Mucosal Immunity and HIV-1 Infection: Applications for Mucosal AIDS Vaccine Development

Part of the Current Topics in Microbiology and Immunology book series (CT MICROBIOLOGY, volume 354)


Natural transmission of human immunodeficiency virus type 1 (HIV-1) occurs through gastrointestinal and vaginal mucosa. These mucosal tissues are major reservoirs for initial HIV replication and amplification, and the sites of rapid CD4+ T cell depletion. In both HIV-infected humans and SIV-infected macaques, massive loss of CD4+ CCR5+ memory T cells occurs in the gut and vaginal mucosa within the first 10–14 days of infection. Induction of local HIV-specific immune responses by vaccines may facilitate effective control of HIV or SIV replication at these sites. Vaccines that induce mucosal responses, in particular CD8+ cytotoxic T lymphocytes (CTL), have controlled viral replication at mucosal sites and curtailed systemic dissemination. Thus, there is strong justification for development of next generation vaccines that induce mucosal immune effectors against HIV-1 including CD8+ CTL, CD4+ T helper cells and secretory IgA. In addition, further understanding of local innate mechanisms that impact early viral replication will greatly inform future vaccine development. In this review, we examine the current knowledge concerning mucosal AIDS vaccine development. Moreover, we propose immunization strategies that may be able to elicit an effective immune response that can protect against AIDS as well as other mucosal infections.


Cholera Toxin Peptide Vaccine Modify Vaccinia Ankara Mucosal Vaccination Mucosal Adjuvant 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. Acierno PM, Schmitz JE, Gorgone DA et al (2006) Preservation of functional virus-specific memory CD8+ T lymphocytes in vaccinated, simian human immunodeficiency virus-infected rhesus monkeys. J Immunol 176:5338–5345PubMedGoogle Scholar
  2. Ahlers JD, Belyakov IM (2009a) Strategies for optimizing targeting and delivery of mucosal HIV vaccines. Eur J Immunol 39:2657–2669PubMedCrossRefGoogle Scholar
  3. Ahlers JD, Belyakov IM (2009b) Strategies for recruiting and targeting dendritic cells for optimizing HIV vaccines. Trends Mol Med 15:263–274PubMedCrossRefGoogle Scholar
  4. Ahlers JD, Belyakov IM (2010a) Lessons learned from natural infection: focusing on the design of protective T cell vaccines for HIV/AIDS. Trends Immunol 31:120–130PubMedCrossRefGoogle Scholar
  5. Ahlers JD, Belyakov IM (2010b) Memories that last forever: strategies for optimizing vaccine T-cell memory. Blood 115:1678–1689PubMedCrossRefGoogle Scholar
  6. Ahlers JD, Belyakov IM (2010c) New paradigms for generating effective CD8+ T cell responses against HIV-1/AIDS. Discov Med 9:528–537PubMedGoogle Scholar
  7. Ahlers JD, Belyakov IM, Matsui S et al (2001a) Mechanisms of cytokine synergy essential for vaccine protection against viral challenge. Int Immunol 13:897–908PubMedCrossRefGoogle Scholar
  8. Ahlers JD, Belyakov IM, Matsui S et al (2001b) Signals delivered through TCR instruct IL-12R expression: IL-12 and TNFα synergize for IL-12R expression at low antigen dose. Int Immunol 13:1433–1442PubMedCrossRefGoogle Scholar
  9. Ahlers JD, Belyakov IM, Terabe M et al (2002) A push-pull approach to maximize vaccine efficacy: abrogating suppression with an IL-13 inhibitor while augmenting help with GM-CSF and CD40L. Proc Natl Acad Sci USA 99:13020–13025PubMedCrossRefGoogle Scholar
  10. Ahlers JD, Belyakov IM, Berzofsky JA (2003) Cytokine, chemokine and costimulatory molecule modulation to enhance efficacy of HIV vaccines. Curr Mol Med 3:285–301PubMedCrossRefGoogle Scholar
  11. Alexander-Miller MA, Leggatt GR, Berzofsky JA (1996) Selective expansion of high or low avidity cytotoxic T lymphocytes and efficacy for adoptive immunotherapy. Proc Natl Acad Sci USA 93:4102–4107PubMedCrossRefGoogle Scholar
  12. Allen TM, Vogel TU, Fuller DH et al (2000) Induction of AIDS virus-specific CTL activity in fresh, unstimulated peripheral blood lymphocytes from rhesus macaques vaccinated with a DNA prime/modified vaccinia virus Ankara boost regimen. J Immunol 164:4968–4978PubMedGoogle Scholar
  13. Amara RR, Villinger F, Altman JD et al (2001) Control of a mucosal challenge and prevention of AIDS by a multiprotein DNA/MVA vaccine. Science 292:69–74PubMedCrossRefGoogle Scholar
  14. Appay V, Nixon DF, Donahoe SM et al (2000) HIV-specific CD8(+) T cells produce antiviral cytokines but are impaired in cytolytic function. J Exp Med 192:63–75PubMedCrossRefGoogle Scholar
