T Cells in the Female Reproductive Tract Can Both Block and Facilitate HIV Transmission

Author(s): Christopher J. Miller, Ronald S. Veazey*

Journal Name: Current Immunology Reviews (Discontinued)

Volume 15 , Issue 1 , 2019


Because HIV is sexually transmitted, there is considerable interest in defining the nature of anti-HIV immunity in the female reproductive tract (FRT) and in developing ways to elicit antiviral immunity in the FRT through vaccination. Although it is assumed that the mucosal immune system of the FRT is of central importance for protection against sexually transmitted diseases, including HIV, this arm of the immune system has only recently been studied. Here, we provide a brief review of the role of T cells in the FRT in blocking and facilitating HIV transmission.

Keywords: Vagina, cervix, T cell, HIV, sexually transmitted disease, viral infections.

Rosendahl Huber S, van Beek J, de Jonge J, Luytjes W, van Baarle D. T cell responses to viral infections - opportunities for Peptide vaccination. Front Immunol 2014; 5: 171.
Matloubian M, Concepcion RJ, Ahmed R. CD4+ T cells are required to sustain CD8+ cytotoxic T-cell responses during chronic viral infection. J Virol 1994; 68(12): 8056-63.
Schmitz JE, Kuroda MJ, Santra S, et al. Control of viremia in simian immunodeficiency virus infection by CD8+ lymphocytes. Science 1999; 283: 857-60.
Shoukry NH, Grakoui A, Houghton M, et al. Memory CD8+ T cells are required for protection from persistent hepatitis C virus infection. J Exp Med 2003; 197(12): 1645-55.
Snyder CM. Buffered memory: A hypothesis for the maintenance of functional, virus-specific CD8(+) T cells during cytomegalovirus infection. Immunol Res 2011; 51(2-3): 195-204.
Griffin DE, Lin WH, Pan CH. Measles virus, immune control, and persistence. FEMS Microbiol Rev 2012; 36(3): 649-62.
Sridhar S, Begom S, Bermingham A, et al. Cellular immune correlates of protection against symptomatic pandemic influenza. Nat Med 2013; 19(10): 1305-12.
Wilkinson TM, Li CK, Chui CS, et al. Preexisting influenza-specific CD4+ T cells correlate with disease protection against influenza challenge in humans. Nat Med 2012; 18(2): 274-80.
Soghoian DZ, Jessen H, Flanders M, et al. HIV-specific cytolytic CD4 T cell responses during acute HIV infection predict disease outcome. Sci Transl Med 2012; 4(123): 123ra25.
Pantaleo G, Fauci AS. Immunopathogenesis of HIV infection. Annu Rev Microbiol 1996; 50: 825-54.
Musey L, Hughes J, Schacker T, Shea T, Corey L, McElrath MJ. Cytotoxic-T-cell responses, viral load, and disease progression in early human immunodeficiency virus type 1 infection. N Engl J Med 1997; 337: 1267-74.
Rinaldo C, Huang XL, Fan ZF, et al. High levels of anti-Human Immunodeficiency Virus type 1 (HIV-1) memory cytotoxic T-lymphocyte activity and low viral load are associated with lack of disease in HIV-1-infected long-term nonprogressors. J Virol 1995; 69: 5838-42.
Klein MR, van Baalen CA, Holwerda AM, et al. Kinetics of Gag-specific cytotoxic T lymphocyte responses during the clinical course of HIV-1 infection: A longitudinal analysis of rapid progressors and long-term asymptomatics. J Exp Med 1995; 181: 1365-72.
Goulder PJ, Phillips RE, Colbert RA, et al. Late escape from an immunodominant cytotoxic T-lymphocyte response associated with progression to AIDS. Nat Med 1997; 3(2): 212-7.
