Generic placeholder image

Current Immunology Reviews (Discontinued)


ISSN (Print): 1573-3955
ISSN (Online): 1875-631X

Review Article

Barriers of Mucosal Entry of HIV/SIV

Author(s): Ann M. Carias* and Thomas J. Hope

Volume 15, Issue 1, 2019

Page: [4 - 13] Pages: 10

DOI: 10.2174/1573395514666180604084404

Price: $65


Most new HIV infections, over 80%, occur through sexual transmission. During sexual transmission, the virus must bypass specific female and male reproductive tract anatomical barriers to encounter viable target cells. Understanding the generally efficient ability of these barriers to exclude HIV and the precise mechanisms of HIV translocation beyond these genital barriers is essential for vaccine and novel therapeutic development. In this review, we explore the mucosal, barriers of cervico-vaginal and penile tissues that comprise the female and male reproductive tracts. The unique cellular assemblies of the squamous and columnar epithelium are illustrated highlighting their structure and function. Each anatomical tissue offers a unique barrier to virus entry in healthy individuals. Unfortunately barrier dysfunction can lead to HIV transmission. How these diverse mucosal barriers have the potential to fail is considered, highlighting those anatomical areas that are postulated to offer a weaker barrier and are; therefore, more susceptible to viral ingress. Risk factors, such as sexually transmitted infections, microbiome dysbiosis, and high progestin environments are also associated with increased acquisition of HIV. How these states may affect the integrity of mucosal barriers leading to HIV acquisition are discussed suggesting mechanisms of transmission and revealing potential targets for intervention.

Keywords: HIV infection, female reproductive tract, vaginal transmission, target cells, hormonal contraception, HIV risk.