  15. Baba TW, Liska V, Hofmann-Lehmann R et al (2000) Human neutralizing monoclonal antibodies of the IgG1 subtype protect against mucosal simian-human immunodeficiency virus infection. Nat Med 6:200–206PubMedCrossRefGoogle Scholar
  16. Bafica A, Scanga CA, Schito M et al (2004) Influence of coinfecting pathogens on HIV expression: evidence for a role of Toll-like receptors. J Immunol 172:7229–7234PubMedGoogle Scholar
  17. Barnett SW, Srivastava IK, Kan E et al (2008) Protection of macaques against vaginal SHIV challenge by systemic or mucosal and systemic vaccinations with HIV-envelope. AIDS 22:339–348PubMedCrossRefGoogle Scholar
  18. Barouch DH, Santra S, Schmitz JE et al (2000) Control of viremia and prevention of clinical AIDS in rhesus monkeys by cytokine-augmented DNA vaccination. Science 290:486–492PubMedCrossRefGoogle Scholar
  19. Beagley KW, Elson CO (1992) Cells and cytokines in mucosal immunity and inflammation. Gastroenterol Clin North Am 21:347–366PubMedGoogle Scholar
  20. Belshe RB, Gorse GJ, Mulligan MJ, Evans TG, Keefer MC, Excler JL, Duliege AM, Tartaglia J, Cox WI, McNamara J, Hwang KL, Bradney A, Montefiori D, Weinhold KJ (1998) Induction of immune responses to HIV-1 by canarypox virus (ALVAC) HIV-1 and gp120 SF-2 recombinant vaccines in uninfected volunteers. NIAID AIDS Vaccine Evaluation Group. Aids 12:2407–2415PubMedCrossRefGoogle Scholar
  21. Belyakov IM, Ahlers JD (2008) Functional CD8(+) CTLs in mucosal sites and HIV infection: moving forward toward a mucosal AIDS vaccine. Trends Immunol 29:574–585PubMedCrossRefGoogle Scholar
  22. Belyakov IM, Ahlers JD (2009b) What role does the route of immunization play in the generation of protective immunity against mucosal pathogens? J Immunol 183:6883–6892PubMedCrossRefGoogle Scholar
  23. Belyakov IM, Ahlers JD (2009a) Comment on “trafficking of antigen-specific CD8+ T lymphocytes to mucosal surfaces following intramuscular vaccination”. J Immunol 182:1779–1780PubMedCrossRefGoogle Scholar
  24. Belyakov IM, Ahlers JD, Berzofsky JA (2004a) Mucosal AIDS vaccines: current status and future directions. Expert Rev Vaccines 3: Suppl 65–73CrossRefGoogle Scholar
  25. Belyakov IM, Berzofsky JA (2004b) Immunobiology of mucosal HIV infection and the basis for development of a new generation of mucosal AIDS vaccines. Immunity 20:247–253PubMedCrossRefGoogle Scholar
  26. Belyakov IM, Clements JD, Ahlers JD, Strober W, Berzofsky JA (1999a) Approaches to improve engineered HIV vaccine which induce mucosal immunity. J Human Virol 2:217–210Google Scholar
  27. Belyakov IM, Ahlers JD, Brandwein BY et al (1998a) The importance of local mucosal HIV-specific CD8+ cytotoxic T lymphocytes for resistance to mucosal-viral transmission in mice and enhancement of resistance by local administration of IL-12. J Clin Invest 102:2072–2081PubMedCrossRefGoogle Scholar
  28. Belyakov IM, Derby MA, Ahlers JD et al (1998b) Mucosal immunization with HIV-1 peptide vaccine induces mucosal and systemic cytotoxic T lymphocytes and protective immunity in mice against intrarectal recombinant HIV-vaccinia challenge. Proc Natl Acad Sci USA 95:1709–1714PubMedCrossRefGoogle Scholar
  29. Belyakov IM, Kelsall B, Strober W et al (1998c) Use of rIL-12 for enhancing the mucosal cytotoxic T lymphocyte response to a peptide HIV vaccine. J Invest Med 46:216AGoogle Scholar
  30. Belyakov IM, Klinman D, Kuznetsov VA, Moniuszko M, Ahlers JD, Kelsall B, Strober W, Franchini G, Berzofsky JA (2004c) Progress on new mucosal vaccine stategies for HIV. FASEB Journal 18:A821–A821Google Scholar
  31. Belyakov IM, Wyatt LS, Ahlers JD et al (1998d) Induction of mucosal CTL response by intrarectal immunization with a replication-deficient recombinant vaccinia virus expressing HIV 89.6 envelope protein. J Virol 72:8264–8272PubMedGoogle Scholar
  32. Belyakov IM, Moss B, Strober W et al (1999) Mucosal vaccination overcomes the barrier to recombinant vaccinia immunization caused by preexisting poxvirus immunity. Proc Natl Acad Sci USA 96:4512–4517PubMedCrossRefGoogle Scholar
  33. Belyakov IM, Ahlers JD, Clements JD et al (2000) Interplay of cytokines and adjuvants in the regulation of mucosal and systemic HIV-specific cytotoxic T lymphocytes. J Immunol 165:6454–6462PubMedGoogle Scholar
  34. Belyakov IM, Hel Z, Kelsall B et al (2001a) Mucosal AIDS vaccine reduces disease and viral load in gut reservoir and blood after mucosal infection of macaques. Nat Med 7:1320–1326PubMedCrossRefGoogle Scholar