Jin X, Bauer DE, Tuttleton SE, Lewin S, et al. Dramatic rise in plasma viremia after CD8(+) T cell depletion in simian immunodeficiency virus-infected macaques. J Exp Med 1999; 189: 991-8.
Pereyra F, Jia X, McLaren PJ, et al. The major genetic determinants of HIV-1 control affect HLA class I peptide presentation. Science 2010; 330(6010): 1551-7.
Ranasinghe S, Flanders M, Cutler S, et al. HIV-specific CD4 T cell responses to different viral proteins have discordant associations with viral load and clinical outcome. J Virol 2012; 86(1): 277-83.
Park CO, Kupper TS. The emerging role of resident memory T cells in protective immunity and inflammatory disease. Nat Med 2015; 21(7): 688-97.
Sallusto F, Lenig D, Forster R, Lipp M, Lanzavecchia A. Two subsets of memory T lymphocytes with distinct homing potentials and effector functions. Nature 1999; 401(6754): 708-12.
Fuhlbrigge RC, Kieffer JD, Armerding D, Kupper TS. Cutaneous lymphocyte antigen is a specialized form of PSGL-1 expressed on skin-homing T cells. Nature 1997; 389(6654): 978-81.
Berlin C, Berg EL, Briskin MJ, et al. a4b7 Integrin mediates lymphocyte binding to the mucosal vascular addressin MAdCAM-1. Cell 1993; 74: 185-95.
Qualai J, Cantero J, Li LX, et al. Adhesion molecules associated with female genital tract infection. PLoS One 2016; 11(6): e0156605.
Jiang X, Clark RA, Liu L, Wagers AJ, Fuhlbrigge RC, Kupper TS. Skin infection generates non-migratory memory CD8+ T(RM) cells providing global skin immunity. Nature 2012; 483(7388): 227-31.
Wang X, Xu H, Alvarez X, et al. Distinct expression patterns of CD69 in mucosal and systemic lymphoid tissues in primary SIV infection of rhesus macaques. PLoS One 2011; 6(11): e27207.
Mackay LK, Stock AT, Ma JZ, et al. Long-lived epithelial immunity by Tissue-Resident Memory T (TRM) cells in the absence of persisting local antigen presentation. Proc Natl Acad Sci USA 2012; 109(18): 7037-42.
Iwasaki A. Antiviral immune responses in the genital tract: Clues for vaccines. Nat Rev Immunol 2010; 10(10): 699-711.
Neutra MR, Kozlowski PA. Mucosal vaccines: The promise and the challenge. Nat Rev Immunol 2006; 6(2): 148-58.
Lee HK, Zamora M, Linehan MM, et al. Differential roles of migratory and resident DCs in T cell priming after mucosal or skin HSV-1 infection. J Exp Med 2009; 206(2): 359-70.
Nakanishi Y, Lu B, Gerard C, Iwasaki A. CD8(+) T lymphocyte mobilization to virus-infected tissue requires CD4(+) T-cell help. Nature 2009; 462(7272): 510-3.
Sheridan BS, Lefrancois L. Regional and mucosal memory T cells. Nat Immunol 2011; 12(6): 485-91.
Carbone FR. Tissue-resident memory T cells and fixed immune surveillance in nonlymphoid organs. J Immunol 2015; 195(1): 17-22.
Gebhardt T, Wakim LM, Eidsmo L, Reading PC, Heath WR, Carbone FR. Memory T cells in nonlymphoid tissue that provide enhanced local immunity during infection with herpes simplex virus. Nat Immunol 2009; 10(5): 524-30.
Roth KL, Bhavanam S, Jiang H, et al. Delayed but effective induction of mucosal memory immune responses against genital HSV-2 in the absence of secondary lymphoid organs. Mucosal Immunol 2013; 6(1): 56-68.
Gillgrass AE, Tang VA, Towarnicki KM, Rosenthal KL, Kaushic C. Protection against genital herpes infection in mice immunized under different hormonal conditions correlates with induction of vagina-associated lymphoid tissue. J Virol 2005; 79(5): 3117-26.
Wang Y, Sui Y, Kato S, et al. Vaginal type-II mucosa is an inductive site for primary CD8(+) T-cell mucosal immunity. Nat Commun 2015; 6: 6100.
