Abstract
Immune protection in the female reproductive tract (FRT) has evolved to meet the challenges of sexually transmitted bacterial and viral pathogens, allogeneic spermatozoa, and an immunologically distinct semi-allogeneic fetus. Throughout the FRT, the innate immune system is essential for the recognition and initial response to incoming pathogens. Key mediators of innate immune protection examined in this review include epithelial cells, stromal fibroblasts, macrophages, DC, and neutrophils from the Fallopian tubes, uterus, cervix and vagina. These innate immune cells respond to pathogens resulting in the secretion of cytokines, chemokines, antimicrobials, and production of intracellular proteins that protect, activate and recruit both innate and adaptive immune cells. Human immunodeficiency virus (HIV) infection can occur throughout the FRT, including the ovary, and is modulated by multiple factors including age of the individual, epithelial barrier integrity, composition of the vaginal microbiome, and hormonal status. Alterations in immune function due to hormonal changes that optimize conditions for successful fertilization create a hypothesized “window of vulnerability” that lasts from ovulation into the secretory stage of the menstrual cycle. The goal of this review is to summarize the multiple levels of protection against HIV infection in the FRT and thereby providing a foundation for the design of vaccines for protection against sexually-transmitted infections (STI) including HIV.
Keywords: Hormones, innate immune protection, HIV, human female reproductive tract, fallopian tubes, sexually transmitted infection.
[1]
WHO. Progress report 2011: Global HIV/AIDS response2011.
Available from:. http://www.who.int/hiv/pub/progress_report2011/ en/index.html
[3]
Haase AT. Early events in sexual transmission of HIV and SIV and opportunities for interventions. Annu Rev Med 2011; 62: 127-39.
[4]
Zhang Z, Schuler T, Zupancic M, et al. Sexual transmission and propagation of SIV and HIV in resting and activated CD4+ T cells. Science 1999; 286(5443): 1353-7.
[5]
Veazey RS, DeMaria M, Chalifoux LV, et al. Gastrointestinal tract as a major site of CD4+ T cell depletion and viral replication in SIV infection. Science 1998; 280(5362): 427-31.
[6]
Sattentau Q, Dalgleish A, Weiss R, Beverley P. Epitopes of the CD4 antigen and HIV infection. Science 1986; 234(4780): 1120-3.
[7]
Deng H, Liu R, Ellmeier W, et al. Identification of a major co-receptor for primary isolates of HIV-1. Nature 1996; 381(6584): 661-6.
[8]
Feng Y, Broder CC, Kennedy PE, Berger EA. HIV-1 entry cofactor: Functional cDNA cloning of a seven-transmembrane, G protein-coupled receptor. Science 1996; 272(5263): 872-7.
[9]
Turville SG, Arthos J, Mac Donald K, et al. HIV GP120 receptors on human dendritic cells. Blood 2001; 98(8): 2482-8.
[10]
Patel M, Yanagishita M, Roderiquez G, et al. Cell-surface heparan sulfate proteoglycan mediates HIV-1 infection of T-cell lines. AIDS Res Hum Retroviruses 1993; 9(2): 167-74.
[11]
Bhat S. Galactose to ceramide linkage is essential for the binding of a polyclonal antibody to galactosyl ceramide. J Neuroimmunol 1992; 41(1): 105-10.
[12]
Stoddard E, Cannon G, Ni H, et al. GP340 expressed on human genital epithelia binds HIV-1 envelope protein and facilitates viral transmission. J Immunol 2007; 179(5): 3126-32.
[13]
Arthos J, Cicala C, Martinelli E, et al. HIV-1 envelope protein binds to and signals through integrin α4β7, the gut mucosal homing receptor for peripheral T cells. Nat Immunol 2008; 9(3): 301-9.
[14]
Li Q, Estes JD, Schlievert PM, et al. Glycerol monolaurate prevents mucosal SIV transmission. Nature 2009; 458(7241): 1034-8.
[15]
Stieh DJ, Maric D, Kelley ZL, et al. Vaginal challenge with an SIV-based dual reporter system reveals that infection can occur throughout the upper and lower female reproductive tract. PLoS Pathog 2014; 10(10): e1004440.
[16]
Stieh DJ, Matias E, Xu H, et al. Th17 cells are preferentially infected very early after vaginal transmission of SIV in Macaques. Cell Host Microbe 2016; 19(4): 529-40.
