Role of Chemokines and Their Receptors in the Pathogenesis of HIV Infection

  • Frederick S. Lee
  • Gabriele Kuschert
  • Otto O. Yang
  • Andrew D. Luster
Part of the Infectious Disease book series (ID)


The chemokines comprise a rapidly expanding group of chemotactic cytokines now known to play a critical role in regulating leukocyte trafficking during development and in homeostasis, inflammation, and infection. In the brief period since the original description of platelet factor 4 (PF4) (1) and interferon-inducible protein of 10 kDa (IP-10) (2) this family has grown to more than 50 members. Numerous studies now link chemokines to the pathogenesis of a wide range of inflammatory processes including asthma, atherosclerosis, pneumonia, meningitis, psoriasis, rheumatoid arthritis, inflammatory bowel disease, and sarcoidosis, among others (3). Many also play roles in angiogenesis, hematopoiesis, and fetal development.


Human Immunodeficiency Virus Infection Chemokine Receptor Acquire Immune Deficiency Syndrome Simian Immunodeficiency Virus Chemokine Receptor CXCR4 
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.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Deuel TF, Keim PS, Farmer M, Heinrikson RL. Amino acid sequence of human platelet factor 4. Proc Natl Acad Sci USA 1977; 74: 2256–8.PubMedCrossRefGoogle Scholar
  2. 2.
    Luster AD, Unkeless JC, Ravetch JV. Gamma-interferon transcriptionally regulates an early-response gene containing homology to platelet proteins. Nature 1985; 315: 672–6.PubMedCrossRefGoogle Scholar
  3. 3.
    Luster AD. Chemokines: chemotactic cytokines that mediate inflammation. N Engl J Medicine 1998; 388: 436–45.Google Scholar
  4. 4.
    Horuk R, Chitnis CE, Darbonne WC, Colby TJ, Rybicki A, Hadley TJ, et al. A receptor for the malarial parasite Plasmodium vivax: the erythrocyte chemokine receptor. Science 1993; 261: 1182–4.PubMedCrossRefGoogle Scholar
  5. 5.
    Lalani AS, Masters J, Zeng W, Barrett J, Pannu R, Everett H, et al. Use of chemokine receptors by poxviruses. Science 1999; 286: 1968–71.PubMedCrossRefGoogle Scholar
  6. 6.
    Berger EA, Murphy PM, Farber JM. Chemokine receptors as HIV-1 coreceptors: roles in viral entry, tropism, and disease. Annu Rev Immunol 1999; 17: 657–700.PubMedCrossRefGoogle Scholar
  7. 7.
    Locati M, Murphy P. Chemokines and chemokine receptors: biology and clinical relevance in inflammation and AIDS. Annu Rev Med 1999; 50: 425–40.PubMedCrossRefGoogle Scholar
  8. 8.
    Baggiolini M. Chemokines and leukocyte traffic. Nature 1998; 392: 565–8.PubMedCrossRefGoogle Scholar
  9. 9.
    Kelner GS, Kennedy J, Bacon KB, Kleyensteuber S, Largaespada DA, Jenkins NA, et al. Lymphotactin: a cytokine that represents a new class of chemokine. Science 1994; 266: 1395–9.PubMedCrossRefGoogle Scholar
  10. 10.
    Bazan JF, Bacon KB, Hardiman G, Wang W, Soo K, Rossi D, et al. A new class of membrane-bound chemokine with a CX3C motif. Nature 1997; 385: 640–4.PubMedCrossRefGoogle Scholar
  11. 11.
    Haskell C, Cleary M, Charo I. Molecular uncoupling of fractalkine-mediated cell adhesion and cignal transduction. Rapid flow arrest of CX3CR1-expressing cells is independent of G-protein activation. J Biol Chem 1999; 274: 10053–8.PubMedCrossRefGoogle Scholar
  12. 12.
    Luster AD, Rothenberg ME. The role of the monocyte chemoattractant protein and eotaxin subfamily of chemokines in allergic inflammation. J Leuk Biol 1997; 62: 620–33.Google Scholar
  13. 13.
    Bockaert J, Pin JP. Molecular tinkering of G protein-coupled receptors: an evolutionary success. EMBO J 1999; 18: 1723–9.CrossRefGoogle Scholar
  14. 14.
    Cyster JG. Chemokines and the homing of dendritic cells to the T cell areas of lymphoid organs [comment]. J Exp Med 1999; 189: 447–50.PubMedCrossRefGoogle Scholar
  15. 15.
    Dutt P, Wang JF, Groopman JE. Stromal cell-derived factor-1 alpha and stem cell factor/kit ligand share signaling pathways in hemopoietic progenitors: a potential mechanism for cooperative induction of chemotaxis. J Immunol 1998; 161: 3652–8.PubMedGoogle Scholar
  16. 16.
    Becknew S. G-protein activation by chemokines. In: Horuk R (ed). Methods in Enzymology, Chemokine Receptors. San Diego: Academic Press, 1997, pp. 309–26.CrossRefGoogle Scholar
  17. 17.
    Laudanna C, Campbell JJ, Butcher EC. Role of Rho in chemoattractant-activated leukocyte adhesion through integrins. Science 1996; 271: 981–3.PubMedCrossRefGoogle Scholar
  18. 18.