Bebell LM, Passmore JA, Williamson C, et al. Relationship between levels of inflammatory cytokines in the genital tract and CD4+ cell counts in women with acute HIV-1 infection. J Infect Dis 2008; 198(5): 710-4.
Roberts L, Passmore JA, Mlisana K, et al. Genital tract inflammation during early HIV-1 infection predicts higher plasma viral load set point in women. J Infect Dis 2012; 205(2): 194-203.
Southern PJ. Missing out on the biology of heterosexual HIV-1 transmission. Trends Microbiol 2013; 21(5): 245-52.
Kelly KA, Chan AM, Butch A, Darville T. Two different homing pathways involving integrin beta7 and E-selectin significantly influence trafficking of CD4 cells to the genital tract following Chlamydia muridarum infection. Am J Reprod Immunol 2009; 61(6): 438-45.
Kelly KA, Natarajan S, Ruther P, Wisse A, Chang MH, Ault KA. Chlamydia trachomatis infection induces mucosal addressin cell adhesion molecule-1 and vascular cell adhesion molecule-1, providing an immunologic link between the fallopian tube and other mucosal tissues. J Infect Dis 2001; 184(7): 885-91.
Kelly KA, Walker JC, Jameel SH, Gray HL, Rank RG. Differential regulation of CD4 lymphocyte recruitment between the upper and lower regions of the genital tract during Chlamydia trachomatis infection. Infect Immun 2000; 68(3): 1519-28.
Kelly KA, Wiley D, Wiesmeier E, Briskin M, Butch A, Darville T. The combination of the gastrointestinal integrin (alpha4beta7) and selectin ligand enhances T-Cell migration to the reproductive tract during infection with Chlamydia trachomatis. Am J Reprod Immunol 2009; 61(6): 446-52.
Hawkins RA, Rank RG, Kelly KA. Expression of mucosal homing receptor alpha4beta7 is associated with enhanced migration to the Chlamydia-infected murine genital mucosa in vivo. Infect Immun 2000; 68(10): 5587-94.
Hirbod T, Kimani J, Tjernlund A, et al. Stable CD4 expression and local immune activation in the ectocervical mucosa of HIV-infected women. J Immunol 2013; 191(7): 3948-54.
McKinnon LR, Nyanga B, Chege D, et al. Characterization of a human cervical CD4+ T cell subset coexpressing multiple markers of HIV susceptibility. J Immunol 2011; 187(11): 6032-42.
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.
Rodriguez-Garcia M, Barr FD, Crist SG, Fahey JV, Wira CR. Phenotype and susceptibility to HIV infection of CD4+ Th17 cells in the human female reproductive tract. Mucosal Immunol 2014; 7(6): 1375-85.
Byrareddy SN, Kallam B, Arthos J, et al. Targeting alpha4beta7 integrin reduces mucosal transmission of simian immunodeficiency virus and protects gut-associated lymphoid tissue from infection. Nat Med 2014; 20(12): 1397-400.
Veazey RS, Klasse PJ, Schader SM, et al. Protection of macaques from vaginal SHIV challenge by vaginally delivered inhibitors of virus-cell fusion. Nature 2005; 438(7064): 99-102.
Lederman MM, Veazey RS, Offord R, et al. Prevention of vaginal SHIV transmission in rhesus macaques through inhibition of CCR5. Science 2004; 306(5695): 485-7.
Pereira LE, Onlamoon N, Wang X, et al. Preliminary in vivo efficacy studies of a recombinant rhesus anti-alpha(4)beta(7) monoclonal antibody. Cell Immunol 2009; 259(2): 165-76.
Kader M, Wang X, Piatak M, et al. Alpha4(+)beta7(hi)CD4(+) memory T cells harbor most Th-17 cells and are preferentially infected during acute SIV infection. Mucosal Immunol 2009; 2(5): 439-49.