  35. Belyakov IM, Wang J, Koka R et al (2001b) Activating CTL precursors to reveal CTL function without skewing the repertoire by in vitro expansion. Eur J Immunol 31:3557–3566PubMedCrossRefGoogle Scholar
  36. Belyakov IM, Hammond SA, Ahlers JD et al (2004) Transcutaneous immunization induces mucosal CTL and protective immunity by migration of primed skin dendritic cells. J Clin Invest 113:998–1007PubMedGoogle Scholar
  37. Belyakov IM, Isakov D, Zhu Q et al (2006a) Enhancement of CD8+ T cell immunity in the lung by CpG ODN increases protective efficacy of a Modified Vaccinia Ankara vaccine against lethal poxvirus infection even in CD4-deficient host. J Immunol 177:6336–6343PubMedGoogle Scholar
  38. Belyakov IM, Kuznetsov VA, Kelsall B et al (2006b) Impact of vaccine-induced mucosal high avidity CD8+ CTLs in delay of AIDS-viral dissemination from mucosa. Blood 107:3258–3264PubMedCrossRefGoogle Scholar
  39. Belyakov IM, Isakov D, Zhu Q et al (2007a) A novel functional CTL avidity/activity compartmentalization to the site of mucosal immunization contributes to protection of macaques against simian/human immunodeficiency viral depletion of mucosal CD4+ T cells. J Immunol 178:7211–7221PubMedGoogle Scholar
  40. Belyakov IM, Kozlowski S, Mage M et al (2007b) Role of {alpha}3 domain of class I MHC molecules in the activation of high- and low-avidity CD8+ CTLs. Int Immunol 19:1413–1420PubMedCrossRefGoogle Scholar
  41. Belyakov IM, Ahlers JD, Nabel GJ et al (2008) Generation of functionally active HIV-1 specific CD8(+) CTL in intestinal mucosa following mucosal, systemic or mixed prime-boost immunization. Virology 381:106–115PubMedCrossRefGoogle Scholar
  42. Bennett MS, Ng HL, Dagarag M et al (2007) Epitope-dependent avidity thresholds for cytotoxic T-lymphocyte clearance of virus-infected cells. J Virol 81:4973–4980PubMedCrossRefGoogle Scholar
  43. Berzofsky JA, Ahlers JD, Belyakov IM (2001) Strategies for designing and optimizing new generation vaccines. Nature Reviews Immunology 1:209–219PubMedCrossRefGoogle Scholar
  44. Berzofsky JA, Ahlers JD, Derby MA, Pendleton CD, Arichi T, Belyakov IM (1999) Approaches to improve engineered vaccines for human immunodeficiency virus (HIV) and other viruses that cause chronic infections. Immunol Rev 170:151–172PubMedCrossRefGoogle Scholar
  45. Berzofsky JA, Ahlers J, Janik J et al (2004) Progress on new vaccine strategies against chronic viral infections. J Clin Invest 114:450–462PubMedGoogle Scholar
  46. Biragyn A, Belyakov IM, Chow YH et al (2002) DNA vaccines encoding human immunodeficiency virus-1 glycoprotein 120 fusions with proinflammatory chemoattractants induce systemic and mucosal immune responses. Blood 100:1153–1159PubMedCrossRefGoogle Scholar
  47. Braun MC, He J, Wu C-Y, Kelsall BL (1999) Cholera toxin suppresses interleukin (IL)-12 production and IL-12 receptor B1 and B2 chain expression. J Exp Med 189:541–552PubMedCrossRefGoogle Scholar
  48. Brenchley JM, Schacker TW, Ruff LE et al (2004) CD4+ T cell depletion during all stages of HIV disease occurs predominantly in the gastrointestinal tract. J Exp Med 200:749–759PubMedCrossRefGoogle Scholar
  49. Bruhl P, Kerschbaum A, Eibl MM et al (1998) An experimental prime-boost regimen leading to HIV type 1-specific mucosal and systemic immunity in BALB/c mice. AIDS Res Hum Retroviruses 14:401–407PubMedCrossRefGoogle Scholar
  50. Caputo A, Brocca-Cofano E, Castaldello A et al (2008) Characterization of immune responses elicited in mice by intranasal co-immunization with HIV-1 Tat, gp140 DeltaV2Env and/or SIV Gag proteins and the nontoxicogenic heat-labile Escherichia coli enterotoxin. Vaccine 26:1214–1227PubMedCrossRefGoogle Scholar
  51. Castro BA, Homsy J, Lennette E et al (1992) HIV-1 expression in chimpanzees can be activated by CD8+ cell depletion or CMV infection. Clin Immunol Immunopathol 65:227–233PubMedCrossRefGoogle Scholar
  52. Clayton F, Kapetanovic S, Kotler DP (2001) Enteric microtubule depolymerization in HIV infection: a possible cause of HIV-associated enteropathy. AIDS 15:123–124PubMedCrossRefGoogle Scholar
  53. Dale CJ, Thomson S, De Rose R et al (2006) Prime-boost strategies in DNA vaccines. Methods Mol Med 127:171–197PubMedGoogle Scholar
  54. Denning TL, Wang YC, Patel SR et al (2007) Lamina propria macrophages and dendritic cells differentially induce regulatory and interleukin 17-producing T cell responses. Nat Immunol 8:1086–1094PubMedCrossRefGoogle Scholar