[17]
Allen IC, Moore CB, Schneider M, et al. NLRX1 protein attenuates inflammatory responses to infection by interfering with the RIG-I-MAVS and TRAF6-NF-kappaB signaling pathways. Immunity 2011; 34(6): 854-65.
[18]
Moore CB, Bergstralh DT, Duncan JA, et al. NLRX1 is a regulator of mitochondrial antiviral immunity. Nature 2008; 451(7178): 573-7.
[19]
Guo H, Konig R, Deng M, et al. NLRX1 sequesters STING to negatively regulate the interferon response, thereby facilitating the replication of HIV-1 and DNA Viruses. Cell Host Microbe 2016; 19(4): 515-28.
[20]
Chen ML, Pittet MJ, Gorelik L, et al. Regulatory T cells suppress tumor-specific CD8 T cell cytotoxicity through TGF-beta signals in vivo. Proc Natl Acad Sci USA 2005; 102(2): 419-24.
[21]
Shen Z, Rodriguez-Garcia M, Ochsenbauer C, Wira CR. Characterization of immune cells and infection by HIV in human ovarian tissues. Am J Reprod Immunol 2017; 78(1)
[22]
Wira CR, Rodriguez-Garcia M, Patel MV. The role of sex hormones in immune protection of the female reproductive tract. Nat Rev Immunol 2015; 15(4): 217-30.
[23]
Zervomanolakis I, Ott HW, Hadziomerovic D, et al. Physiology of upward transport in the human female genital tract. Ann N Y Acad Sci 2007; 1101: 1-20.
[24]
Bagasra O, Freund M, Weidmann J, Harley G. Interaction of human immunodeficiency virus with human sperm in vitro. J Acquir Immune Defic Syndr 1988; 1: 431-5.
[25]
Brogi A, Presentini R, Solazzo D, Piomboni P, Costantino-Ceccarini E. Interaction of human immunodeficiency virus type 1 envelope glycoprotein gp120 with a galactoglycerolipid associated with human sperm. AIDS Res Hum Retroviruses 1996; 12: 483-9.
[26]
Givan AL, White HD, Stern JE, et al. Flow cytometric analysis of leukocytes in the human female reproductive tract: comparison of fallopian tube, uterus, cervix, and vagina. Am J Reprod Immunol 1997; 38(5): 350-9.
[27]
Poonia B, Walter L, Dufour J, Harrison R, Marx PA, Veazey RS. Cyclic changes in the vaginal epithelium of normal rhesus macaques. J Endocrinol 2006; 190(3): 829-35.
[28]
Smith SM, Mefford M, Sodora D, et al. Topical estrogen protects against SIV vaginal transmission without evidence of systemic effect. AIDS 2004; 18(12): 1637-43.
[29]
Kersh EN, Ritter J, Butler K, et al. Relationship of estimated SHIV acquisition time points during the menstrual cycle and thinning of vaginal epithelial layers in pigtail macaques. Sex Transm Dis 2015; 42(12): 694-701.
[30]
Marx PA, Spira AI, Gettie A, et al. Progesterone implants enhance SIV vaginal transmission and early virus load. Nat Med 1996; 2(10): 1084-9.
[31]
Bahamondes L, Trevisan M, Andrade L, et al. The effect upon the human vaginal histology of the long-term use of the injectable contraceptive Depo-Provera. Contraception 2000; 62(1): 23-7.
[32]
Miller L, Patton DL, Meier A, Thwin SS, Hooton TM, Eschenbach DA. Depomedroxyprogesterone-induced hypoestrogenism and changes in vaginal flora and epithelium. Obstet Gynecol 2000; 96(3): 431-9.
[33]
Ildgruben AK, Sjöberg IM, Hammarström M-LKC. Influence of hormonal contraceptives on the immune cells and thickness of human vaginal epithelium. Obstet Gynecol 2003; 102(3): 571-82.
[34]
Mauck CK, Callahan MM, Baker J, et al. The effect of one injection of Depo-Provera® on the human vaginal epithelium and cervical ectopy. Contraception 1999; 60(1): 15-24.
[35]
Noguchi LM, Richardson BA, Baeten JM, et al. Risk of HIV-1 acquisition among women who use different types of injectable progestin contraception in South Africa: A prospective cohort study. Lancet HIV 2015; 2(7): e279-87.
