Journal of Urban Health

, Volume 83, Issue 1, pp 5–17 | Cite as

Resistance to HIV Infection

  • M. Marmor
  • K. Hertzmark
  • S. M. Thomas
  • P. N. Halkitis
  • M. Vogler
HIV Perspectives After 25 Years


The biological correlates of an effective immune response that could contain or prevent HIV infection remain elusive despite substantial scientific accomplishments in understanding the interactions among the virus, the individual and the community. The observation that some individuals appear to possess resistance to HIV infection or its consequences has generated a host of epidemiologic investigations to identify biological or behavioral characteristics of these individuals. These data might hold the keys to developing appropriate strategies for mimicking the effective responses of those who appear immune. In this paper we review genetic mechanisms including the role of chemokines and their receptors, cytokines, host genetic immune response to HIV infection, local immune response correlating with behavioral variables, co-infection and immune based mechanisms that have been elucidated so far. We offer suggestions for how to use these observations as platforms for future research to further understand natural resistance to HIV infection through cohort studies, population genotype sampling, mathematical modeling of virus–host interactions and behavioral analyses.


Resistance HIV infection Susceptibility Progression 


  1. 1.
    Fowke KR, Nagelkerke NJ, Kimani J, et al. Resistance to HIV-1 infection among persistently seronegative prostitutes in Nairobi, Kenya. Lancet. 1996;348(9038):1347–1351.CrossRefPubMedGoogle Scholar
  2. 2.
    Kaul R, Dong T, Plummer FA, et al. CD8(+) lymphocytes respond to different HIV epitopes in seronegative and infected subjects. J Clin Invest. 2001;107(10):1303–1310.PubMedCrossRefGoogle Scholar
  3. 3.
    Kaul R, Rutherford J, Rowland-Jones SL, et al. HIV-1 Env-specific cytotoxic T-lymphocyte responses in exposed, uninfected Kenyan sex workers: a prospective analysis. AIDS. 2004;18(15):2087–2089.CrossRefPubMedGoogle Scholar
  4. 4.
    McNicholl JM, Promadej N. Insights into the role of host genetic and T-cell factors in resistance to HIV transmission from studies of highly HIV-exposed Thais. Immunol Res. 2004;29(1–3):161–174.CrossRefPubMedGoogle Scholar
  5. 5.
    Goh WC, Markee J, Akridge RE, et al. Protection against human immunodeficiency virus type 1 infection in persons with repeated exposure: evidence for T cell immunity in the absence of inherited CCR5 coreceptor defects. J Infect Dis. 1999;179(3):548–557.CrossRefPubMedGoogle Scholar
  6. 6.
    Hoffman R. Hematology: Basic Principles and Practice. 4th ed. Elsevier; 2005.Google Scholar
  7. 7.
    Farquhar C, Rowland-Jones S, Mbori-Ngacha D, et al. Human leukocyte antigen (HLA) B*18 and protection against mother-to-child HIV type 1 transmission. AIDS Res Hum Retrovir. 2004;20(7):692–697.CrossRefPubMedGoogle Scholar
  8. 8.
    Kuhn L, Coutsoudis A, Moodley D, et al. T-helper cell responses to HIV envelope peptides in cord blood: protection against intrapartum and breast-feeding transmission. AIDS. 2001;15(1):1–9.CrossRefPubMedGoogle Scholar
  9. 9.
    Clerici M, Levin JM, Kessler HA, et al. HIV-specific T-helper activity in seronegative health care workers exposed to contaminated blood. JAMA. 1994;271(1):42–46.CrossRefPubMedGoogle Scholar
  10. 10.