  55. Dickinson BL, Clements JD (1995) Dissociation of Escherichia coli heat-labile enterotoxin adjuvanticity from ADP-ribosyltransferase activity. Infect Immun 63:1617–1623PubMedGoogle Scholar
  56. Dickinson BL, Clements JD (1996) Use of Escherichia coli heat-liable enterotoxin as an oral adjuvant. In: Mucosal Vaccines. Academic Press, New York, pp 73–87Google Scholar
  57. Dzutsev AH, Belyakov IM, Isakov DV et al (2007) Avidity of CD8 T cells sharpens immunodominance. Int Immunol 19:497–507PubMedCrossRefGoogle Scholar
  58. Egan MA, Chong SY, Rose NF et al (2004) Immunogenicity of attenuated vesicular stomatitis virus vectors expressing HIV type 1 Env and SIV Gag proteins: comparison of intranasal and intramuscular vaccination routes. AIDS Res Hum Retroviruses 20:989–1004PubMedCrossRefGoogle Scholar
  59. Eichelberger M, Allan W, Zijlstra M et al (1991) Clearance of influenza virus respiratory infection in mice lacking class I major histocompatibility complex-restricted CD8+ T cells. J Exp Med 174:875–880PubMedCrossRefGoogle Scholar
  60. Elson CO (1996) Cholera toxin as a mucosal adjuvant. In: Kiyono H, McGhee JR, Ogra PL (eds) Mucosal Vaccines. Academic Press, San Diego, pp 59–72Google Scholar
  61. Enioutina EY, Visic D, Daynes RA (2000) The induction of systemic and mucosal immune responses to antigen-adjuvant compositions administered into the skin: alterations in the migratory properties of dendritic cells appears to be important for stimulating mucosal immunity. Vaccine 18:2753–2767PubMedCrossRefGoogle Scholar
  62. Eo SK, Gierynska M, Kamar AA et al (2001) Prime-boost immunization with DNA vaccine: mucosal route of administration changes the rules. J Immunol 166:5473–5479PubMedGoogle Scholar
  63. Estcourt MJ, Ramsay AJ, Brooks A et al (2002) Prime-boost immunization generates a high frequency, high-avidity CD8(+) cytotoxic T lymphocyte population. Int Immunol 14:31–37PubMedCrossRefGoogle Scholar
  64. Evans DT, Chen LM, Gillis J et al (2003) Mucosal priming of simian immunodeficiency virus-specific cytotoxic T-lymphocyte responses in rhesus macaques by the Salmonella type III secretion antigen delivery system. J Virol 77:2400–2409PubMedCrossRefGoogle Scholar
  65. Funkhouser A, Clements ML, Slome S et al (1993) Antibodies to recombinant gp160 in mucosal secretions and sera of persons infected with HIV-1 and seronegative vaccine recipients. AIDS Res Hum Retroviruses 9:627–632PubMedCrossRefGoogle Scholar
  66. Gallichan WS, Rosenthal KL (1996) Long-lived cytotoxic T lymphocyte memory in mucosal tissues after mucosal but not systemic immunization. J Exp Med 184:1879–1890PubMedCrossRefGoogle Scholar
  67. Gallimore A, Dumrese T, Hengartner H et al (1998) Protective immunity does not correlate with the hierarchy of virus-specific cytotoxic T cell responses to naturally processed peptides. J Exp Med 187:1647–1657PubMedCrossRefGoogle Scholar
  68. Gao X-M, Zheng B, Liew FY et al (1991) Priming of influenza virus-specific cytotoxic T lymphocytes vivo by short synthetic peptides. J Immunol 147:3268–3273PubMedGoogle Scholar
  69. Gherardi MM, Najera JL, Perez-Jimenez E et al (2003) Prime-boost immunization schedules based on influenza virus and vaccinia virus vectors potentiate cellular immune responses against human immunodeficiency virus Env protein systemically and in the genitorectal draining lymph nodes. J Virol 77:7048–7057PubMedCrossRefGoogle Scholar
  70. Gherardi MM, Perez-Jimenez E, Najera JL et al (2004) Induction of HIV immunity in the genital tract after intranasal delivery of a MVA vector: enhanced immunogenicity after DNA prime-modified vaccinia virus Ankara boost immunization schedule. J Immunol 172:6209–6220PubMedGoogle Scholar
  71. Glenn GM, Scharton-Kersten T, Vassell R et al (1998) Transcutaneous immunization with cholera toxin protects mice against lethal mucosal toxin challenge. J Immunol 161:3211–3214PubMedGoogle Scholar
  72. Glenn GM, Taylor DN, Li X et al (2000) Transcutaneous immunization: a human vaccine delivery strategy using a patch. Nat Med 6:1403–1406PubMedCrossRefGoogle Scholar
  73. Gockel CM, Bao S, Beagley KW (2000) Transcutaneous immunization induces mucosal and systemic immunity: a potent method for targeting immunity to the female reproductive tract. Mol Immunol 37:537–544PubMedCrossRefGoogle Scholar
  74. Hanke T, Blanchard TJ, Schneider J et al (1998) Enhancement of MHC class I-restricted peptide-specific T cell induction by a DNA prime/MVA boost vaccination regime. Vaccine 16:439–445PubMedCrossRefGoogle Scholar