UNAIDS. 2015 Report on the global AIDS epidemic, 2015.
CDC. HIV in the United States: At a Glance. 2015..
Zhang LQ, MacKenzie P, Cleland A, Holmes EC, Brown AJ, Simmonds P. Selection for specific sequences in the external envelope protein of human immunodeficiency virus type 1 upon primary infection. J Virol 1993; 67(6): 3345-56.
Dragic T, Litwin V, Allaway GP, et al. HIV-1 entry into CD4+ cells is mediated by the chemokine receptor CC-CKR-5. Nature 1996; 381(6584): 667-73.
Royce RA, Sena A, Cates W Jr, Cohen MS. Sexual transmission of HIV. N Engl J Med 1997; 336(15): 1072-8.
Gray RH, Wawer MJ, Brookmeyer R, et al. Probability of HIV-1 transmission per coital act in monogamous, heterosexual, HIV-1-discordant couples in Rakai, Uganda. Lancet 2001; 357(9263): 1149-53.
Powers KA, Poole C, Pettifor AE, Cohen MS. Rethinking the heterosexual infectivity of HIV-1: A systematic review and meta-analysis. Lancet Infect Dis 2008; 8(9): 553-63.
Wawer MJ, Gray RH, Sewankambo NK, et al. Rates of HIV-1 transmission per coital act, by stage of HIV-1 infection, in Rakai, Uganda. J Infect Dis 2005; 191(9): 1403-9.
Burgos MH. Roig de V-L. Cell junctions in the human vaginal epithelium. Am J Obstet Gynecol 1970; 108(4): 565-71.
Sousa S, Lecuit M, Cossart P. Microbial strategies to target, cross or disrupt epithelia. Curr Opin Cell Biol 2005; 17(5): 489-98.
Dinh MH, Okocha EA, Koons A, Veazey RS, Hope TJ. Expression of structural proteins in human female and male genital epithelia and implications for sexually transmitted infections. Biol Reprod 2012; 86(2): 32.
Shattock RJ, Moore JP. Inhibiting sexual transmission of HIV-1 infection. Nat Rev Microbiol 2003; 1(1): 25-34.
Miller CJ, Shattock RJ. Target cells in vaginal HIV transmission. Microbes Infect 2003; 5(1): 59-67.
Pendergrass PB, Belovicz MW, Reeves CA. Surface area of the human vagina as measured from vinyl polysiloxane casts. Gynecol Obstet Invest 2003; 55(2): 110-3.
Hamilton CE. Observations on the cervical mucosa of the rhesus monkey Contrib Embryol 1949; 33(213-221): 81-102
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.
Carias A, McCoombe S, McRaven M, et al. Defining theinteraction of HIV-1 with the mucosal barriers of the female reproductive tract. J Virol 2013; 87(21): 11388-400.
Coombs RW, Reichelderfer PS, Landay AL. Recent observations on HIV type-1 infection in the genital tract of men and women. AIDS 2003; 17(4): 455-80.
Pudney J, Quayle AJ, Anderson DJ. Immunological microenvironments in the human vagina and cervix: Mediators of cellular immunity are concentrated in the cervical transformation zone Biol Reprod 2005; 73(6): 1253-63.
O’Farrell N, Morison L, Moodley P, et al. Association between HIV and subpreputial penile wetness in uncircumcised men in South Africa. J Acquir Immune Defic Syndr 2006; 43(1): 69-77.
Dinh MH, Anderson MR, McRaven MD, et al. Visualization of HIV-1 interactions with penile and foreskin epithelia: Clues for female-to-male HIV transmission. PLoS Pathog 2015; 11(3): e1004729.
Anderson D, Politch JA, Pudney J. HIV infection and immune defense of the penis. Am J Reprod Immunol 2011; 65(3): 220-9.
Ganor Y, Zhou Z, Bodo J, et al. The adult penile urethra is a novel entry site for HIV-1 that preferentially targets resident urethral macrophages. Mucosal Immunol 2013; 6(4): 776-86.
Stevenson JG, Umstead GS. Sexual dysfunction due to antihypertensive agents. Drug Intell Clin Pharm 1984; 18(2): 113-21.
Bomsel M. Transcytosis of infectious human immunodeficiency virus across a tight human epithelial cell line barrier. Nat Med 1997; 3(1): 42-7.
Hladik F, Sakchalathorn P, Ballweber L, et al. Initial events in establishing vaginal entry and infection by Human Immunodeficiency Virus Type-1Immunity 2007; 26(2): 257-70.
Miller CJ, Alexander NJ, Vogel P, Anderson J, Marx PA. Mechanism of genital transmission of SIV: A hypothesis based on transmission studies and the location of SIV in the genital tract of chronically infected female rhesus macaques. J Med Primatol 1992; 21(2-3): 64-8.