    Pinto LA, Sullivan J, Berzofsky JA, et al. ENV-specific cytotoxic T lymphocyte responses in HIV seronegative health care workers occupationally exposed to HIV-contaminated body fluids. J Clin Invest. 1995;96(2):867–876.PubMedCrossRefGoogle Scholar
  11. 11.
    Makedonas G, Bruneau J, Lin H, Sekaly RP, Lamothe F, Bernard NF. HIV-specific CD8 T-cell activity in uninfected injection drug users is associated with maintenance of seronegativity. AIDS. 2002;16(12):1595–1602.CrossRefPubMedGoogle Scholar
  12. 12.
    Barretina J, Blanco J, Gutierrez A, et al. Evaluation of the putative role of C–C chemokines as protective factors of HIV-1 infection in seronegative hemophiliacs exposed to contaminated hemoderivatives. Transfusion. 2000;40(4):461–467.CrossRefPubMedGoogle Scholar
  13. 13.
    Easterbrook PJ. Long-term non-progression in HIV infection: definitions and epidemiological issues. J Infect. 1999;38(2):71–73.CrossRefPubMedGoogle Scholar
  14. 14.
    Marmor M, Sheppard HW, Donnell D, et al. Homozygous and heterozygous CCR5-Delta32 genotypes are associated with resistance to HIV infection. J Acquir Immune Defic Syndr. 2001;27(5):472–481.PubMedGoogle Scholar
  15. 15.
    Salkowitz JR, Bruse SE, Meyerson H, et al. CCR5 promoter polymorphism determines macrophage CCR5 density and magnitude of HIV-1 propagation in vitro. Clin Immunol. 2003;108(3):234–240.CrossRefPubMedGoogle Scholar
  16. 16.
    O'Brien SJ, Moore JP. The effect of genetic variation in chemokines and their receptors on HIV transmission and progression to AIDS. Immunol Rev. 2000;177:99–111.CrossRefPubMedGoogle Scholar
  17. 17.
    de Silva E, Stumpf MP. HIV and the CCR5-Delta32 resistance allele. FEMS Microbiol Lett. 2004;241(1):1–12.CrossRefPubMedGoogle Scholar
  18. 18.
    Pokorny V, McQueen F, Yeoman S, et al. Evidence for negative association of the chemokine receptor CCR5 d32 polymorphism with rheumatoid arthritis. Ann Rheum Dis. 2005;64(3):487–490.CrossRefPubMedGoogle Scholar
  19. 19.
    Contopoulos-Ioannidis DG, O'Brien TR, Goedert JJ, Rosenberg PS, Ioannidis JP. Effect of CCR5-delta32 heterozygosity on the risk of perinatal HIV-1 infection: a meta-analysis.[erratum appears in J Acquir Immune Defic Syndr. 2003 Apr 15;32(5):575]. J Acquir Immune Defic Syndr. 2003;32(1):70–76.PubMedGoogle Scholar
  20. 20.
    Philpott S, Weiser B, Tarwater P, et al. CC chemokine receptor 5 genotype and susceptibility to transmission of human immunodeficiency virus type 1 in women. J Infect Dis. 2003;187(4):569–575.CrossRefPubMedGoogle Scholar
  21. 21.
    Hogan CM, Hammer SM. Host determinants in HIV infection and disease. Part 2: genetic factors and implications for antiretroviral therapeutics. Ann Intern Med. 2001;134(10):978–996.PubMedGoogle Scholar
  22. 22.
    Kostrikis LG. Impact of natural chemokine receptor polymorphisms on perinatal transmission of human immunodeficiency virus type 1. Teratology. 2000;61(5):387–390.CrossRefPubMedGoogle Scholar
  23. 23.
    Louisirirotchanakul S, Liu H, Roongpisuthipong A, et al. Genetic analysis of HIV-1 discordant couples in Thailand: association of CCR2 64I homozygosity with HIV-1-negative status. J Acquir Immune Defic Syndr. 2002;29(3):314–315.PubMedGoogle Scholar
  24. 24.
    Kaslow RA, Dorak T, Tang JJ. Influence of host genetic variation on susceptibility to HIV type 1 infection. J Infect Dis. 2005;191(Suppl 1):S68–S77.CrossRefPubMedGoogle Scholar
  25. 25.