[36]
Polis CB, Curtis KM, Hannaford PC, et al. An updated systematic review of epidemiological evidence on hormonal contraceptive methods and HIV acquisition in women. AIDS 2016; 30(17): 2665-83.
[37]
Morrison CS, Bright P, Wong EL, et al. Hormonal contraceptive use, cervical ectopy, and the acquisition of cervical infections. Sex Transm Dis 2004; 31(9): 561-7.
[38]
Socías ME, Duff P, Shoveller J, et al. Use of injectable hormonal contraception and HSV-2 acquisition in a cohort of female sex workers in Vancouver, Canada. Sex Transm Dis 2017; 93(4): 284-9.
[39]
Grabowski MK, Gray RH, Makumbi F, et al. Use of injectable hormonal contraception and women’s risk of herpes simplex virus type 2 acquisition: A prospective study of couples in Rakai, Uganda. Lancet Glob Health 2015; 3(8): e478-86.
[40]
Arnold JT, Kaufman DG, Seppala M, Lessey BA. Endometrial stromal cells regulate epithelial cell growth in vitro: A new co-culture model. Hum Reprod 2001; 16(5): 836-45.
[41]
Malmström E, Sennström M, Holmberg A, et al. The importance of fibroblasts in remodelling of the human uterine cervix during pregnancy and parturition. Mol Hum Reprod 2007; 13(5): 333-41.
[42]
Singer CF, Marbaix E, Lemoine P, Courtoy PJ, Eeckhout Y. Local cytokines induce differential expression of matrix metalloproteinases but not their tissue inhibitors in human endometrial fibroblasts. Eur J Biochem 1999; 259(1-2): 40-5.
[43]
Grant KS, Wira CR. Effect of mouse uterine stromal cells on epithelial cell transepithelial Resistance (TER) and TNFα and TGFβ release in culture. Biol Reprod 2003; 69(3): 1091-8.
[44]
Eyster KM, Hansen KA, Winterton E, Klinkova O, Drappeau D, Mark-Kappeler CJ. Reciprocal communication between endometrial stromal cells and macrophages. Reprod Sci 2010; 17(9): 809-22.
[45]
Klinkova O, Hansen KA, Winterton E, Mark CJ, Eyster KM. Two-way communication between endometrial stromal cells and monocytes. Reprod Sci 2010; 17(2): 125-36.
[46]
Itoh H, Nasu K, Nishida M, Matsumoto H, Yuge A, Narahara H. Human oviductal stromal fibroblasts, but not oviductal epithelial cells, express Toll-like receptor 4: The site-specific mucosal immunity of the human fallopian tube against bacterial infection. Am J Reprod Immunol 2006; 56(2): 91-101.
[47]
Coleman KD, Ghosh M, Crist SG, et al. Modulation of Hepatocyte Growth Factor Secretion in Human Female Reproductive Tract Stromal Fibroblasts by Poly (I:C) and Estradiol. Am J Reprod Immunol 2012; 67(1): 44-53.
[48]
Neidleman JA, Chen JC, Kohgadai N, et al. Mucosal stromal fibroblasts markedly enhance HIV infection of CD4+ T cells. PLoS Pathog 2017; 13(2): e1006163.
[49]
Wira CR, Fahey JV, Sentman CL, Pioli PA, Shen L. Innate and adaptive immunity in female genital tract: Cellular responses and interactions. Immunol Rev 2005; 206: 306-35.
[50]
Starkey PM, Clover LM, Rees MCP. Variation during the menstrual cycle of immune cell populations in human endometrium. Eur J Obstet Gynecol Reprod Biol 1991; 39(3): 203-7.
[51]
Shen R, Richter HE, Clements RH, et al. Macrophages in vaginal but not intestinal mucosa are monocyte-like and permissive to human immunodeficiency virus type 1 infection. J Virol 2009; 83(7): 3258-67.
[52]
Cassol E, Cassetta L, Alfano M, Poli G. Macrophage polarization and HIV-1 infection. J Leukoc Biol 2010; 87(4): 599-608.
[53]
Collins KB, Patterson BK, Naus GJ, Landers DV, Gupta P. Development of an in vitro organ culture model to study transmission of HIV-1 in the female genital tract. Nat Med 2000; 6(4): 475-9.
