6, IL-1, and NFKB, and lower expression of genes supporting epithelial barrier integrity. An integrated multivariate analysis demonstrated that networks of microbial dysbiosis and inflammation best discriminated the CCVR arm from the other contraceptive groups, while genes involved in epithelial cell differentiation were predictive of the Net-En and COC arms. Collectively, these data from a randomized trial represent the most comprehensive “omics” analyses of the cervicovaginal response to HCs and provide important mechanistic guidelines for the provision of HCs in sub-Saharan Africa.

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Section: Discussionsupporting

confidence: 93%