    Ioannidis JP, Rosenberg PS, Goedert JJ, et al. Effects of CCR5-Delta32, CCR2-64I, and SDF-1 3′A alleles on HIV-1 disease progression: an international meta-analysis of individual-patient data. Ann Intern Med. 2001;135(9):782–795.PubMedGoogle Scholar
  26. 26.
    Valentin A, Lu W, Rosati M, et al. Dual effect of interleukin 4 on HIV-1 expression: implications for viral phenotypic switch and disease progression. Proc Natl Acad Sci USA. 1998;95(15):8886–8891.CrossRefPubMedGoogle Scholar
  27. 27.
    Nakayama EE, Hoshino Y, Xin X, et al. Polymorphism in the interleukin-4 promoter affects acquisition of human immunodeficiency virus type 1 syncytium-inducing phenotype. J Virol. 2000;74(12):5452–5459.CrossRefPubMedGoogle Scholar
  28. 28.
    Nakayama EE, Meyer L, Iwamoto A, et al. Protective effect of interleukin-4 -589T polymorphism on human immunodeficiency virus type 1 disease progression: relationship with virus load. J Infect Dis. 2002;185(8):1183–1186.CrossRefPubMedGoogle Scholar
  29. 29.
    Kwa D, van Rij RP, Boeser-Nunnink B, Vingerhoed J, Schuitemaker H. Association between an interleukin-4 promoter polymorphism and the acquisition of CXCR4 using HIV-1 variants. AIDS. 2003;17(7):981–985.CrossRefPubMedGoogle Scholar
  30. 30.
    Singh KK, Hughes MD, Chen J, Spector SA. Lack of protective effects of interleukin-4-589-C/T polymorphism against HIV-1-related disease progression and central nervous system impairment, in children. J Infect Dis. 2004;189(4):587–592.CrossRefPubMedGoogle Scholar
  31. 31.
    Kollmann TR, Pettoello-Mantovani M, Katopodis NF, et al. Inhibition of acute in vivo human immunodeficiency virus infection by human interleukin 10 treatment of SCID mice implanted with human fetal thymus and liver. Proc Natl Acad Sci USA. 1996;93(7):3126–3131.CrossRefPubMedGoogle Scholar
  32. 32.
    Shin HD, Winkler C, Stephens JC, et al. Genetic restriction of HIV-1 pathogenesis to AIDS by promoter alleles of IL10. Proc Natl Acad Sci USA. 2000;97(26):14467–14472.CrossRefPubMedGoogle Scholar
  33. 33.
    Carrington M, O'Brien SJ. The influence of HLA genotype on AIDS. Annu Rev Med. 2003;54:535–551.CrossRefPubMedGoogle Scholar
  34. 34.
    Rowland-Jones SL, Dong T, Fowke KR, et al. Cytotoxic T cell responses to multiple conserved HIV epitopes in HIV-resistant prostitutes in Nairobi. J Clin Invest. 1998;102(9):1758–1765.PubMedCrossRefGoogle Scholar
  35. 35.
    Rowland-Jones SL, McMichael A. Immune responses in HIV-exposed seronegatives: have they repelled the virus? Curr Opin Immunol. 1995;7(4):448–455.CrossRefPubMedGoogle Scholar
  36. 36.
    Rowland-Jones SL, Nixon DF, Aldhous MC, et al. HIV-specific cytotoxic T-cell activity in an HIV-exposed but uninfected infant. Lancet. 1993;341(8849):860–861.CrossRefPubMedGoogle Scholar
  37. 37.
    Dorak MT, Tang J, Penman-Aguilar A, et al. Transmission of HIV-1 and HLA-B allele-sharing within serodiscordant heterosexual Zambian couples. Lancet. 2004;363(9427):2137–2139.CrossRefPubMedGoogle Scholar
  38. 38.
    MacDonald KS, Embree J, Njenga S, et al. Mother–child class I HLA concordance increases perinatal human immunodeficiency virus type 1 transmission. J Infect Dis. 1998;177(3):551–556.PubMedCrossRefGoogle Scholar
  39. 39.
    MacDonald KS, Fowke KR, Kimani J, et al. Influence of HLA supertypes on susceptibility and resistance to human immunodeficiency virus type 1 infection. J Infect Dis. 2000;181(5):1581–1589.CrossRefPubMedGoogle Scholar
