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1.
J Infect Dis ; 225(7): 1151-1161, 2022 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-32780807

RESUMO

BACKGROUND: The hormonal contraceptive depot medroxyprogesterone acetate (DMPA) may be associated with an increased risk of acquiring human immunodeficiency virus (HIV). We hypothesize that DMPA use influences the ectocervical tissue architecture and HIV target cell localization. METHODS: Quantitative image analysis workflows were developed to assess ectocervical tissue samples collected from DMPA users and control subjects not using hormonal contraception. RESULTS: Compared to controls, the DMPA group exhibited a significantly thinner apical ectocervical epithelial layer and a higher proportion of CD4+CCR5+ cells with a more superficial location. This localization corresponded to an area with a nonintact E-cadherin net structure. CD4+Langerin+ cells were also more superficially located in the DMPA group, although fewer in number compared to the controls. Natural plasma progesterone levels did not correlate with any of these parameters, whereas estradiol levels were positively correlated with E-cadherin expression and a more basal location for HIV target cells of the control group. CONCLUSIONS: DMPA users have a less robust epithelial layer and a more apical distribution of HIV target cells in the human ectocervix, which could confer a higher risk of HIV infection. Our results highlight the importance of assessing intact genital tissue samples to gain insights into HIV susceptibility factors.


Assuntos
Anticoncepcionais Femininos , Infecções por HIV , Colo do Útero/metabolismo , Anticoncepcionais Femininos/efeitos adversos , Feminino , HIV , Humanos , Acetato de Medroxiprogesterona/efeitos adversos
2.
Biol Reprod ; 92(3): 68, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25588510

RESUMO

Currently, whether hormonal contraceptives affect male to female human immunodeficiency virus (HIV) transmission is being debated. In this study, we investigated whether the use of progesterone-based intrauterine devices (pIUDs) is associated with a thinning effect on the ectocervical squamous epithelium, down-regulation of epithelial junction proteins, and/or alteration of HIV target cell distribution in the human ectocervix. Ectocervical tissue biopsies from healthy premenopausal volunteers using pIUDs were collected and compared to biopsies obtained from two control groups, namely women using combined oral contraceptives (COCs) or who do not use hormonal contraceptives. In situ staining and image analysis were used to measure epithelial thickness and the presence of HIV receptors in tissue biopsies. Messenger RNA levels of epithelial junction markers were measured by quantitative PCR. The epithelial thickness displayed by women in the pIUD group was similar to those in the COC group, but significantly thinner as compared to women in the no hormonal contraceptive group. The thinner epithelial layer of the pIUD group was specific to the apical layer of the ectocervix. Furthermore, the pIUD group expressed significantly lower levels of the tight junction marker ZO-1 within the epithelium as compared to the COC group. Similar expression levels of HIV receptors and coreceptors CD4, CCR5, DC-SIGN, and Langerin were observed in the three study groups. Thus, women using pIUD displayed a thinner apical layer of the ectocervical epithelium and reduced ZO-1 expression as compared to control groups. These data suggest that pIUD use may weaken the ectocervical epithelial barrier against invading pathogens, including HIV.


Assuntos
Colo do Útero/metabolismo , Colo do Útero/patologia , Anticoncepcionais Orais Combinados , Dispositivos Intrauterinos Medicados , RNA Mensageiro/metabolismo , Proteína da Zônula de Oclusão-1/metabolismo , Adolescente , Adulto , Antígenos CD/metabolismo , Biópsia , Antígenos CD4/metabolismo , Estudos de Casos e Controles , Suscetibilidade a Doenças , Epitélio/metabolismo , Epitélio/patologia , Feminino , Infecções por HIV , Humanos , Lectinas Tipo C/metabolismo , Lectinas de Ligação a Manose/metabolismo , Receptores CCR5/metabolismo , Receptores de HIV/metabolismo , Adulto Jovem , Proteína da Zônula de Oclusão-1/genética
3.
Vaccines (Basel) ; 9(3)2021 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-33806390