[54]
Cummins JE Jr, Guarner J, Flowers L, et al. Preclinical testing of candidate topical microbicides for anti-human immunodeficiency virus type 1 activity and tissue toxicity in a human cervical explant culture. Antimicrob Agents Chemother 2007; 51(5): 1770-9.
[55]
Greenhead P, Hayes P, Watts PS, Laing KG, Griffin GE, Shattock RJ. Parameters of human immunodeficiency virus infection of human cervical tissue and inhibition by vaginal virucides. J Virol 2000; 74(12): 5577-86.
[56]
Quillay H, El Costa H, Marlin R, et al. Distinct characteristics of endometrial and decidual macrophages and regulation of their permissivity to HIV-1 infection by SAMHD1. J Virol 2015; 89(2): 1329-39.
[57]
Banchereau J, Steinman RM. Dendritic cells and the control of immunity. Nature 1998; 392(6673): 245-52.
[58]
Steinman RM, Hemmi H. Dendritic cells: Translating innate to adaptive immunity. Curr Top Microbiol Immunol 2006; 311: 17-58.
[59]
Iijima N, Linehan MM, Saeland S, Iwasaki A. Vaginal epithelial dendritic cells renew from bone marrow precursors. Proc Natl Acad Sci USA 2007; 104(48): 19061-6.
[60]
Iijima N, Linehan MM, Zamora M, et al. Dendritic cells and B cells maximize mucosal Th1 memory response to herpes simplex virus. J Exp Med 2008; 205(13): 3041-52.
[61]
Altfeld M, Fadda L, Frleta D, Bhardwaj N. DCs and NK cells: Critical effectors in the immune response to HIV-1. Nat Rev Immunol 2011; 11(3): 176-86.
[62]
Liu K, Victora GD, Schwickert TA, et al. In vivo analysis of dendritic cell development and homeostasis. Science 2009; 324(5925): 392-7.
[63]
Randolph GJ, Ochando J, Partida-Sanchez S. Migration of dendritic cell subsets and their precursors. Annu Rev Immunol 2008; 26: 293-316.
[64]
Wu L. KewalRamani VN. Dendritic-cell interactions with HIV: infection and viral dissemination. Nat Rev Immunol 2006; 6(11): 859-68.
[65]
Rodriguez-Garcia M, Shen Z, Barr FD, et al. Dendritic cells from the human female reproductive tract rapidly capture and respond to HIV. Mucosal Immunol 2017; 10(2): 531-44.
[66]
Duluc D, Gannevat J, Anguiano E, et al. Functional diversity of human vaginal APC subsets in directing T-cell responses. Mucosal Immunol 2013; 6(3): 626-38.
[67]
Shen R, Kappes JC, Smythies LE, Richter HE, Novak L, Smith PD. Vaginal myeloid dendritic cells transmit founder HIV-1. J Virol 2014; 88(13): 7683-8.
[68]
Cunningham AL, Donaghy H, Harman AN, Kim M, Turville SG. Manipulation of dendritic cell function by viruses. Curr Opin Microbiol 2010; 13(4): 524-9.
[69]
Lambotin M, Raghuraman S, Stoll-Keller F, Baumert TF, Barth H. A look behind closed doors: Interaction of persistent viruses with dendritic cells. Nat Rev Microbiol 2010; 8(5): 350-60.
[70]
Mselle TF, Meadows SK, Eriksson M, et al. Unique characteristics of NK cells throughout the human female reproductive tract. Clin Immunol 2007; 124(1): 69-76.
[71]
Mselle TF, Howell AL, Ghosh M, Wira CR, Sentman CL. Human uterine natural killer cells but not blood natural killer cells inhibit human immunodeficiency virus type 1 infection by secretion of CXCL12. J Virol 2009; 83(21): 11188-95.
[72]
Evans J, Salamonsen LA. Inflammation, leukocytes and menstruation. Rev Endocr Metab Disord 2012; 13(4): 277-88.
[73]
Selsted ME, Ouellette AJ. Defensins in granules of phagocytic and non-phagocytic cells. Trends Cell Biol 1995; 5(3): 114-9.
[74]
Anderson JM, Van Itallie CM. Physiology and function of the tight junction. Cold Spring Harb Perspect Biol 2009; 1(2): a002584.