  40. 40.
    MacDonald KS, Embree JE, Nagelkerke NJ, et al. The HLA A2/6802 supertype is associated with reduced risk of perinatal human immunodeficiency virus type 1 transmission. J Infect Dis. 2001;183(3):503–506.CrossRefPubMedGoogle Scholar
  41. 41.
    Ahuja SK, Catano G. Sharing is caring, except when it comes to HLA-class-I alleles in HIV-1 transmission. Lancet. 2004;363(9427):2103–2104.CrossRefPubMedGoogle Scholar
  42. 42.
    Yang C, Li M, Limpakarnjanarat K, et al. Polymorphisms in the CCR5 coding and noncoding regions among HIV type 1-exposed, persistently seronegative female sex-workers from Thailand. AIDS Res Human Retrovir. 2003;19(8):661–665.CrossRefGoogle Scholar
  43. 43.
    Kaul R, Rowland-Jones SL, Kimani J, et al. New insights into HIV-1 specific cytotoxic T-lymphocyte responses in exposed, persistently seronegative Kenyan sex workers. Immunol Lett. 2001;79(1–2):3–13.CrossRefPubMedGoogle Scholar
  44. 44.
    Rowland-Jones SL, Pinheiro S, Kaul R, et al. How important is the ‘quality’ of the cytotoxic T lymphocyte (CTL) response in protection against HIV infection? Immunol Lett. 2001;79:15–20.CrossRefPubMedGoogle Scholar
  45. 45.
    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(3):1602–1611.PubMedGoogle Scholar
  46. 46.
    Kaul R, Rowland-Jones SL, Kimani J, et al. Late seroconversion in HIV-resistant Nairobi prostitutes despite pre-existing HIV-specific CD8+ responses.[comment]. J Clin Invest. 2001;107(3):341–349.PubMedCrossRefGoogle Scholar
  47. 47.
    Beyrer C, Artenstein AW, Rugpao S, et al. Epidemiologiv and biologic characterization of a cohort of human immunodeficiency virus type 1 highly exposed, persistently seronegative female sex workers in Northern Thailand. J Infect Dis. 1999;179:59–67.CrossRefPubMedGoogle Scholar
  48. 48.
    Broliden K, Hinkula J, Devito C, et al. Functional HIV-1 specific IgA antibodies in HIV-1 exposed, persistently IgG seronegative female sex workers. Immunol Lett. 2001;79:29–36.CrossRefPubMedGoogle Scholar
  49. 49.
    Belec L, Ghys PD, Hocini H, et al. Cervicovaginal secretory antibodies to human immunodeficiency virus type 1 (HIV-1) that block viral transcytosis through tight epithelial barriers in highly exposed HIV-1-seronegative African women. J Infect Dis. 2001;184(11):1412–1422.CrossRefPubMedGoogle Scholar
  50. 50.
    Polgreen PM, Xiang J, Chang Q, Stapleton JT. GB virus type C/hepatitis G virus: a non-pathogenic flavivirus associated with prolonged survival in HIV-infected individuals. Microbes Infect. 2003;5(13):1255–1261.CrossRefPubMedGoogle Scholar
  51. 51.
    Williams CF, Klinzman D, Yamashita TE, et al. Persistent GB virus C infection and survival in HIV-infected men. N Engl J Med. 2004;350(10):981–990.CrossRefPubMedGoogle Scholar
  52. 52.
    Xiang J, Wunschmann S, Diekema DJ, et al. Effect of coinfection with GB virus C on survival among patients with HIV infection. N Engl J Med. 2001;345(10):707–714.CrossRefPubMedGoogle Scholar
  53. 53.
    Pomerantz RJ, Nunnari G. HIV and GB virus C—can two viruses be better than one? N Engl J Med 2004;350(10):963–965.CrossRefPubMedGoogle Scholar
  54. 54.
    Canducci F, Uberti Foppa C, Boeri E, et al. Characterization of GBV-C infection in HIV-1 infected patients. J Biol Regul Homeost Agents. 2003;17(2):191–194.PubMedGoogle Scholar
  55. 55.
