Transcriptomics

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Unexpected Inflammatory Effects of Intravaginal Gels (Universal Placebo Gel and Nonoxynol-9) on the Upper Female Reproductive Tract: an Experimental Crossover Study


ABSTRACT: Intravaginal HIV microbicides could provide women with a self-controlled means for HIV prevention, but results from clinical trials have been largely disappointing. We postulated that unrecognized effects of intravaginal gels on the upper female reproductive tract (FRT) might contribute to the lower-than-expected efficacy of HIV microbicides. In this observational crossover study, 28 healthy female volunteers used no product (control cycle) or used a nightly application of intravaginal nonoxynol-9 gel [N9] as a 'failed' microbicide or the universal placebo gel [UPG] as a 'safe' gel, from the end of menses to the mid-luteal phase (intervention cycles). They then underwent sample collection for measurements of T-cell phenotypes, transcriptional profiling, and protein levels from 3 anatomic sites above the vagina: the cervical transformation zone, the endocervix and the endometrium. We used hierarchical statistical models to estimate mean (95% CI) intervention:control fold-changes in relevant phenotype levels. Exposure to N9 and UPG generated a common 'harm signature' that included transcriptional up-regulation of inflammatory genes CCL20 and IL8 in the cervix, decreased protein concentrations of secretory leukocyte protease inhibitor and increased percentages of terminally differentiated CD4+ effector T-cells in the endocervix, and transcriptional up-regulation of inflammatory mediators KIR3DS1, glycodelin-A, and osteopontin in the endometrium. These results underscore the need to consider the effects of microbicide agents and gel excipients on the upper FRT in studies of vaginal microbicides. Given the pro-inflammatory effects of UPG on the upper FRT, it may not be a suitable placebo for microbicide trials. Upper tract effects of intravaginal gels in women. This is a cross sectional study involving control samples versus treatment for two tissue types.

ORGANISM(S): Homo sapiens  

SUBMITTER: Jean Perry   Ruth M Greenblatt  Fatima Barragan  Uma Shanmugasundaram  Barbara L Shacklett  Joan F Hilton  Brittni A Johnson  Jane Pannell  Linda C Giudice  Karen K Smith-McCune  Juan C Irwin  Linda Giudice  Joseph C Chen  Margaret Takeda 

PROVIDER: E-GEOD-58090 | ArrayExpress | 2015-08-10

SECONDARY ACCESSION(S): GSE58090PRJNA248884

REPOSITORIES: GEO, ArrayExpress

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Publications

Unexpected Inflammatory Effects of Intravaginal Gels (Universal Placebo Gel and Nonoxynol-9) on the Upper Female Reproductive Tract: A Randomized Crossover Study.

Smith-McCune Karen K   Chen Joseph C JC   Greenblatt Ruth M RM   Shanmugasundaram Uma U   Shacklett Barbara L BL   Hilton Joan F JF   Johnson Brittni B   Irwin Juan C JC   Giudice Linda C LC  

PloS one 20150715 7


Intravaginal anti-HIV microbicides could provide women with a self-controlled means for HIV prevention, but results from clinical trials have been largely disappointing. We postulated that unrecognized effects of intravaginal gels on the upper female reproductive tract might contribute to the lower-than-expected efficacy of HIV microbicides. Our objective was to study the effects of intravaginal gels on the immune microenvironment of the cervix and uterus. In this randomized crossover study, 27  ...[more]

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