Morrison CS, Richardson BA, Mmiro F, et al. Hormonal contraception and the risk of HIV acquisition. AIDS 2007; 21(1): 85-95.
Kell PD, Barton SE, Edmonds DK, Boag FC. HIV infection in a patient with Meyer-Rokitansky-Kuster-Hauser syndrome. J R Soc Med 1992; 85(11): 706-7.
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.
Auvert B, Taljaard D, Lagarde E, Sobngwi-Tambekou J, Sitta R, Puren A. Randomized, controlled intervention trial of male circumcision for reduction of HIV infection risk: The ANRS 1265 Trial. PLoS Med 2005; 2(11): e298.
Bailey RC, Moses S, Parker CB, et al. Male circumcision for HIV prevention in young men in Kisumu, Kenya: A randomised controlled trial. Lancet 2007; 369(9562): 643-56.
Gray RH, Kigozi G, Serwadda D, et al. Male circumcision for HIV prevention in men in Rakai, Uganda: A randomised trial. Lancet 2007; 369(9562): 657-66.
McCoombe SG, Short RV. Potential HIV-1 target cells in the human penis. AIDS 2006; 20(11): 1491-5.
Patterson BK, Landay A, Siegel JN, et al. Susceptibility to human immunodeficiency virus-1 infection of human foreskin and cervical tissue grown in explant culture. Am J Pathol 2002; 161(3): 867-73.
Dinh MH, McRaven MD, Kelley Z, Penugonda S, Hope TJ. Keratinization of the adult male foreskin and implications for male circumcision. AIDS 2010; 24(6): 899-906.
Qin Q, Zheng XY, Wang YY, Shen HF, Sun F, Ding W. Langerhans’ cell density and degree of keratinization in foreskins of Chinese preschool boys and adults. Int Urol Nephrol 2009; 41(4): 747-53.
Kigozi G, Wawer M, Ssettuba A, et al. Foreskin surface area and HIV acquisition in Rakai, Uganda (size matters). AIDS 2009; 23(16): 2209-13.
Fahrbach KM, Barry SM, Anderson MR, Hope TJ. Enhanced cellular responses and environmental sampling within inner foreskin explants: Implications for the Foreskin’s role in HIV transmission. Mucosal Immunol 2010; 3(4): 410-8.
Ganor Y, Zhou Z, Tudor D, et al. Within 1 h, HIV-1 uses viral synapses to enter efficiently the inner, but not outer, foreskin mucosa and engages Langerhans-T cell conjugates. Mucosal Immunol 2010; 3(5): 506-22.
Tobian AA, Quinn TC. Prevention of syphilis: Another positive benefit of male circumcision. Lancet Glob Health 2014; 2(11): e623-4.
Cook LS, Koutsky LA, Holmes KK. Circumcision and sexually transmitted diseases. Am J Public Health 1994; 84(2): 197-201.
Ma ZM, Dutra J, Fritts L, Miller CJ. Lymphatic dissemination of Simian Immunodeficiency Virus after penile inoculation. J Virol 2016; 90(8): 4093-104.
Nicolosi A, Correa Leite ML, Musicco M, et al. The efficiency of male-to-female and female-to-male sexual transmission of the human immunodeficiency virus: A study of 730 stable couples. Italian Study Group on HIV Heterosexual Transmission. Epidemiology 1994; 5(6): 570-5.
Gregson S, Nyamukapa CA, Garnett GP, et al. Sexual mixing patterns and sex-differentials in teenage exposure to HIV infection in rural Zimbabwe. Lancet 2002; 359(9321): 1896-903.
Quinn TC, Overbaugh J. HIV/AIDS in women: An expanding epidemic. Science 2005; 308(5728): 1582-3.
Wasserheit JN. HIV infection and other STDs: So close and yet so far. Sex Transm Dis 1999; 26(10): 549-50.
Wasserheit JN. Epidemiological synergy. Interrelationships between human immunodeficiency virus infection and other sexually transmitted diseases. Sex Transm Dis 1992; 19(2): 61-77.
de Vincenzi I. A longitudinal study of human immunodeficiency virus transmission by heterosexual partners European Study Group on Heterosexual Transmission of HIV New Engl J Med 94;¶ 331(6): 341-6
Lazzarin A, Saracco A, Musicco M, Nicolosi A. Man-to-woman sexual transmission of the human immunodeficiency virus. Risk factors related to sexual behavior, man’s infectiousness, and woman’s susceptibility. Italian Study Group on HIV Heterosexual Transmission. Arch Intern Med 1991; 151(12): 2411-6.