  75. Heise C, Miller CJ, Lackner A et al (1994) Primary acute simian immunodeficiency virus infection of intestinal lymphoid tissue is associated with gastrointestinal dysfunction. J Infect Dis 169:1116–1120PubMedCrossRefGoogle Scholar
  76. Heit A, Gebhardt F, Lahl K et al (2008) Circumvention of regulatory CD4(+) T cell activity during cross-priming strongly enhances T cell-mediated immunity. Eur J Immunol 38:1585–1597PubMedCrossRefGoogle Scholar
  77. Hel Z, Nacsa J, Kelsall BL et al (2001) Impairment of Gag-specific D8+ T-cell function in mucosal and sytemic compartments of SIVmac251- and SHIVKU2-infected macaques. J Virol 75:11483–11495PubMedCrossRefGoogle Scholar
  78. Hel Z, Nacsa J, Tryniszewska E et al (2002) Containment of simian immunodeficiency virus infection in vaccinated macaques: correlation with the magnitude of virus-specific pre- and postchallenge CD4+ and CD8+ T cell responses. J Immunol 169:4778–4787PubMedGoogle Scholar
  79. Horner AA, Datta SK, Takabayashi K et al (2001) Immunostimulatory DNA-based vaccines elicit multifaceted immune responses against HIV at systemic and mucosal sites. J Immunol 167:1584–1591PubMedGoogle Scholar
  80. Huang X, Xu J, Qiu C et al (2007) Mucosal priming with PEI/DNA complex and systemic boosting with recombinant TianTan vaccinia stimulate vigorous mucosal and systemic immune responses. Vaccine 25:2620–2629PubMedCrossRefGoogle Scholar
  81. Jin X, Bauer DE, Tuttleton SE et al (1999) Dramatic rise in plasma viremia after CD8+ T cell depletion in simian immunodeficiency virus-infected macaques. J Exp Med 189:991–998PubMedCrossRefGoogle Scholar
  82. Kaneko H, Bednarek I, Wierzbicki A et al (2000) Oral DNA vaccination promotes mucosal and systemic immune responses to HIV envelope glycoprotein. Virology 267:8–16PubMedCrossRefGoogle Scholar
  83. Kaufman DR, Liu J, Carville A et al (2008) Trafficking of antigen-specific CD8+ T lymphocytes to mucosal surfaces following intramuscular vaccination. J Immunol 181:4188–4198PubMedGoogle Scholar
  84. Kotler DP, Gaetz HP, Lange M et al (1984) Enteropathy associated with the acquired immunodeficiency syndrome. Ann Intern Med 101:421–428PubMedGoogle Scholar
  85. Kozlowski PA, Neutra MR (2003) The role of mucosal immunity in prevention of HIV transmission. Curr Mol Med 3:217–228PubMedCrossRefGoogle Scholar
  86. Kozlowski PA, Cu-Uvin S, Neutra MR, Flanigan TP (1997) Comparison of the oral, rectal, and vaginal immunization routes for induction of antibodies in rectal and genital tract secretions of women. Infect Immun 65:1387–1394PubMedGoogle Scholar
  87. Kuroda MJ, Schmitz JE, Barouch DH et al (1998) Analysis of Gag-specific cytotoxic T lymphocytes in simian immunodeficiency virus-infected rhesus monkeys by cell staining with a tetrameric major histocompatibility complex class I-peptide complex. J Exp Med 187:1373–1381PubMedCrossRefGoogle Scholar
  88. Lena P, Villinger F, Giavedoni L et al (2002) Co-immunization of rhesus macaques with plasmid vectors expressing IFN-gamma, GM-CSF, and SIV antigens enhances anti-viral humoral immunity but does not affect viremia after challenge with highly pathogenic virus. Vaccine 20(Suppl 4):A69–A79PubMedCrossRefGoogle Scholar
  89. Li Q, Duan L, Estes JD et al (2005) Peak SIV replication in resting memory CD4+ T cells depletes gut lamina propria CD4+ T cells. Nature 434:1148–1152PubMedGoogle Scholar
  90. Li Z, Zhang M, Zhou C et al (2008) Novel vaccination protocol with two live mucosal vectors elicits strong cell-mediated immunity in the vagina and protects against vaginal virus challenge. J Immunol 180:2504–2513PubMedGoogle Scholar
  91. Lin SW, Cun AS, Harris-McCoy K et al (2007) Intramuscular rather than oral administration of replication-defective adenoviral vaccine vector induces specific CD8+ T cell responses in the gut. Vaccine 25:2187–2193PubMedCrossRefGoogle Scholar
  92. Lukacher AE, Braciale VL, Braciale TJ (1984) In vivo effector function of influenza virus-specific cytotoxic T lymphocyte clones is highly specific. J Exp Med 160:814–826PubMedCrossRefGoogle Scholar
  93. Manrique M, Kozlowski PA, Wang SW et al (2009) Nasal DNA-MVA SIV vaccination provides more significant protection from progression to AIDS than a similar intramuscular vaccination. Mucosal Immunol 2:536–550PubMedCrossRefGoogle Scholar
  94. Marinaro M, Staats HF, Hiroi T, Jackson RJ, Coste M, Boyaka PN, Okahashi N, Yamamoto M, Kiyono H, Bluethmann H, Fujihashi K, McGhee JR (1995) Mucosal adjuvant effect of cholera toxin in mice results from induction of T helper 2 (Th2) cells and IL-4. J.Immunol. 155:4621–4629PubMedGoogle Scholar