RESUMO

Immunological correlates of natural resistance to HIV have been identified in HIV-exposed seronegative (HESN) individuals and include a low-inflammatory genital mucosal status. The cervicovaginal epithelium has not been studied for such correlates despite constituting an important barrier against sexual HIV transmission. To fill this gap in knowledge, we collected samples of blood, cervical mononuclear cells, cervicovaginal lavage, and ectocervical tissue from Kenyan HESN sex workers (n = 29) and controls (n = 33). The samples were analyzed by flow cytometry, protein profiling, 16S rRNA gene sequencing, in situ image analysis, and tissue-based RNA sequencing. A significantly higher relative proportion of regulatory T cells in blood (B7+CD25hiFoxP3+CD127loCD4+ and B7+Helios+FoxP3+CD4+), and a significantly lower proportion of activated cervical T cells (CCR5+CD69+CD4+ and CCR5+CD69+CD8+), were found in the HESN group compared with the controls. In contrast, there were no statistically significant differences between the study groups in cervicovaginal protein and microbiome compositions, ectocervical epithelial thickness, E-cadherin expression, HIV receptor expression, and tissue RNA transcriptional profiles. The identification of an intact ectocervical microenvironment in HESN individuals add new data to current knowledge about natural resistance to sexual transmission of HIV.

4.
AIDS Res Hum Retroviruses ; 35(3): 236-246, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30585733

RESUMO

Depot medroxyprogesterone acetate (DMPA) is the most common hormonal contraceptive used by women in sub-Saharan Africa, however, it has been epidemiologically associated with HIV infections. To assess whether DMPA has an effect on the number and activation of HIV target cells, this study assessed the levels and phenotype of blood- and mucosal-derived HIV target cells among women using DMPA. Thirty-five HIV uninfected women from the Pumwani Sex Worker cohort from Nairobi, Kenya were enrolled in the study (15 using DMPA and 20 not using hormonal contraception). Blood (plasma and peripheral blood mononuclear cells) and cervicovaginal (lavage, cervical cells, and ectocervical biopsies) samples were collected. Cellular phenotype and activation status were determined by flow cytometry, cytokine levels were assessed by bead array and image analysis assessed cell number and phenotype in situ. In blood, the proportion of HIV target cells and activated T cells was lower in DMPA users versus those not using hormonal contraceptives. However, analysis of cervical mononuclear cells showed that DMPA users had elevated levels of activated T cells (CD4+CD69+) and expressed lower levels of the HIV co-receptor CCR5 on a per cell basis, while tissue samples showed that in the ectocervix, DMPA users had a higher proportion of CD4+CCR5+ T cells. This study demonstrates that DMPA users had higher levels of activated T cells and HIV target cells in the genital tract. The increased pool of mucosal HIV target cells provides new biological information about the potential impact of DMPA on HIV susceptibility.


Assuntos
Linfócitos T CD4-Positivos , Colo do Útero/imunologia , Anticoncepcionais Femininos/farmacologia , Acetato de Medroxiprogesterona/farmacologia , Receptores CCR5/metabolismo , Profissionais do Sexo , Adulto , Colo do Útero/efeitos dos fármacos , Estudos de Coortes , Anticoncepcionais Femininos/administração & dosagem , Anticoncepcionais Femininos/efeitos adversos , Estudos Transversais , Citocinas/sangue , Suscetibilidade a Doenças/induzido quimicamente , Feminino , Infecções por HIV/imunologia , Humanos , Quênia , Ativação Linfocitária/efeitos dos fármacos , Acetato de Medroxiprogesterona/administração & dosagem , Acetato de Medroxiprogesterona/efeitos adversos
5.
BMJ Open ; 5(2): e006627, 2015 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-25694458