[75]
Iwanaga S, Inokuchi T, Notohara A, Higashi R, Murakami M, Kato T. Alterations in tight junctions of human endometrial epithelial cells during normal menstrual cycle--freeze-fracture electron microscopic study. Nippon Sanka Fujinka Gakkai Zasshi 1985; 37(12): 2847-52.
[76]
Murphy CR, Rogers PA, Hosie MJ, Leeton J, Beaton L. Tight junctions of human uterine epithelial cells change during the menstrual cycle: A morphometric study. Acta Anat (Basel) 1992; 144(1): 36-8.
[77]
Gorodeski GI. Estrogen biphasic regulation of paracellular permeability of cultured human vaginal-cervical epithelia. J Clin Endocrinol Metab 2001; 86(9): 4233-43.
[78]
Gorodeski GI. Estrogen modulation of epithelial permeability in cervical-vaginal cells of premenopausal and postmenopausal women. Menopause 2007; 14(6): 1012-9.
[79]
Gorodeski GI. Aging and estrogen effects on transcervical-transvaginal epithelial permeability. J Clin Endocrinol Metab 2005; 90(1): 345-51.
[80]
Zeng R, Li X, Gorodeski GI. Estrogen abrogates transcervical tight junctional resistance by acceleration of occludin modulation. J Clin Endocrinol Metab 2004; 89(10): 5145-55.
[81]
Nazli A, Chan O, Dobson-Belaire WN, et al. Exposure to HIV-1 directly impairs mucosal epithelial barrier integrity allowing microbial translocation. PLoS Pathog 2010; 6(4): e1000852.
[82]
Lai SK, Hida K, Shukair S, et al. Human immunodeficiency virus type 1 is trapped by acidic but not by neutralized human cervicovaginal mucus. J Virol 2009; 83(21): 11196-200.
[83]
Shukair SA, Allen SA, Cianci GC, et al. Human cervicovaginal mucus contains an activity that hinders HIV-1 movement. Mucosal Immunol 2013; 6(2): 427-34.
[84]
Gipson IK, Ho SB, Spurr-Michaud SJ, et al. Mucin genes expressed by human female reproductive tract epithelia. Biol Reprod 1997; 56(4): 999-1011.
[85]
Vigil P, Cortés ME, Zúñiga A, Riquelme J, Ceric F. Scanning electron and light microscopy study of the cervical mucus in women with polycystic ovary syndrome. J Elect Micro 2009; 58(1): 21-7.
[86]
Elstein M. Functions and physical properties of mucus in the female genital tract. Br Med Bull 1978; 34(1): 83-8.
[87]
Fahrbach KM, Malykhina O, Stieh DJ, Hope TJ. Differential binding of IgG and IgA to mucus of the female reproductive tract. PLoS One 2013; 8(10): e76176.
[88]
Witkin SS, Linhares IM, Giraldo P. Bacterial flora of the female genital tract: Function and immune regulation. Best Pract Res Clin Obstet Gynaecol 2007; 21(3): 347-54.
[89]
Ravel J, Gajer P, Abdo Z, et al. Vaginal microbiome of reproductive-age women. Proc Natl Acad Sci USA 2011; 108(Suppl. 1): 4680-7.
[90]
Ma B, Forney LJ, Ravel J. Vaginal microbiome: Rethinking health and disease. Annu Rev Microbiol 2012; 66(1): 371-89.
[91]
Shannon B, Yi TJ, Perusini S, et al. Association of HPV infection and clearance with cervicovaginal immunology and the vaginal microbiota. . Mucosal Immunol 2017; 10(5): 1310-9.
[92]
Anahtar MN, Byrne EH, Doherty KE, et al. Cervicovaginal bacteria are a major modulator of host inflammatory responses in the female genital tract. Immunity 2015; 42(5): 965-76.
[93]
Borgdorff H, Gautam R, Armstrong SD, et al. Cervicovaginal microbiome dysbiosis is associated with proteome changes related to alterations of the cervicovaginal mucosal barrier. Mucosal Immunol 2016; 9(3): 621-33.
[94]
Ahmed N, Hayashi T, Hasegawa A, et al. Suppression of human immunodeficiency virus type 1 replication in macrophages by commensal bacteria preferentially stimulating Toll-like receptor 4. J Gen Virol 2010; 91(11): 2804-13.