    Richmond A, Mueller S, White JR, Schraw W. C-X-C chemokine receptor desensitization mediated through ligand-enhanced receptor phosphorylation on serine residues. In: Horuk R (ed). Methods in Enzymology, Chemokine Receptors. San Diego: Academic Press, 1997, pp. 3–15.CrossRefGoogle Scholar
  19. 19.
    Feng Y, Broder CC, Kennedy PE, Berger EA. HIV-1 entry cofactor: functional cloning of a seven-transmembrane, G protein-coupled receptor. Science 1996; 272: 872–7.PubMedCrossRefGoogle Scholar
  20. 20.
    Cocchi F, DeVico AL, Garzino-Demo A, Arya SK, Gallo RC, Lusso P. Identification of RANTES, MIP-la, and MIP-113 as the major HIV-suppressive factors produced by CD8+ T cells. Science 1995; 270: 1811–5.PubMedCrossRefGoogle Scholar
  21. 21.
    Deng H, Liu R, Ellmeier W, Choe S, Unutmaz D, Burkhart M, et al. Identification of a major co-receptor for primary isolates of HIV-1. Nature 1996; 381: 661–6.PubMedCrossRefGoogle Scholar
  22. 22.
    Dragic T, Litwin V, Allaway GP, Martin SR, Huang Y, Nagashima KA, et al. HIV-1 entry into CD4+ cells is mediated by the chemokine receptor CC-CKR-5. Nature 1996; 381: 667–73.PubMedCrossRefGoogle Scholar
  23. 23.
    Alkhatib G, Combadiere C, C. BC, Feng Y, Kennedy PE, Murphy PM, et al. CC CKR5: a RANTES, MIP-1 alpha, MIP-1 beta receptor as a fusion cofactor for macrophage-tropic HIV-1. Science 1996; 272: 1955–8.PubMedCrossRefGoogle Scholar
  24. 24.
    Doranz BJ, Rucker J, Yi Y, Smyth RJ, Samson M, Peiper SC, et al. A dual-tropic primary HIV-1 isolate that uses fusin and the 13-chemokine receptors CKR-5, CKR-3, and CKR-2b as fusion cofactors. Cell 1996; 85: 1149–58.PubMedCrossRefGoogle Scholar
  25. 25.
    Choe H, Farzan M, Sun Y, Sullivan N, Rollins B, Ponath PD, et al. The 13-chemokines receptors CCR3 and CCR5 facilitate infection by primary HIV-1 isolates. Cell 1996; 85: 1135–48.PubMedCrossRefGoogle Scholar
  26. 26.
    Berger EA, Doms RW, Fenyo EM, Korber BT, Littman DR, Moore JP, et al. A new classification for HIV-1. Nature 1998; 391: 240.PubMedCrossRefGoogle Scholar
  27. 27.
    Horuk R, Hesselgesser J, Zhou Y, Faulds D, Halks-Miller M, Harvey S, et al. The CC chemokine I-309 inhibits CCR8-dependent infection by diverse HIV-1 strains. J Biol Chem 1998; 273: 386–91.PubMedCrossRefGoogle Scholar
  28. 28.
    Combadiere C, Salzwedel K, Smith ED, Tiffany HL, Berger EA, Murphy PM. Identification of CX3CR1. A chemotactic receptor for the human CX3C chemokine fractalkine and a fusion coreceptor for HIV-1. J Biol Chem 1998; 273: 23799–804.PubMedCrossRefGoogle Scholar
  29. 29.
    Rucker J, Edinger AL, Sharron M, Samson M, Lee B, Berson JF, et al. Utilization of chemokine receptors, orphan receptors, and herpesvirus-encoded receptors by diverse human and simian immunodeficiency viruses. J Virol 1997; 71: 8999–9007.PubMedGoogle Scholar
  30. 30.
    Liao F, Alkahatib G, Peden KWC, Sharma G, Berger EA, Farber JM. STRL33, a novel chemokine receptor-like protein, functions as a fusion cofactor for both macrophage-tropic and T cell line-tropic HIV-1. J Exp Med 1997; 185: 2015–23.PubMedCrossRefGoogle Scholar
  31. 31.
    Deng H, Unutmaz D, Kewalramani VN, Littman DR. Expression cloning of new receptors used by simian and human immunodeficiency viruses. Nature 1997; 388: 296–300.PubMedCrossRefGoogle Scholar
  32. 32.
    Edinger AL, Hoffman TL, Sharron M, Lee B, O’Dowd B, Doms RW. Use of GPR1, GPR15, and STRL33 as coreceptors by diverse human immunodeficiency virus type 1 and simian immunodeficiency virus envelope proteins. Virology 1998; 249: 367–78.PubMedCrossRefGoogle Scholar
  33. 33.
    Shimizu N, Soda Y, Kanbe K, Liu HY, Jinno A, Kitamura T, et al. An orphan G protein-coupled receptor, GPR1, acts as a coreceptor to allow replication of human immunodeficiency virus types 1 and 2 in brain-derived cells. J Virol 1999; 73: 5231–9.PubMedGoogle Scholar
  34. 34.