  95. Marx PA, Compans RW, Gettie A et al (1993) Protection against vaginal SIV transmission with microencapsulated vaccine. Science 260:1323–1327PubMedCrossRefGoogle Scholar
  96. Mascola JR, Stiegler G, VanCott TC et al (2000) Protection of macaques against vaginal transmission of a pathogenic HIV-1/SIV chimeric virus by passive infusion of neutralizing antibodies. Nat Med 6:207–210PubMedCrossRefGoogle Scholar
  97. Masopust D, Ha SJ, Vezys V et al (2006) Stimulation history dictates memory CD8 T cell phenotype: implications for prime-boost vaccination. J Immunol 177:831–839PubMedGoogle Scholar
  98. Mazzoli S, Trabattoni D, Lo Caputo S et al (1997) HIV-specific mucosal and cellular immunity in HIV-seronegative partners of HIV-seropositive individuals. Nat Med 3:1250–1257PubMedCrossRefGoogle Scholar
  99. McKay PF, Schmitz JE, Barouch DH et al (2002) Vaccine protection against functional CTL abnormalities in simian human immunodeficiency virus-infected rhesus monkeys. J Immunol 168:332–337PubMedGoogle Scholar
  100. McMichael AJ (2006) HIV vaccines. Annu Rev Immunol 24:227–255PubMedCrossRefGoogle Scholar
  101. Mehandru S, Poles MA, Tenner-Racz K et al (2004) Primary HIV-1 infection is associated with preferential depletion of CD4+ T lymphocytes from effector sites in the gastrointestinal tract. J Exp Med 200:761–770PubMedCrossRefGoogle Scholar
  102. Mercier GT, Nehete PN, Passeri MF et al (2007) Oral immunization of rhesus macaques with adenoviral HIV vaccines using enteric-coated capsules. Vaccine 25:8687–8701PubMedCrossRefGoogle Scholar
  103. Mestecky J, Jackson S (1994) Reassessment of the impact of mucosal immunity in infection with the human immunodeficiency virus (HIV) and design of relevant vaccines. J Clin Immunol 14:259–272PubMedCrossRefGoogle Scholar
  104. Morris CB, Cheng E, Thanawastien A et al (2000) Effectiveness of intranasal immunization with HIV-gp160 Env CTL epitope peptide (E7) in combination with the mucosal adjuvant LT(R192G). Vaccine 18:1944–1951PubMedCrossRefGoogle Scholar
  105. Morrow G, Vachot L, Vagenas P et al (2007) Current concepts of HIV transmission. Curr HIV/AIDS Rep 4:29–35PubMedCrossRefGoogle Scholar
  106. Murphey-Corb M, Wilson LA, Trichel AM et al (1999) Selective induction of protective MHC class I restricted CTL in the intestinal lamina propria of rhesus monkeys by transient SIV infection of the colonic mucosa. J Immunol 162:540–549PubMedGoogle Scholar
  107. Neeson P, Boyer J, Kumar S et al (2006) A DNA prime-oral Listeria boost vaccine in rhesus macaques induces a SIV-specific CD8 T cell mucosal response characterized by high levels of alpha4beta7 integrin and an effector memory phenotype. Virology 354:299–315PubMedCrossRefGoogle Scholar
  108. Neutra MR, Kozlowski PA (2006) Mucosal vaccines: the promise and the challenge. Nat Rev Immunol 6:148–158PubMedCrossRefGoogle Scholar
  109. O’Connor DH, Allen TM, Vogel TU et al (2002) Acute phase cytotoxic T lymphocyte escape is a hallmark of simian immunodeficiency virus infection. Nat Med 8:493–499PubMedCrossRefGoogle Scholar
  110. Oh S, Hodge JW, Ahlers JD et al (2003) Selective induction of high avidity CTL by altering the balance of signals from antigen presenting cells. J Immunol 170:2523–2530PubMedGoogle Scholar
  111. O’Neill E, Martinez I, Villinger F et al (2002) Protection by SIV VLP DNA prime/protein boost following mucosal SIV challenge is markedly enhanced by IL-12/GM-CSF co-administration. J Med Primatol 31:217–227PubMedCrossRefGoogle Scholar
  112. Pal R, Venzon D, Santra S et al (2006) Systemic immunization with an ALVAC-HIV-1/protein boost vaccine strategy protects rhesus macaques from CD4+ T-cell loss and reduces both systemic and mucosal SHIVKU2 RNA levels. J Virol 80:3732–3742PubMedCrossRefGoogle Scholar
  113. Peacock JW, Nordone SK, Jackson SS et al (2004) Gender differences in human immunodeficiency virus type 1-specific CD8 responses in the reproductive tract and colon following nasal peptide priming and modified vaccinia virus Ankara boosting. J Virol 78:13163–13172PubMedCrossRefGoogle Scholar
  114. Pinczewski J, Zhao J, Malkevitch N et al (2005) Enhanced immunity and protective efficacy against SIVmac251 intrarectal challenge following ad-SIV priming by multiple mucosal routes and gp120 boosting in MPL-SE. Viral Immunol 18:236–243PubMedCrossRefGoogle Scholar