[95]
Gosmann C, Anahtar MN, Handley SA, et al. Lactobacillus-deficient cervicovaginal bacterial communities are associated with increased HIV acquisition in young South African women. Immunity 2017; 46(1): 29-37.
[96]
Zevin AS, Xie IY, Birse K, et al. Microbiome composition and function drives wound-healing impairment in the female genital tract. PLoS Pathog 2016; 12(9): e1005889.
[97]
Fahey JV, Wright JA, Shen L, et al. Estradiol selectively regulates innate immune function by polarized human uterine epithelial cells in culture. Mucosal Immunol 2008; 1(4): 317-25.
[98]
Wira CR, Fahey JV, Ghosh M, Patel MV, Hickey DK, Ochiel DO. Sex hormone regulation of innate immunity in the female reproductive tract: the role of epithelial cells in balancing reproductive potential with protection against sexually transmitted pathogens. Am J Reprod Immunol 2010; 63(6): 544-65.
[99]
Fahey JV, Schaefer TM, Channon JY, Wira CR. Secretion of cytokines and chemokines by polarized human epithelial cells from the female reproductive tract. Humanit Rep 2005; 20(6): 1439-46.
[100]
Pivarcsi A, Nagy I, Koreck A, et al. Microbial compounds induce the expression of pro-inflammatory cytokines, chemokines and human beta-defensin-2 in vaginal epithelial cells. Microbes Infect 2005; 7(9-10): 1117-27.
[101]
Patel MV, Fahey JV, Rossoll RM, Wira CR. Innate immunity in the vagina (part i): estradiol inhibits hbd2 and elafin secretion by human vaginal epithelial cells. Am J Reprod Immunol 2013; 69(5): 463-74.
[102]
Ganz T. Defensins: Antimicrobial peptides of innate immunity. Nat Rev Immunol 2003; 3(9): 710-20.
[104]
Cole AM, Cole AL. Antimicrobial polypeptides are key anti-HIV-1 effector molecules of cervicovaginal host defense. Am J Reprod Immunol 2008; 59(1): 27-34.
[105]
Hein M, Valore EV, Helmig RB, Uldbjerg N, Ganz T. Antimicrobial factors in the cervical mucus plug. Am J Obstet Gynecol 2002; 187(1): 137-44.
[106]
Venkataraman N, Cole AL, Svoboda P, Pohl J, Cole AM. Cationic polypeptides are required for Anti-HIV-1 activity of human vaginal fluid. J Immunol 2005; 175(11): 7560-7.
[107]
Ghosh M, Fahey JV, Shen Z, et al. Anti-HIV activity in cervical-vaginal secretions from HIV-positive and -negative women correlate with innate antimicrobial levels and IgG antibodies. PLoS One 2010; 5(6): e11366.
[108]
Keller MJ, Zerhouni-Layachi B, Cheshenko N, et al. PRO 2000 gel inhibits HIV and herpes simplex virus infection following vaginal application: A double-blind placebo-controlled trial. J Infect Dis 2006; 193(1): 27-35.
[109]
Wira CR, Fahey JV, Ghosh M, Patel MV, Hickey DK, Ochiel DO. Sex hormone regulation of innate immunity in the female reproductive tract: the role of epithelial cells in balancing reproductive potential with protection against sexually transmitted pathogens. Am J Reprod Immunol 2010; 63(6): 544-65.
[110]
Keller MJ, Guzman E, Hazrati E, et al. PRO 2000 elicits a decline in genital tract immune mediators without compromising intrinsic antimicrobial activity. AIDS 2007; 21(4): 467-76.
[111]
Cortez V, Odem-Davis K, Lehman DA, Mabuka J, Overbaugh J. Quotidian changes of genital tract cytokines in human immunodeficiency virus-1-infected women during the menstrual cycle. . Open Forum Infect Dis 2014; 1(1): ofu002.
[112]
Valore EV, Park CH, Igreti SL, Ganz T. Antimicrobial components of vaginal fluid. Am J Obstet Gynecol 2002; 187(3): 561-8.
[113]
Patel MV, Ghosh M, Fahey JV, Ochsenbauer C, Rossoll RM, Wira CR. Innate immunity in the vagina (Part II): Anti-HIV activity and antiviral content of human vaginal secretions. Am J Reprod Immunol 2014; 72(1): 22-33.