    Royce RA, Sena A, Cates W Jr., Cohen MS. Sexual transmission of HIV. N Engl J Med. 1997;336(15):1072–1078.CrossRefPubMedGoogle Scholar
  56. 56.
    Sha BE, Zariffard MR, Wang QJ, et al. Female genital-tract HIV load correlates inversely with Lactobacillus species but positively with bacterial vaginosis and Mycoplasma hominis. J Infect Dis. 2005;191(1):25–32.CrossRefPubMedGoogle Scholar
  57. 57.
    Celum CL, Robinson NJ, Cohen MS. Potential effect of HIV type 1 antiretroviral and herpes simplex virus type 2 antiviral therapy on transmission and acquisition of HIV type 1 infection. J Infect Dis. 2005;191(Suppl 1):S107–S114.CrossRefPubMedGoogle Scholar
  58. 58.
    Seed J, Allen S, Mertens T, et al. Male circumcision, sexually transmitted disease, and risk of HIV. J Acquir Immune Defic Syndr Human Retrovirol. 1995;8(1):83–90.Google Scholar
  59. 59.
    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.CrossRefPubMedGoogle Scholar
  60. 60.
    Lowy E, Ross MW. “It'll never happen to me”: gay men's beliefs, perceptions and folk constructions of sexual risk. AIDS Educ Prev. 1994;6(6):467–482.PubMedGoogle Scholar
  61. 61.
    Halkitis PN, Parsons JT. Oral sex and HIV risk reduction: perceived risk, behavior and strategies among young HIV negative gay men. J Psychol Human Sex. 2000;11(4):1–24.CrossRefGoogle Scholar
  62. 62.
    Des Jarlais DC, Vanichseni S, Marmor M, et al. “Why I am not infected with HIV”: implications for long-term HIV risk reduction and HIV vaccine trials. J Acquir Immune Defic Syndr Human Retrovirol. 1997;16(5):393–399.Google Scholar
  63. 63.
    Fishbein M. The role of theory in HIV prevention. AIDS Care. 2000;12(3):273–278.PubMedCrossRefGoogle Scholar
  64. 64.
    Cochran SD, Keidan J, Kalechstein A. Sexually transmitted diseases and acquired immunodeficiency syndrome (AIDS). Changes in risk reduction behaviors among young adults. Sex Transm Dis. 1990;17(2):80–86.PubMedCrossRefGoogle Scholar
  65. 65.
    Bartholow BN, Buchbinder S, Celum C, et al. HIV sexual risk behavior over 36 months of follow-up in the world's first HIV vaccine efficacy trial. J Acquir Immune Defic Syndr. 2005;39(1):90–101.CrossRefPubMedGoogle Scholar
  66. 66.
    Aspinwall LG, Kemeny ME, Taylor SE, Schneider SG, Dudley JP. Psychosocial predictors of gay men's AIDS risk-reduction behavior. Health Psychol. 1991;10(6):432–444.CrossRefPubMedGoogle Scholar
  67. 67.
    Halkitis PN, Zade DD, Shrem M, Marmor M. Beliefs about HIV non-infection and risky sexual behavior among MSM. AIDS Educ Prev. 2004;16(5):448–458.CrossRefPubMedGoogle Scholar
  68. 68.
    Ho DD, Neumann AU, Perelson AS, Chen W, Leonard JM, Markowitz M. Rapid turnover of plasma virions and CD4 lymphocytes in HIV-1 infection. Nature. 1995;373(6510):123–126.CrossRefPubMedGoogle Scholar
  69. 69.
    Wodarz D, Nowak MA. Mathematical models of HIV pathogenesis and treatment. BioEssays. 2002;24(12):1178–1187.CrossRefPubMedGoogle Scholar

Copyright information

© The New York Academy of Medicine 2006

Authors and Affiliations

  • M. Marmor
    • 1
    • 2
    • 3
  • K. Hertzmark
  • S. M. Thomas
  • P. N. Halkitis
  • M. Vogler
  1. 1.Department of Environmental MedicineNew York University School of MedicineNew YorkUSA
  2. 2.Department of MedicineNew York University School of MedicineNew YorkUSA
  3. 3.The Center for AIDS ResearchNew York University School of MedicineNew YorkUSA

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