Plummer FA, Simonsen JN, Cameron DW, et al. Cofactors in male-female sexual transmission of human immunodeficiency virus type 1. J Infect Dis 1991; 163(2): 233-9.
Freeman EE, Weiss HA, Glynn JR, Cross PL, Whitworth JA, Hayes RJ. Herpes simplex virus 2 infection increases HIV acquisition in men and women: Systematic review and meta-analysis of longitudinal studies. AIDS 2006; 20(1): 73-83.
Kaul R, Kimani J, Nagelkerke NJ, et al. Monthly antibiotic chemoprophylaxis and incidence of sexually transmitted infections and HIV-1 infection in Kenyan sex workers: A randomized controlled trial. JAMA 2004; 291(21): 2555-62.
Wald A, Link K. Risk of human immunodeficiency virus infection in herpes simplex virus type 2-seropositive persons: A meta-analysis. J Infect Dis 2002; 185(1): 45-52.
Weiss HA, Buve A, Robinson NJ, et al. The epidemiology of HSV-2 infection and its association with HIV infection in four urban African populations. AIDS 2001; 15(Suppl. 4): S97-S108.
Serwadda D, Gray RH, Sewankambo NK, et al. Human immunodeficiency virus acquisition associated with genital ulcer disease and herpes simplex virus type 2 infection: A nested case-control study in Rakai, Uganda. J Infect Dis 2003; 188(10): 1492-7.
Celum CL. The interaction between herpes simplex virus and human immunodeficiency virus. Herpes 2004; 11(Suppl. 1): 36A-45A.
Rebbapragada A, Wachihi C, Pettengell C, et al. Negative mucosal synergy between Herpes simplex type 2 and HIV in the female genital tract. AIDS 2007; 21(5): 589-98.
Shattock RJ, Griffin GE, Gorodeski GI. In vitro models of mucosal HIV transmission. Nat Med 2000; 6(6): 607-8.
Kaul R, Pettengell C, Sheth PM, et al. The genital tract immune milieu: an important determinant of HIV susceptibility and secondary transmission. J Reprod Immunol 2008; 77(1): 32-40.
Plummer FA. Heterosexual transmission of human immunodeficiency virus type 1 (HIV): Interactions of conventional sexually transmitted diseases, hormonal contraception and HIV-1AIDS Res Hum Retroviruses 1998; 14(Suppl. 1): S5-S10.
Laga M, Manoka A, Kivuvu M, et al. Non-ulcerative sexually transmitted diseases as risk factors for HIV-1 transmission in women: results from a cohort study. AIDS 1993; 7(1): 95-102.
Kapiga SH, Shao JF, Lwihula GK, Hunter DJ. Risk factors for HIV infection among women in Dar-es-Salaam, Tanzania. J Acquir Immune Defic Syndr 1994; 7(3): 301-9.
Carias AM, Allen SA, Fought AJ, et al. Increases in endogenous or exogenous progestins promote virus-target cell interactions within the non-human primate female reproductive tract. PLoS Pathog 2016; 12(9): e1005885.
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.
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.
Price LB, Liu CM, Johnson KE, et al. The effects of circumcision on the penis microbiome. PLoS One 2010; 5(1): e8422.
Liu CM, Hungate BA, Tobian AA, et al. Male circumcision significantly reduces prevalence and load of genital anaerobic bacteria. MBio 2013; 4(2): e00076.
Gunsar C, Kurutepe S, Alparslan O, et al. The effect of circumcision status on periurethral and glanular bacterial flora. Urol Int 2004; 72(3): 212-5.
Guttman JA, Samji FN, Li Y, Vogl AW, Finlay BB. Evidence that tight junctions are disrupted due to intimate bacterial contact and not inflammation during attaching and effacing pathogen infection in vivo. Infect Immun 2006; 74(11): 6075-84.
Martin DA, Towne JE, Kricorian G, et al. The emerging role of IL-17 in the pathogenesis of psoriasis: Preclinical and clinical findings. J Invest Dermatol 2013; 133(1): 17-26.
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.
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.
Sodora DL, Gettie A, Miller CJ, Marx PA. Vaginal transmission of SIV: assessing infectivity and hormonal influences in macaques inoculated with cell-free and cell-associated viral stocks. AIDS Res Hum Retroviruses 1998; 14(Suppl. 1): S119-23.