RESUMO

OBJECTIVES: Skin biopsies from local sites of herpes simplex virus 2 (HSV-2)-induced ulcers can show infiltrates of inflammatory cells several months after macroscopic healing. We hypothesise that foreskin tissue samples of asymptomatic HSV-2 seropositive men had remaining signs of inflammation at the molecular level. Even in the absence of clinical lesions, genital inflammation may contribute to increased HIV susceptibility on sexual exposure to the virus. SETTING: Foreskin tissue samples were collected from men undergoing elective circumcision in Kisumu, Kenya. PARTICIPANTS: The foreskin tissue samples (n=86) were stratified into study groups based on HSV-2 serology and assessed for mRNA expression of inflammatory markers. Markers of interest were further assessed by immunohistochemical staining within the tissue samples. RESULTS: The two study groups had comparable levels of all molecular markers (CD3, CD4, CD8, CD69, CCR5, HLA-DR, Langerin, DC-SIGN, Mannose Receptor 1, IL-1, IL-6, TNF-α, ß7, IgA, IFN-α, CCL5, E-cadherin, ZO-1 and occludin), except for lower mRNA levels of the epithelial junction protein claudin-1 in the HSV-2 seropositive group (p=0.008). Although mRNA levels of claudin-1 were lower in HSV-2 seropositive individuals, the corresponding protein could be visualised in the foreskin epithelium of all samples tested. CONCLUSIONS: Whereas no general inflammation was demonstrated in the foreskin of asymptomatic HSV-2 seropositive individuals, a decreased expression of claudin-1 indicates a less robust genital epithelial barrier. An intact epithelial barrier is essential for blocking mucosal entry of genital infections, including HIV.


Assuntos
Claudina-1/metabolismo , Prepúcio do Pênis/metabolismo , Infecções por HIV/etiologia , Herpes Genital/metabolismo , Herpesvirus Humano 2 , Mediadores da Inflamação/metabolismo , Inflamação/metabolismo , Adolescente , Adulto , Biomarcadores/metabolismo , Herpes Genital/complicações , Herpes Genital/virologia , Humanos , Quênia , Masculino , RNA Mensageiro/metabolismo , Adulto Jovem
6.
Am J Reprod Immunol ; 72(5): 475-84, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25087845

RESUMO

PROBLEM: Sex hormones can influence the immune defenses of the female genital tract (FGT) and its susceptibility to infections. Here we investigated the effect of different hormonal contraceptives on the production of antimicrobial peptides (AMPs) in different compartments of the female genital mucosa (FGM), secretions and tissue. METHOD OF STUDY: Cervicovaginal secretions (CVS) and ectocervical tissue samples obtained from women using progesterone intrauterine devices (pIUD) (n = 23) and combined oral contraceptives (COC) (n = 23) were analyzed for the expression and in situ localization of HNP1-3, BD-2, LL-37, SLPI and trappin-2 by ELISA, real-time PCR and immunohistochemistry. RESULTS: Women using COC had significantly lower mRNA levels of BD-2 and trappin-2 in ectocervical tissue than pIUD users. The two groups showed no differences in CVS concentration, as well as similar in situ expression patterns in ectocervical tissue, of all five AMPs. CONCLUSIONS: The use of hormonal contraceptives influences AMP expression differently in genital secretions compared to ectocervical tissue. This suggests that the impact of sex hormones on local immune defenses varies in different compartments of the FGM, and likely in different locations across the FGT.


Assuntos
Peptídeos Catiônicos Antimicrobianos/biossíntese , Anticoncepcionais Orais Hormonais/administração & dosagem , Regulação da Expressão Gênica/efeitos dos fármacos , Genitália Feminina/metabolismo , Dispositivos Intrauterinos , Adolescente , Adulto , Peptídeos Catiônicos Antimicrobianos/imunologia , Feminino , Regulação da Expressão Gênica/imunologia , Genitália Feminina/imunologia , Humanos
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