[114]
Delany S, Rosas R, Mlaba N, et al. Comparison of cervicovaginal lavage, cervicovaginal lavage enriched with cervical swab, and vaginal tampon for the detection of HIV-1 RNA and HSV-2 DNA in genital secretions. J Acquir Immune Defic Syndr 2008; 49(4): 406-9.
[115]
Dezzutti CS, Hendrix CW, Marrazzo JM, et al. Performance of swabs, lavage, and diluents to quantify biomarkers of female genital tract soluble mucosal mediators. PLoS One 2011; 6(8): e23136.
[116]
Fehring RJ, Schneider M, Raviele K. Variability in the phases of the menstrual cycle. J Obstet Gynecol Neonatal Nurs 2006; 35(3): 376-84.
[117]
Kayisli UA, Mahutte NG, Arici A. Uterine chemokines in reproductive physiology and pathology. Am J Reprod Immunol 2002; 47(4): 213-21.
[118]
Coleman KD, Wright JA, Ghosh M, Wira CR, Fahey JV. Estradiol modulation of hepatocyte growth factor by stromal fibroblasts in the female reproductive tract. Fertil Steril 2009; 92(3): 1107-9.
[119]
Grant-Tschudy KS, Wira CR. Paracrine mediators of mouse uterine epithelial cell transepithelial resistance in culture. J Reprod Immunol 2005; 67(1-2): 1-12.
[120]
Haddad SN, Wira CR. Keratinocyte growth factor stimulates macrophage inflammatory protein 3alpha and keratinocyte-derived chemokine secretion by mouse uterine epithelial cells. Am J Reprod Immunol 2010; 64(3): 197-211.
[121]
Hampton AL, Rogers PA, Affandi B, Salamonsen LA. Expression of the chemokines, monocyte chemotactic protein (MCP)-1 and MCP-2 in endometrium of normal women and Norplant users, does not support a central role in macrophage infiltration into endometrium. J Reprod Immunol 2001; 49(2): 115-32.
[122]
Ghosh M, Shen Z, Schaefer TM, Fahey JV, Gupta P, Wira CR. CCL20/MIP3a is a Novel Anti-HIV-1 Molecule of the Human Female Reproductive Tract. Am J Reprod Immunol 2009; 62(1): 60-71.
[123]
Pioli PA, Amiel E, Schaefer TM, Connolly JE, Wira CR, Guyre PM. Differential expression of Toll-like receptors 2 and 4 in tissues of the human female reproductive tract. Infect Immun 2004; 72(10): 5799-806.
[124]
Fichorova RN, Cronin AO, Lien E, Anderson DJ, Ingalls RR. Response to Neisseria gonorrhoeae by cervicovaginal epithelial cells occurs in the absence of toll-like receptor 4-mediated signaling. J Immunol 2002; 168(5): 2424-32.
[125]
Ghosh M, Schaefer TM, Fahey JV, Wright JA, Wira CR. Antiviral responses of human Fallopian tube epithelial cells to toll-like receptor 3 agonist poly(I:C). Fertil Steril 2008; 89(5)(Suppl.): 1497-506.
[126]
Schaefer TM, Fahey JV, Wright JA, Wira CR. Innate immunity in the human female reproductive tract: Antiviral response of uterine epithelial cells to the TLR3 agonist poly(I:C). J Immunol 2005; 174(2): 992-1002.
[127]
Andersen JM, Al-Khairy D, Ingalls RR. Innate immunity at the mucosal surface: role of toll-like receptor 3 and toll-like receptor 9 in cervical epithelial cell responses to microbial pathogens. Biol Reprod 2006; 74(5): 824-31.
[128]
Hirata T, Osuga Y, Hirota Y, et al. Evidence for the presence of toll-like receptor 4 system in the human endometrium. J Clin Endocrinol Metab 2005; 90(1): 548-56.
[129]
Itoh H, Nasu K, Nishida M, Matsumoto H, Yuge A, Narahara H. Human oviductal stromal fibroblasts, but not oviductal epithelial cells, express Toll-like receptor 4: The site-specific mucosal immunity of the human fallopian tube against bacterial infection. Am J Reprod Immunol 2006; 56(2): 91-101.
[130]
Wira CR, Fahey JV. A new strategy to understand how HIV infects women: identification of a window of vulnerability during the menstrual cycle. AIDS 2008; 22(15): 1909-17.