    Farzan M, Choe H, Martin K, Marcon L, Hofmann W, Karlsson G, et al. Two orphan seventransmembrane segment receptors which are expressed in CD4-positive cells support simian immunodeficiency virus infection. J Exp Med 1997; 186: 405–11.PubMedCrossRefGoogle Scholar
  35. 35.
    Samson M, Edinger AL, Stordeur P, Rucker J, Verhasselt V, Sharron M, et al. ChemR23, a putative chemoattractant receptor, is expressed in monocyte-derived dendritic cells and macrophages and is a coreceptor for SIV and some primary HIV-1 strains. Eur J Immunol 1998; 28: 1689–700.PubMedCrossRefGoogle Scholar
  36. 36.
    Choe H, Farzan M, Konkel M, Martin K, Sun Y, Marcon L, et al. The orphan seven-transmembrane receptor apj supports the entry or primary T-cell-line-tropic and dualtropic human immunodeficiency virus type 1. J Virol 1998; 7: 6113–8.Google Scholar
  37. 37.
    Edinger AL, Hoffman TL, Sharron M, Lee B, Yi Y, Choe W, et al. An orphan seven-transmembrane domain receptor expressed widely in the brain functions as a coreceptor for human immunodeficiency virus type 1 and simian immunodeficiency virus. J Virol 1998; 72: 7934–40.PubMedGoogle Scholar
  38. 38.
    Wyatt R, Sodroski J. The HIV-1 envelope glycoproteins: fusogens, antigens, and immunogens. Science 1998; 280: 1884–8.PubMedCrossRefGoogle Scholar
  39. 39.
    Lapham CK, Ouyang J, Chandrasekhar B, Nguyen NY, Dimitrov DS, Golding H. Evidence of cell-surface association between fusin and the CD4-gp120 complex in human cell lines. Science 1996; 274: 602–5.PubMedCrossRefGoogle Scholar
  40. 40.
    Kwong PD, Wyatt R, Robinson J, Sweet RW, Sodroski J, Hendrickson WA. Structure of an HIV gp120 envelope glycoprotein in complex with the CD4 receptor and a neutralizing human antibody. Nature 1998; 393: 648–59.PubMedCrossRefGoogle Scholar
  41. 41.
    Rizzuto CD, Wyatt R, Hernandez-Ramos N, Sun Y, Kwong PD, Hendrickson WA, et al. A conserved HIV gp120 glycoprotein structure involved in chemokine receptor binding. Science 1998; 280: 1949–53.PubMedCrossRefGoogle Scholar
  42. 42.
    Wyatt R, Kwong PD, Desjardins E, Sweet RW, Robinson J, Hendrickson WA, et al. The antigenic structure of the HIV gp120 envelope glycoprotein. Nature 1998; 393: 705–11.PubMedCrossRefGoogle Scholar
  43. 43.
    Weissman D, Rabin RL, Arthos J, Rubbert A, Dybul M, Swofford R, et al. Macrophage-tropic HIV and SIV envelope proteins induce a signal through the CCR5 chemokine receptor. Nature 1997; 389: 981–5.PubMedCrossRefGoogle Scholar
  44. 44.
    Alkhatib G, Locati M, Kennedy PE, Murphy PM, Berger EA. HIV-1 coreceptor activity of CCR5 and its inhibition by chemokines: independence from G protein signaling and importance of coreceptor downmodulation. Virology 1997; 234: 340–8.PubMedCrossRefGoogle Scholar
  45. 45.
    Gosling J, Monteclaro FS, Atchison RE, Arai H, Tsou C-L, Goldsmith MA, et al. Molecular uncoupling of C-C chemoking receptor 5-induced chemotaxis and signal transduction from HIV-1 coreceptor activity. Proc Natl Acad Sci USA 1997; 94: 5061–6.PubMedCrossRefGoogle Scholar
  46. 46.
    Aramori I, Ferguson SS, Bieniasz PD, Zhang J, Cullen B, Cullen MG. Molecular mechanism of desensitization of the chemokine receptor CCR-5: receptor signaling and internalization are dissociable from its role as an HIV-1 co-receptor. EMBO J 1997; 15: 4606–16.Google Scholar
  47. 47.
    Hu H, Shioda T, Hari T, Moriya C, Kato A, Sakai Y, et al. Dissociation of ligand-induced internalization of CXCR-4 from its co-receptor activity for HIV-1 Env-mediated membrane fusion. Arch Virol 1998; 143: 851–61.PubMedCrossRefGoogle Scholar
  48. 48.
    Rucker J, Samson M, Doranz BJ, Libert F, Berson JF, Yi Y, et al. Regions in beta-chemokine receptors CCR5 and CCR2b that determine HIV-1 cofactor specificity. Cell 1996; 87: 437–46.PubMedCrossRefGoogle Scholar
  49. 49.
    Alkhatib G, Ahuja SS, Light D, Mummidi S, Berger EA, Ahuja SK. CC chemokine receptor 5-mediated signaling and HIV-1 co-receptor activity share common structural determinants. Critical residues in the third extracellular loop support HIV-1 fusion. J Biol Chem 1997; 272: 19771–6.PubMedCrossRefGoogle Scholar
  50. 50.