  115. Porgador A, Staats HF, Faiola B et al (1997) Intranasal immunization with CTL epitope peptides from HIV-1 or ovalbumin and the mucosal adjuvant cholera toxin induces peptide-specific CTLs and protection against tumor development in vivo. J Immunol 158:834–841PubMedGoogle Scholar
  116. Ranasinghe C, Medveczky JC, Woltring D et al (2006) Evaluation of fowlpox-vaccinia virus prime-boost vaccine strategies for high-level mucosal and systemic immunity against HIV-1. Vaccine 24:5881–5895PubMedCrossRefGoogle Scholar
  117. Ranasinghe C, Turner SJ, McArthur C et al (2007) Mucosal HIV-1 pox virus prime-boost immunization induces high-avidity CD8+ T cells with regime-dependent cytokine/granzyme B profiles. J Immunol 178:2370–2379PubMedGoogle Scholar
  118. Scharton-Kersten T, Yu J, Vassell R et al (2000) Transcutaneous immunization with bacterial ADP-ribosylating exotoxins, subunits, and unrelated adjuvants. Infect Immun 68:5306–5313PubMedCrossRefGoogle Scholar
  119. Schmitz JE, Kuroda MJ, Santra S et al (1999) Control of viremia in simian immunodeficiency virus infection by CD8+ lymphocytes. Science 283:857–860PubMedCrossRefGoogle Scholar
  120. Sedlik C, Dadaglio G, Saron MF et al (2000) In vivo induction of a high-avidity, high-frequency cytotoxic T-lymphocyte response is associated with antiviral protective immunity. J Virol 74:5769–5775PubMedCrossRefGoogle Scholar
  121. Sharpe S, Hanke T, Tinsley-Bown A et al (2003) Mucosal immunization with PLGA-microencapsulated DNA primes a SIV-specific CTL response revealed by boosting with cognate recombinant modified vaccinia virus Ankara. Virology 313:13–21PubMedCrossRefGoogle Scholar
  122. Sharpstone D, Neild P, Crane R et al (1999) Small intestinal transit, absorption, and permeability in patients with AIDS with and without diarrhoea. Gut 45:70–76PubMedCrossRefGoogle Scholar
  123. Shata MT, Reitz MS Jr, DeVico AL et al (2001) Mucosal and systemic HIV-1 Env-specific CD8(+) T-cells develop after intragastric vaccination with a Salmonella Env DNA vaccine vector. Vaccine 20:623–629PubMedCrossRefGoogle Scholar
  124. Shevach EM (2002) CD4+ CD25+ suppressor T cells: more questions than answers. Nat Rev Immunol 2:389–400PubMedGoogle Scholar
  125. Shiver JW, Fu TM, Chen L et al (2002) Replication-incompetent adenoviral vaccine vector elicits effective anti-immunodeficiency virus immunity. Nature 415:331–335PubMedCrossRefGoogle Scholar
  126. Snyder JT, Alexander-Miller MA, Berzofsky JA et al (2003) Molecular mechanisms and biological significance of CTL avidity. Curr HIV Res 1:287–294PubMedCrossRefGoogle Scholar
  127. Spira AI, Marx PA, Patterson BK et al (1996) Cellular targets of infection and route of viral dissemination after an intravaginal inoculation of simian immunodeficiency virus into rhesus macaques. J Exp Med 183:215–225PubMedCrossRefGoogle Scholar
  128. Staats HF, Ennis FA Jr (1999) IL-1 is an effective adjuvant for mucosal and systemic immune responses when coadministered with protein immunogens. J Immunol 162:6141–6147PubMedGoogle Scholar
  129. Staats HF, Bradney CP, Gwinn WM et al (2001) Cytokine requirements for induction of systemic and mucosal CTL after nasal immunization. J Immunol 167:5386–5394PubMedGoogle Scholar
  130. Stevceva L, Alvarez X, Lackner AA et al (2002) Both mucosal and systemic routes of immunization with the live, attenuated NYVAC/simian immunodeficiency virus SIV(gpe) recombinant vaccine result in gag-specific CD8(+) T-cell responses in mucosal tissues of macaques. J Virol 76:11659–11676PubMedCrossRefGoogle Scholar
  131. Sui Y, Zhu Q, Gagnon S et al (2010) Innate and adaptive immune correlates of vaccine and adjuvant-induced control of mucosal transmission of SIV in macaques. Proc Natl Acad Sci USA 107:9843–9848PubMedCrossRefGoogle Scholar
  132. Sutmuller RPM, Van Duivenvoorde LM, Van Elsas A et al (2001) Synergism of cytotoxic T lymphocyte-associated antigen 4 blockade and depletion of CD25+ regulatory T cells in antitumor therapy reveals alternative cytotoxic T lymphocyte responses. J Exp Med 194:823–832PubMedCrossRefGoogle Scholar
  133. Suvas S, Kumaraguru U, Pack CD et al (2003) CD4+CD25+ T cells regulate virus-specific primary and memory CD8+ T cell responses. J Exp Med 198:889–901PubMedCrossRefGoogle Scholar
  134. Tatsis N, Lin SW, Harris-McCoy K et al (2007) Multiple immunizations with adenovirus and MVA vectors improve CD8+ T cell functionality and mucosal homing. Virology 367:156–167PubMedCrossRefGoogle Scholar
  135. Taylor PM, Askonas BA (1986) Influenza nucleoprotein-specific cytotoxic T-cell clones are protective in vivo. Immunology 58:417–420PubMedGoogle Scholar