[131]
Vishwanathan SA, Guenthner PC, Lin CY, et al. High susceptibility to repeated, low-dose, vaginal shiv exposure late in the luteal phase of the menstrual cycle of pigtail macaques. J Acquir Immune Defic Syndr 2011; 57(4): 261-4.
[132]
Kersh EN, Henning T, Vishwanathan SA, et al. SHIV susceptibility changes during the menstrual cycle of pigtail macaques. J Med Primatol 2014; 43: 310-6.
[133]
Saba E, Origoni M, Taccagni G, et al. Productive HIV-1 infection of human cervical tissue ex vivo is associated with the secretory phase of the menstrual cycle. Mucosal Immunol 2013; 6(6): 1081-90.
[134]
Vishwanathan SA, Burgener A, Bosinger SE, et al. Cataloguing of potential HIV susceptibility factors during the menstrual cycle of pig-tailed macaques by using a systems biology approach. J Virol 2015; 89(18): 9167-77.
[135]
Sonnex C. Influence of ovarian hormones on urogenital infection. Sex Transm Infect 1998; 74(1): 11-9.
[136]
Rodriguez-Garcia M, Biswas N, Patel MV, et al. Estradiol reduces susceptibility of CD4+ T cells and macrophages to HIV-Infection. PLoS One 2013; 8(4): e62069.
[137]
Fahey JV, Wright JA, Shen L, et al. Estradiol selectively regulates innate immune function by polarized human uterine epithelial cells in culture. Mucosal Immunol 2008; 1(4): 317-25.
[138]
Africander D, Louw R, Verhoog N, Noeth D, Hapgood JP. Differential regulation of endogenous pro-inflammatory cytokine genes by medroxyprogesterone acetate and norethisterone acetate in cell lines of the female genital tract. Contraception 2011; 84(4): 423-35.
[139]
Calla NEQ, Miguel RDV, Boyaka PN, et al. Medroxyprogesterone acetate and levonorgestrel increase genital mucosal permeability and enhance susceptibility to genital herpes simplex virus type 2 infection. Mucosal Immunol 2016; 9(6): 1571-83.
[140]
Goldfien GA, Barragan F, Chen J, et al. Progestin-containing contraceptives alter expression of host defense-related genes of the endometrium and cervix. Reprod Sci 2015; 22(7): 814-28.
[141]
Deese J, Masson L, Miller W, et al. Injectable Progestin-only contraception is associated with increased levels of pro-inflammatory cytokines in the female genital tract. Am J Reprod Immunol 2015; 74(4): 357-67.
[142]
Ghosh M, Rodriguez-Garcia M, Wira CR. Immunobiology of genital tract trauma: Endocrine regulation of HIV acquisition in women following sexual assault or genital tract mutilation. Am J Reprod Immunol 2013; 69(Suppl. 1): 51-60.
[143]
Klot JF, Auerbach JD, Veronese F, et al. Greentree white paper: sexual violence, genitoanal injury, and HIV: Priorities for research, policy, and practice. AIDS Res Hum Retroviruses 2012; 28(11): 1379-88.
[144]
Wira CR, Veronese F. Mucosal immunity in the male and female reproductive tract and prevention of HIV transmission. Am J Reprod Immunol 2011; 65(3): 182-5.
[145]
U.S. Department of Justice. National Crime Victimization Survey.
2009-2013. U.S. Department of Justice, 2014..
[146]
Zink T, Fargo JD, Baker RB, Buschur C, Fisher BS, Sommers MS. Comparison of methods for identifying ano-genital injury after consensual intercourse. J Emerg Med 2010; 39(1): 113-8.
[147]
Brawner BM, Sommers MS, Moore K, et al. Exploring genitoanal injury and HIV risk among women: Menstrual phase, hormonal birth control, and injury frequency and prevalence. J Acquir Immune Defic Syndr 2016; 71(2): 207-12.
[148]
Li Y, Marshall CM, Rees HC, Nunez A, Ezeanolue E, Ehiri J. Intimate partner violence and HIV infection among women: A systematic review and meta-analysis. J Int AIDS Soc 2014; 17(18445): 1-12.
[149]
Porter KA, Turpin J, Begg L, et al. Understanding the intersection of young age, mucosal injury, and HIV susceptibility. AIDS Res Hum Retroviruses 2016; 32(10-11): 1149-58.
Article Metrics
72
5