    Lu Z, Berson JF, Chen Y, Turner JD, Zhang T, Sharron M, et al. Evolution of HIV-1 coreceptor usage through interactions with distinct CCR5 and CXCR4 domains. Proc Natl Acad Sci USA 1997; 94: 6426–31.PubMedCrossRefGoogle Scholar
  51. 51.
    Rabut GE, Konner JA, Kajumo F, Moore JP, Dragic T. Alanine substitutions of polar and nonpolar residues in the amino-terminal domain of CCR5 differently impair entry of macrophage-and dualtropic isolates of human immunodeficiency virus type 1. J Virol 1998; 72: 3464–8.PubMedGoogle Scholar
  52. 52.
    Endres MJ, Clapman PR, Marsh M, Ahuja M, et al. CD4-independent infection by HIV-2 is mediated by Fusin/CXCR4. Cell 1996; 87: 745–56.PubMedCrossRefGoogle Scholar
  53. 53.
    Reeves JD, McKnight A, Potempa S, Simmons G, Gray PW, Power CA, et al. CD4-independent infection by HIV-2 (ROD/B): use of the 7-transmembrane receptors CXCR-4, CCR-3, and V28 for entry. Virology 1997; 231: 130–4.PubMedCrossRefGoogle Scholar
  54. 54.
    Martin KA, Wyatt R, Farzan M, Choe H, Marcon L, Desjardins E, et al. CD4-independent binding of SIV gp 120 to rhesus CCR5. Science 1997; 278: 1470–3.PubMedCrossRefGoogle Scholar
  55. 55.
    Hesslegesser J, Halks-Miller M, DelVecchio V, Peiper SC, Hoxie J, Kolson DL, et al. CD4independent association between HIV-1 gp120 and CXCR4: functional chemokine receptors are expressed in human neurons. Curr Biol 1997; 7: 112–21.CrossRefGoogle Scholar
  56. 56.
    Bandres JC, Wang QF, O’Leary J, Baleaux F, Amara A, Hoxie JA, et al. Human immunodeficiency virus (HIV) envelope binds to CXCR4 independently of CD4, and binding can be enhanced by interaction with soluble CD4 or by HIV envelope deglycosylation. J Virol 1998; 72: 2500–4.PubMedGoogle Scholar
  57. 57.
    Potempa S, Picard L, Reeves JD, Wilkinson D, Weiss RA, Talbot SI. CD4-independent infection by human immunodeficiency virus type 2 strain ROD/B: the role of the N-terminal domain of CXCR-4 in fusion and entry. J Virol 1997; 71: 4419–24.PubMedGoogle Scholar
  58. 58.
    Reeves JD, Schulz TF. The CD4-independent tropism of human immunodeficiency virus type 2 involves several regions of the envelope protein and correlates with a reduced activation threshold for envelope-mediated fusion. J Virol 1997; 71: 1453–65.PubMedGoogle Scholar
  59. 59.
    Fauci AS. Host factors and the pathogenesis of HIV-induced disease. Nature 1996; 384: 529–34.PubMedCrossRefGoogle Scholar
  60. 60.
    Simonsen JN, Fowke KR, MacDonald KS, Plummer FA. HIV pathogenesis: mechanisms of susceptibility and disease progression. Curr Opin Microbiol 1998; 1: 423–9.PubMedCrossRefGoogle Scholar
  61. 61.
    Paxton WA, Martin SR, Tse D, O’Brien TR, Skurnick J, VanDevanter NL, et al. Relative resistance to HIV-1 of CD4 lymphocytes from persons who remain uninfected despite multiple high-risk sexual exposures. Nat Med 1996; 2: 412–7.PubMedCrossRefGoogle Scholar
  62. 62.
    Dragic T, Litwin V, Allaway GP, Martin SR, Huang Y, Nagashima KA, et al. HIV-1 entry into CD4+ cells is mediated by the chemokine receptor CC- CKR-5 [see comments]. Nature 1996; 381: 667–73.PubMedCrossRefGoogle Scholar
  63. 63.
    Liu R, Paxton WA, Choe S, Ceradini D, Martin SR, Horuk R, et al. Homozygous defect in HIV-1 coreceptor accounts for resistance of some multiply-exposed individuals to HIV-1 infection. Cell 1996; 86: 367–77.PubMedCrossRefGoogle Scholar
  64. 64.
    Samson M, Libert F, Doranz BJ, Rucker J, Liesnard C, Farber C-M, et al. Resistance to HIV-1 infection in caucasion individuals bearing mutant alleles of the CCR-5 chemokine receptor gene. Nature 1996; 332: 722–5.CrossRefGoogle Scholar
  65. 65.
    Dean M, Carrington M, Winkler C, Huttley GA, Smith MW, Allikmets R, et al. Genetic restriction of HIV-1 infection and progression to AIDS by a deletion allele of the CKR5 structural gene. Science 1996; 273: 1856–62.PubMedCrossRefGoogle Scholar
  66. 66.
    Zimmerman PA, Buckler-White A, Alkhatib G, Spalding T, Kubofcik J, Combadiere C, et al. Inherited resistance to HIV-1 conferred by an inactivating mutation in CC chemokine receptor 5: studies in populations with contrasting clinical phenotypes, defined racial background, and quantified risk. Mol Med 1997; 3: 23–36.PubMedGoogle Scholar
  67. 67.
    Benkirane M, Jin D, Chun RF, Koup RA, Jeang K. Mechanism of transdominant inhibition of CCR5-mediated HIV-1 infection by ccr5432. Biol Chem 1997; 272: 30603–6.CrossRefGoogle Scholar
  68. 68.
    Misrahi M, Teglas JP, N’Go N, Burgard M, Mayaux MJ, Rouzioux C, et al. CCR5 chemokine receptor variant in HIV-1 mother-to-child transmission and disease progression in children. French Pediatric HIV Infection Study Group [see comments]. JAMA 1998; 279: 277–80.PubMedCrossRefGoogle Scholar
  69. 69.
    Mangano A, Prada F, Roldan A, Picchio G, Bologna R, Sen L. Distribution of CCR-5 delta32 allele in Argentinian children at risk of HIV-1 infection: its role in vertical transmission [letter]. AIDS 1998; 12: 109–10.PubMedGoogle Scholar
  70. 70.
    Shearer WT, Kalish LA, Zimmerman PA. CCR5 HIV-1 vertical transmission. Women and Infants Transmission Study Group [letter]. J AIDS Hum Retrovirol 1998; 17: 180–1.Google Scholar
  71. 71.
    Rousseau CM, Just JJ, Abrams EJ, Casabona J, Stein Z, King MC. CCR5 de 132 in perinatal HIV-1 infection. J AIDS Hum Retrovirol 1997; 16: 239–42.Google Scholar
  72. 72.
    Huang Y, Paxton WA, Wolinsky SM, Neumann AU, Zhang L, He T, et al. The role of a mutant CCR5 allele in HIV-1 transmission and disease progression. Nat Med 1996; 2: 1240–3.PubMedCrossRefGoogle Scholar
  73. 73.
    Hoffman TL, MacGregor RR, Burger H, Mick R, Doms RW, Collman RG. CCR5 genotypes in sexually active couples discordant for human immunodeficiency virus type 1 infection status. J Infect Dis 1997; 176: 1093–6.PubMedCrossRefGoogle Scholar
  74. 74.
    Garred P. Chemokine-receptor polymorphisms: clarity or confusion for HIV-1 prognosis? [comment]. Lancet 1998; 351: 2–3.PubMedCrossRefGoogle Scholar
  75. 75.
    Libert F, Cochaux P, Beckman G, Samson M, Aksenova M, Cao A, et al. The deltaccr5 mutation conferring protection against HIV-1 in Caucasian populations has a single and recent origin in Northeastern Europe. Hum Mol Genet 1998; 7: 399–406.PubMedCrossRefGoogle Scholar
  76. 76.
    Stephens JC, Reich DE, Goldstein DB, Shin HD, Smith MW, Carrington M, et al. Dating the origin of the CCR5-delta32 AIDS-resistance allele by the coalescence of haplotypes. Am J Hum Genet 1998; 62: 1507–15.PubMedCrossRefGoogle Scholar
  77. 77.
    Martinson JJ, Chapman NH, Rees DC, Liu YT, Clegg JB. Global distribution of the CCR5 gene 32-basepair deletion. Nat Genet 1997; 16: 100–3.PubMedCrossRefGoogle Scholar
  78. 78.
    Carrington M, Kissner T, Gerrard B, Ivanov S, O’Brien SJ, Dean M. Novel alleles of the chemokine-receptor gene CCR5. Am J Hum Genet 1997; 61: 1261–7.PubMedCrossRefGoogle Scholar
  79. 79.
    O’Brien TR, Winkler C, Dean M, Nelson JA, Carrington M, Michael NL, et al. HIV-1 infection in a man homozygous for CCR5 delta 32. Lancet 1997; 349: 1219.PubMedCrossRefGoogle Scholar
  80. 80.
    Michael NL, Nelson JA, KewalRamani VN, Chang G, O’Brien SJ, Mascola JR, et al. Exclusive and persistent use of the entry coreceptor CXCR4 by human immunodeficiency virus type 1 from a subject homozygous for CCR5 delta32. J Virol 1998; 72: 6040–7.PubMedGoogle Scholar
  81. 81.
    Biti R, Ffrench R, Young J, Bennetts B, Stewart G, Liang T. HIV-1 infection in an individual homozygous for the CCR5 deletion allele. Nat Med 1997; 3: 252–3.PubMedCrossRefGoogle Scholar
  82. 82.
    Theodorou I, Meyer L, Magierowska M, Katlama C, Rouzioux C. HIV-1 infection in an individual homozygous for CCR5 delta 32. Seroco Study Group. Lancet 1997; 349: 1219–20.PubMedCrossRefGoogle Scholar
  83. 83.
    Garred P, Eugen-Olsen J, Iversen AK, Benfield TL, Svejgaard A, Hofmann B. Dual effect of CCR5 delta 32 gene deletion in HIV-1-infected patients. Copenhagen AIDS Study Group [letter] [see comments]. Lancet 1997; 349: 1884.PubMedCrossRefGoogle Scholar
  84. 84.
    Cohen OJ, Vaccarezza M, Lam GK, Baird BF, Wildt K, Murphy PM, et al. Heterozygosity for a defective gene for CC chemokine receptor 5 is not the sole determinant for the immunologic and virologic phenotype of HIV-infected long-term nonprogressors. J Clin Invest 1997; 100: 1581–99.PubMedCrossRefGoogle Scholar
  85. 85.
    Quillent C, Oberlin E, Braun J, Rousset D, Gonzalez-Canali G, Metais P, et al. HIV-1-resistance phenotype conferred by combination of two separate inherited mutations of CCR5 gene [see comments]. Lancet 1998; 351: 14–8.PubMedCrossRefGoogle Scholar
  86. 86.
    McDermott DH, Zimmerman PA, Guignard F, Kleeberger CA, Leitman SF, Murphy PM. CCR5 promoter polymorphism and HIV-1 disease progression. Multicenter AIDS Cohort Study (MACS). Lancet 1998; 352: 866–70.PubMedCrossRefGoogle Scholar
  87. 87.
    Mummidi S, Ahuja SS, McDaniel BL, Ahuja SK. The human CC chemokine receptor 5 (CCR5) gene. Multiple transcripts with 5’-end heterogeneity, dual promoter usage, and evidence for polymorphisms within the regulatory regions and noncoding exons. J Biol Chem 1997; 272: 30662–71.PubMedCrossRefGoogle Scholar
  88. 88.
    Martin MP, Dean M, Smith MW, Winkler C, Gerrard B, Michael NL, et al. Genetic acceleration of AIDS progression by a promoter variant of CCR5. Science 1998; 282: 1907–11.PubMedCrossRefGoogle Scholar
  89. 89.
    Easterbrook PJ, Rostron T, Ives N, Troop M, Gazzard BG, Rowland-Jones SL. Chemokine Receptor Polymorphisms and Human Immunodeficiency Virus Disease Progression. J Infect Dis 1999; 180: 1096–105.PubMedCrossRefGoogle Scholar
  90. 90.
    Smith MW, Dean M, Carrington M, Winkler C, Huttley GA, Lomb DA, et al. Contrasting genetic influence of CCR2 and CCR5 variant on HIV-1 infection and disease progression. Science 1997; 277: 959–65.PubMedCrossRefGoogle Scholar
  91. 91.
    Rizzardi GP, Morawetz RA, Vicenzi E, Ghezzi S, Poli G, Lazzarin A, et al. CCR2 polymorphism and HIV disease. Nat Med 1998; 4: 252–3.PubMedCrossRefGoogle Scholar
  92. 92.
    Kostrikis LG, Huang Y, Moore JP, Wolinsky SM, Zhang L, Guo YI, et al. A chemokine receptor CCR2 allele delays HIV-1 disease progression and is associated with a CCR5 promoter mutation. Nat Med 1998; 4: 350.PubMedCrossRefGoogle Scholar
  93. 93.
    Anzala AO, Ball TB, Rostron T, O’Brien SJ, Plummer FA, Rowland-Jones SL. CCR2–64I allele and genotype association with delayed AIDS progression in African women. University of Nairobi Collaboration for HIV Research [letter]. Lancet 1998; 351: 1632–3.PubMedCrossRefGoogle Scholar
  94. 94.
    Michael NL, Louie LG, Rohrbaugh AL, Schultz KA, Dayhoff DE, Wang CE, et al. The role of CCR5 and CCR2 polymorphisms in HIV-1 transmission and disease progression [see comments]. Nat Med 1997; 3: 1160–2.PubMedCrossRefGoogle Scholar
  95. 95.
    Eugen-Olsen J, Iversen AK, Benfield TL, Koppelhus U, Garred P. Chemokine receptor CCR2b 64I polymorphism and its relation to CD4 T- cell counts and disease progression in a Danish cohort of HIV-infected individuals. Copenhagen AIDS cohort. J AIDS Hum Retrovirol 1998; 18: 110–6.Google Scholar
  96. 96.
    Lee B, Doranz BJ, Rana S, Yi Y, Mellado M, Rade JM, et al. Influence of the CCR2–V64I polymorphism on human immunodeficiency virus type 1 coreceptor activity and on chemokine receptor function of CCR2b, CCR3, CCR5, and CXCR4. J Virol 1998; 72: 7450–8.PubMedGoogle Scholar
  97. 97.
    Mummidi S, Ahuja SS, Gonzalez E, Anderson SA, Santiago EN, Stephan KT, et al. Genealogy of the CCR5 locus and chemokine system gene variants associated with altered rates of HIV-1 disease progression. Nat Med 1998; 4: 786.PubMedCrossRefGoogle Scholar
  98. 98.
    Samson M, Soularue P, Vassart G, Parmentier M. The genes encoding the human CCchemokine receptors CC-CKR1 to CC-CKR5 (CMKBR1–CMKBR5) are clustered in the p21.3-p24 region of chromosome 3. Genomics 1996; 36: 522–6.PubMedCrossRefGoogle Scholar
  99. 99.
    Walker CM, Levy JA. A diffusible lymphokine produced by CD8+ T lymphocytes suppresses HIV replication. Immunology 1989; 66: 628–30.PubMedGoogle Scholar
  100. 100.
    Walker CM, Moody DJ, Stites DP, Levy JA. CD8+ lymphocytes can control HIV infection in vitro by suppressing virus replication. Science 1986; 234: 1563–6.PubMedCrossRefGoogle Scholar
  101. 101.
    Bleul CC, Farzan M, Choe H, Parolin C, Clark-Lewis I, Sodroski J, et al. The lymphocyte chemoattractant SDF-1 is a ligand for LESTR/fusin and blocks HIV-1 entry. Nature 1996; 382: 829–33.PubMedCrossRefGoogle Scholar
  102. 102.
    Oberlin E, Amara A, Bachelerie F, Bessia C, Virelizier J-L, Arenzana-Seisdedos F, et al. The CXC chemokine SDF-1 is the ligand for LESTR/fusin and prevents infection by T-cell-lineadapted HIV-1. Nature 1996; 382: 833–5.PubMedCrossRefGoogle Scholar
  103. 103.
    Pal R, Garzino-Demo A, Markham PD, Burns J, Brown M, Gallo RC, et al. Inhibition of HIV-1 infection by the ß-chemokine MDC. Science 1997; 278: 695–8.PubMedCrossRefGoogle Scholar
  104. 104.
    Lee B, Rucker J, Doms RW, Tsang M, Hu X, Dietz M, et al. (3-chemokine MDC and HIV-1 infection. Science 1998; 281 (Technical Comments): 487a.CrossRefGoogle Scholar
  105. 105.
    Murakami T, Nakajima T, Koyanagi Y, Tachibana K, Fujii N, Tamamura H, et al. A small molecule CXCR4 inhibitor that blocks T cell line-tropic HIV-1 infection. J Exp Med 1997; 186: 1389–93.PubMedCrossRefGoogle Scholar
  106. 106.
    Doranz BJ, Grovit-Ferbas K, Sharron MP, Mao S-H, Goetz MB, Daar ES, et al. A small-molecule inhibitor directed against the chemokine receptor CXCR4 prevents its use as an HIV-1 coreceptor. J Exp Med 1997; 186: 1395–400.PubMedCrossRefGoogle Scholar
  107. 107.
    Schols D, Struyf S, Van Damme J, Este JA, Henson G, De Clercq E. Inhibition of T-tropic HIV strains by selective antagonization of the chemokine receptor CXCR4. J Exp Med 1997; 186: 1383–8.PubMedCrossRefGoogle Scholar
  108. 108.
    Donzella GA, Schols D, Lin SW, Este JA, Nagashima KA, Maddon PJ, et al. AMD3100, a small molecule inhibitor of HIV-1 entry via the CXCR4 co-receptor. Nature Medicine 1998; 4: 72–7.PubMedCrossRefGoogle Scholar
  109. 109.
    Heveker N, Montes M, Germeroth L, Amara A, Trautmann A, Alizon M, et al. Dissociation of the signalling and antiviral properties of SDF-1-derived small peptides. Curr Biol 1998; 7: 369–76.CrossRefGoogle Scholar
  110. 110.
    Mack M, Luckow B, Nelson PJ, Cihak J, Simmons G, Clapham PR, et al. Aminooxypentane RANTES induces CCR5 internalization but inhibits recycling: a novel inhibitory mechanism of HIV infectivity. J Exp Med 1998; 187: 1215–24.PubMedCrossRefGoogle Scholar
  111. 111.
    Simmons G, Clapham P, Picard L, Offord RE, Rosenkilde MM, Schwarta TW, et al. Potent inhibition of HIV-1 infectivity in macrophages and lymphocytes by a novel CCR5 antagonist. Science 1997; 276: 276–9.PubMedCrossRefGoogle Scholar
  112. 112.
    Yang OO, Swanberg SL, Lu Z, Dziejman M, McCoy J, Luster AD, et al. Enhanced inhibiton of HIV-1 by Met-SDF-13 correlates with down-modulation of CXCR4. J Virol 1999; 73: 4582–9.PubMedGoogle Scholar
  113. 113.
    Howard OMZ, Korte T, Tarasova NI, Grimm M, Turpin JA, Rice WG, et al. Small molecule inhibitor of HIV-1 cell fusion blocks chemokine receptor-mediated function. J Leuk Biol 1998; 64: 6–13.Google Scholar
  114. 114.
    Signoret N, Oldridge J, Pelchen-Matthews A, Klasse PJ, Tran T, Brass LF, et al. Phorbol esters and SDF-1 induce rapid endocytosis and down modulation of the chemokine receptor CXCR4. J Cell Biol 1997; 139: 651–64.PubMedCrossRefGoogle Scholar
  115. 115.
    Amara A, Le Gall S, Schwartz O, Salamero J, Montes M, Loetscher P, et al. HIV coreceptor downregulation as antiviral principle: SDF-la-dependent internalization of the chemokine receptor CXCR4 contributes to inhibition of HIV replication. J Exp Med 1997; 186: 139–46.PubMedCrossRefGoogle Scholar
  116. 116.