  136. Trumpfheller C, Caskey M, Nchinda G et al (2008) The microbial mimic poly IC induces durable and protective CD4+ T cell immunity together with a dendritic cell targeted vaccine. Proc Natl Acad Sci USA 105:2574–2579PubMedCrossRefGoogle Scholar
  137. Tscharke DC, Karupiah G, Zhou J et al (2005) Identification of poxvirus CD8+ T cell determinants to enable rational design and characterization of smallpox vaccines. J Exp Med 201:95–104PubMedCrossRefGoogle Scholar
  138. Uematsu S, Fujimoto K, Jang MH et al (2008) Regulation of humoral and cellular gut immunity by lamina propria dendritic cells expressing Toll-like receptor 5. Nat Immunol 9:769–776PubMedCrossRefGoogle Scholar
  139. Ulmer JB, Donnelly JJ, Parker SE et al (1993) Heterologous protection against influenza by injection of DNA encoding a viral protein. Science 259:1745–1749PubMedCrossRefGoogle Scholar
  140. Vajdy M, Gardner J, Neidleman J et al (2001) Human immunodeficiency virus type 1 Gag-specific vaginal immunity and protection after local immunizations with sindbis virus-based replicon particles. J Infect Dis 184:1613–1616PubMedCrossRefGoogle Scholar
  141. Veazey RS, DeMaria M, Chalifoux LV et al (1998) Gastrointestinal tract as a major site of CD4+ T cell depletion and viral replication in SIV infection. Science 280:427–431PubMedCrossRefGoogle Scholar
  142. Veazey RS, Marx PA, Lackner AA (2003) Vaginal CD4+ T cells express high levels of CCR5 and are rapidly depleted in simian immunodeficiency virus infection. J Inf Dis 187:769–776CrossRefGoogle Scholar
  143. Vogel TU, Reynolds MR, Fuller DH et al (2003) Multispecific vaccine-induced mucosal cytotoxic T lymphocytes reduce acute-phase viral replication but fail in long-term control of simian immunodeficiency virus SIVmac239. J Virol 77:13348–13360PubMedCrossRefGoogle Scholar
  144. Wilkinson J, Cunningham AL (2006) Mucosal transmission of HIV-1: first stop dendritic cells. Curr Drug Targets 7:1563–1569PubMedCrossRefGoogle Scholar
  145. Wyatt LS, Belyakov IM, Earl PL et al (2008) Enhanced cell surface expression, immunogenicity and genetic stability resulting from a spontaneous truncation of HIV Env expressed by a recombinant MVA. Virology 372:260–272PubMedCrossRefGoogle Scholar
  146. Xu-Amano J, Kiyono H, Jackson RJ, Staats HF, Fujihashi K, Burrows PD, Elson CO, Pillai S, McGhee JR (1993) Helper T cell subsets for immunoglobulin A responses: oral immunization with tetanus toxoid and cholera toxin as adjuvant selectively induces Th2 cells in mucosa associated tissues. J Exp Med 178:1309–1320PubMedCrossRefGoogle Scholar
  147. Yee C, Savage PA, Lee PP et al (1999) Isolation of high avidity melanoma-reactive CTL from heterogeneous populations using peptide-MHC tetramers. J Immunol 162:2227–2234PubMedGoogle Scholar
  148. Yoshizawa I, Mizuochi T, Ogata A et al (2003) Studies on the generation and maintenance of mucosal cytotoxic T lymphocytes against human immunodeficiency virus type 1 Gag in mice. AIDS Res Hum Retroviruses 19:469–479PubMedCrossRefGoogle Scholar
  149. Zeh HJ 3rd, Perry-Lalley D, Dudley ME et al (1999) High avidity CTLs for two self-antigens demonstrate superior in vitro and in vivo antitumor efficacy. J Immunol 162:989–994PubMedGoogle Scholar
  150. Zhang Z-Q, Schuler T, Zupancic M et al (1999) Sexual transmission and propagation of SIV and HIV in resting and activated CD4+ T cells. Science 286:1353–1357PubMedCrossRefGoogle Scholar
  151. Zhou Q, Hidajat R, Peng B et al (2007) Comparative evaluation of oral and intranasal priming with replication-competent adenovirus 5 host range mutant (Ad5hr)-simian immunodeficiency virus (SIV) recombinant vaccines on immunogenicity and protective efficacy against SIV(mac251). Vaccine 25:8021–8035PubMedCrossRefGoogle Scholar
  152. Zhu Q, Egelston C, Vivekanandhan A et al (2008) Toll-like receptor ligands synergize through distinct dendritic cell pathways to induce T cell responses: implications for vaccines. Proc Natl Acad Sci USA 105:16260–16265PubMedCrossRefGoogle Scholar
  153. Zhu Q, Egelston C, Gagnon S et al (2010) Using 3 TLR ligands as a combination adjuvant induces qualitative changes in T cell responses needed for antiviral protection in mice. J Clin Invest 120:607–616PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2011

Authors and Affiliations

  1. 1.Midwest Research Institute110 Thomas Johnson DriveFrederickUSA
  2. 2.National Institute of Allergy and Infectious Diseases, National Institutes of HealthBethesdaUSA

Personalised recommendations