Wang X, Xu H, Gill AF, et al. Monitoring alpha4beta7 integrin expression on circulating CD4+ T cells as a surrogate marker for tracking intestinal CD4+ T-cell loss in SIV infection. Mucosal Immunol 2009; 2(6): 518-26.
Arrode-Bruses G, Goode D, Kleinbeck K, et al. A Small molecule, which competes with MAdCAM-1, activates integrin alpha4beta7 and fails to prevent mucosal transmission of SHIV-SF162P3. PLoS Pathog 2016; 12(6): e1005720.
Fennessey CM, Keele BF. Using nonhuman primates to model HIV transmission. Curr Opin HIV AIDS 2013; 8(4): 280-7.
Veazey RS. Animal models for microbicide safety and efficacy testing. Curr Opin HIV AIDS 2013; 8(4): 295-303.
Lohman BL, Miller CJ, McChesney MB. Antiviral cytotoxic T lymphocytes in vaginal mucosa of simian immunodeficiency virus-infected rhesus macaques. J Immunol 1995; 155(12): 5855-60.
Musey L, Hu Y, Eckert L, Christensen M, Karchmer T, McElrath MJ. HIV-1 induces cytotoxic T lymphocytes in the cervix of infected women. J Exp Med 1997; 185: 293-303.
Stevceva L, Kelsall B, Nacsa J, et al. Cervicovaginal lamina propria lymphocytes: phenotypic characterization and their importance in cytotoxic T-lymphocyte responses to simian immunodeficiency virus SIVmac251. J Virol 2002; 76: 9-18.
Cromwell MA, Carville A, Mansfield K, et al. SIV-specific CD8+ T cells are enriched in female genital mucosa of rhesus macaques and express receptors for inflammatory chemokines. Am J Reprod Immunol 2011; 65(3): 242-7.
Kaul R, Plummer FA, Kimani J, et al. HIV-1-specific mucosal CD8+ lymphocyte responses in the cervix of HIV-1-resistant prostitutes in Nairobi. J Immunol 2000; 164: 1602-11.
Bere A, Denny L, Naicker P, Burgers WA, Passmore JA. HIV-specific T-cell responses detected in the genital tract of chronically HIV-infected women are largely monofunctional. Immunology 2013; 139(3): 342-51.
Gumbi PP, Jaumdally SZ, Salkinder AL, et al. CD4 T cell depletion at the cervix during HIV infection is associated with accumulation of terminally differentiated T cells. J Virol 2011; 85(24): 13333-41.
Olaitan A, Johnson MA, MacLean A, Poulter LW. The distribution of immunocompetent cells in the genital tract of HIV-positive women. AIDS 1996; 10(7): 759-64.
Miller CJ, Li Q, Abel K, et al. Propagation and dissemination of infection after vaginal transmission of simian immunodeficiency virus. J Virol 2005; 79(14): 9217-27.
Reynolds MR, Rakasz E, Skinner PJ, et al. CD8+ T-lymphocyte response to major immunodominant epitopes after vaginal exposure to simian immunodeficiency virus: Too late and too little. J Virol 2005; 79(14): 9228-35.
Stone M, Ma ZM, Genesca M, et al. Limited dissemination of pathogenic SIV after vaginal challenge of rhesus monkeys immunized with a live, attenuated lentivirus. Virology 2009; 392(2): 260-70.
Genescà M, Skinner PJ, Hong JJ, et al. With minimal systemic T-cell expansion, CD8+ T Cells mediate protection of rhesus macaques immunized with attenuated simian-human immunodeficiency virus SHIV89.6 from vaginal challenge with simian immunodeficiency virus. J Virol 2008; 82: 11181-96.
Genesca M, McChesney MB, Miller CJ. Antiviral CD8+ T cells in the genital tract control viral replication and delay progression to AIDS after vaginal SIV challenge in rhesus macaques immunized with virulence attenuated SHIV 89.6. J Intern Med 2009; 265(1): 67-77.

Rights & PermissionsPrintExport Cite as

Article Details

Year: 2019
Published on: 12 April, 2019
Page: [36 - 40]
Pages: 5
DOI: 10.2174/1573395514666180807113928
Price: $65

Article Metrics

PDF: 83