    Tanaka Y, Adams DH, Hubscher S, Hirano H, Siebenlist U, Shaw S. T-cell adhesion induced by proteoglcan-immobilized cytokine MIP-113. Nature 1993; 361: 79–82.PubMedCrossRefGoogle Scholar
  117. 117.
    Rot A. Endothelial cell binding of NAP-1/IL-8: role in neutrophil emigration. Immunol Today 1992; 13: 291–4.PubMedCrossRefGoogle Scholar
  118. 118.
    Luster AD, Greenberg S, Leder P. The IP-10 chemokine binds to a specific cell surface heparan sulfate site shared with platelet factor 4 and inhibits endothelial cell proliferation. J Exp Med 1995; 182: 219–31.PubMedCrossRefGoogle Scholar
  119. 119.
    Middleton J, Neil S, Wintle J, Clark-Lewis I, Moore H, Lam C, et al. Transcytosis and surface presentation of IL-8 by venular endothelial cells. Cell 1997; 91: 385–95.PubMedCrossRefGoogle Scholar
  120. 120.
    Wagner L, Yang OO, Garcia-Zepeda EA, Ge Y, Kalams S, Walker BD, et al. 3-Chemokines are released from HIV-1 specific cytolytic T-cell granules complexed to proteoglycans. Nature 1998; 391: 908–11.PubMedCrossRefGoogle Scholar
  121. 121.
    Oravez T, Pall M, Wang J, Roderiquez G, Ditto M, Norcross MA. Regulation of anti-HIV-1 activity of RANTES by heparan sulfate proteoglycans. J Immunol 1997; 159: 4587–92.Google Scholar
  122. 122.
    Burns JM, Gallo RC, DeVico AL, Lewis GK. A new monoclonal antibody, mAb 4Al2, identifies a role for the glycosaminoglycan (GAG) binding domain of RANTES in the antiviral effect against HIV-1 and intracellular Ca2+ signaling. J Exp Med 1998; 188: 1917–27.PubMedCrossRefGoogle Scholar
  123. 123.
    Gallo RC, Garzino-Demo A, DeVico AL. HIV infection and pathogenesis: what about chemokines? J Clin Immunol 1999; 19: 293–9.PubMedCrossRefGoogle Scholar
  124. 124.
    Paxton WA, Liu R, Kang S, Wu L, Gingeras TR, Landau NR, et al. Reduced HIV-1 infectability of CD4+ lymphocytes from exposed-uninfected individuals: association with low expression of CCR5 and high production of beta-chemokines. Virology 1998; 25: 66–73.CrossRefGoogle Scholar
  125. 125.
    Zagury D, Lachgar A, Chams V, Fall LS, Bernard J, Zagury JF, et al. C-C chemokines, pivotal in protection against HIV type 1 infection. Proc Natl Acad Sci USA 1998; 7: 3857–61.CrossRefGoogle Scholar
  126. 125a.
    Saja K, Bentsman G, Chess L, and Volsky DJ. Endogenous production of 3-chemokines by CD4+ but not CD8, T-cell clones correlates with the clinical state of human immunodeficiency virus type I (HIV-I). Infected individuals and may be responsible for blocking infection with nonsynctium-inducing HIV-I in vitro. J Virol 1998; 876–81.Google Scholar
  127. 126.
    Winkler C, Modi W, Smith MW, Nelson GW, Wu X, Carrington M, et al. Genetic restriction of AIDS pathogenesis by an SDF-1 chemokine gene variant. Science 1998; 279: 389–93.PubMedCrossRefGoogle Scholar
  128. 127.
    Kilby J, Hopkins S, Venetta T, DiMassimo B, Cloud G, Lee J, et al. Potent suppression of HIV-1 replication in humans by T-20, a peptide inhibitor of gp41-mediated virus entry. Nat Med 1998; 4: 1302–7.PubMedCrossRefGoogle Scholar
  129. 128.
    Cairns JS, D’Sousa MP. Chemokines and HIV-1 second receptors: the therapeutic connection. Nat Med 1998; 5: 563–8.CrossRefGoogle Scholar
  130. 129.
    Levine BL, Mosca JD, Riley JL, Carroll RG, Vahey MT, Jagodzinski LL, et al. Antiviral effect and ex vivo CD4+ T cell proliferation in HIV-positive patients as a result of CD28 costimulation. Science 1996; 272: 1939–43.PubMedCrossRefGoogle Scholar
  131. 130.
    Carroll RG, Riley JL, Levine BL, Feng Y, Kaushal S, Ritchey DW, et al. Differential regulation of HIV-1 fusion cofactor expression by CD28 costimulation of CD4+ T cells. Science 1997; 276: 273–6.PubMedCrossRefGoogle Scholar
  132. 131.
    De Clercq E, Yamamoto N, Pauwels R, Balzarini J, Witvrouw M, De Vreese K, et al. Highly potent and selective inhibition of human immunodeficiency virus by the bicyclam derivative JM3100. Antimicrob Agents Chemother 1994; 38: 668–74.PubMedCrossRefGoogle Scholar

Copyright information

© Humana Press Inc., Totowa, NJ 2001

Authors and Affiliations

  • Frederick S. Lee
  • Gabriele Kuschert
  • Otto O. Yang
  • Andrew D. Luster

There are no affiliations available

Personalised recommendations