Smith SM, Baskin GB, Marx PA. Estrogen protects against vaginal transmission of simian immunodeficiency virus. J Infect Dis 2000; 182(3): 708-15.
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.
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.
Hild-Petito S, Veazey RS, Larner JM, Reel JR, Blye RP. Effects of two progestin-only contraceptives, Depo-Provera and Norplant-II, on the vaginal epithelium of rhesus monkeys. AIDS Res Hum Retroviruses 1998; 14(Suppl. 1): S125-30.
Chandra N, Thurman AR, Anderson S, et al. Depot medroxyprogesterone acetate increases immune cell numbers and activation markers in human vaginal mucosal tissues. AIDS Res Hum Retroviruses 2013; 29(3): 592-601.
Gorodeski GI. Estrogen increases the permeability of the cultured human cervical epithelium by modulating cell deformability. Am J Physiol 1998; 275(3 Pt 1): C888-99.
Eschenbach DA, Thwin SS, Patton DL, et al. Influence of the normal menstrual cycle on vaginal tissue, discharge, and microflora. Clin Infect Dis 2000; 30(6): 901-7.
Gipson IK, Moccia R, Spurr-Michaud S, et al. The amount of MUC5B mucin in cervical mucus peaks at midcycle. J Clin Endocrinol Metab 2001; 86(2): 594-600.
Argueso P, Spurr-Michaud S, Tisdale A, Gipson IK. Variation in the amount of T antigen and N-acetyllactosamine oligosaccharides in human cervical mucus secretions with the menstrual cycle. J Clin Endocrinol Metab 2002; 87(12): 5641-8.
Baeten JM, Nyange PM, Richardson BA, et al. Hormonal contraception and risk of sexually transmitted disease acquisition: Results from a prospective study. Am J Obstet Gynecol 2001; 185(2): 380-5.
Heffron R, Donnell D, Rees H, et al. Use of hormonal contraceptives and risk of HIV-1 transmission: A prospective cohort study. Lancet Infect Dis 2012; 12(1): 19-26.
Wand H, Ramjee G. The effects of injectable hormonal contraceptives on HIV seroconversion and on sexually transmitted infections. AIDS 2012; 26(3): 375-80.
Morrison CS, Skoler-Karpoff S, Kwok C, et al. Hormonal contraception and the risk of HIV acquisition among women in South Africa. AIDS 2012; 26(4): 497-504.
Kumwenda NI, Kumwenda J, Kafulafula G, et al. HIV-1 incidence among women of reproductive age in Malawi. Int J STD AIDS 2008; 19(5): 339-41.
Feldblum PJ, Lie CC, Weaver MA, et al. Baseline factors associated with incident HIV and STI in four microbicide trials. Sex Transm Dis 2010; 37(10): 594-601.
Ildgruben AK, Sjoberg IM, Hammarstrom ML. Influence of hormonal contraceptives on the immune cells and thickness of human vaginal epithelium. Obstet Gynecol 2003; 102(3): 571-82.
Quispe Calla NE, Vicetti Miguel RD, 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.
Crook A, Rees H, Ramjee G, et al. Risk of HIV: An Analysis of data from the Microbicides Development Programme Trial 2013.
Devincenzi I, Ancellepark RA, Brunet JB, et al. Comparison of female to male and male to female transmission of HIV in 563 stable couples. BMJ 1992; 304(6830): 809-13.
Overton ET, Shacham E, Singhatiraj E, Nurutdinova D. Incidence of sexually transmitted infections among HIV-infected women using depot medroxyprogesterone acetate contraception. Contraception 2008; 78(2): 125-30.
Reid SE, Dai JY, Wang J, et al. Pregnancy, contraceptive use, and HIV acquisition in HPTN 039: Relevance for HIV prevention trials among African women. J Acquir Immune Defic Syndr 2010; 53(5): 606-13.
Myer L, Denny L, Wright TC, Kuhn L. Prospective study of hormonal contraception and women’s risk of HIV infection in South Africa. Int J Epidemiol 2007; 36(1): 166-74.
Kiddugavu M, Makumbi F, Wawer MJ, et al. Hormonal contraceptive use and HIV-1 infection in a population-based cohort in Rakai, Uganda. AIDS 2003; 17(2): 233-40.
Kapiga SH, Lyamuya EF, Lwihula GK, Hunter DJ. The incidence of HIV infection among women using family planning methods in Dar es Salaam, Tanzania. AIDS 1998; 12(1): 75-84.

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy