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CCL3L1 and CCR5 influence cell-mediated immunity and affect HIV-AIDS pathogenesis via viral entry-independent mechanisms

Nature Immunology volume 8, pages 1324–1336 (2007)Cite this article

Abstract

Although host defense against human immunodeficiency virus 1 (HIV-1) relies mainly on cell-mediated immunity (CMI), the determinants of CMI in humans are poorly understood. Here we demonstrate that variations in the genes encoding the chemokine CCL3L1 and HIV coreceptor CCR5 influence CMI in both healthy and HIV-infected individuals. CCL3L1-CCR5 genotypes associated with altered CMI in healthy subjects were similar to those that influence the risk of HIV transmission, viral burden and disease progression. However, CCL3L1-CCR5 genotypes also modify HIV clinical course independently of their effects on viral load and CMI. These results identify CCL3L1 and CCR5 as major determinants of CMI and demonstrate that these host factors influence HIV pathogenesis through their effects on both CMI and other viral entry–independent mechanisms.

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Figure 1: Relative contributions of steady-state viral load, baseline CD4+ T cell count and CCL3L1-CCR5 genetic risk group (GRG) status to intersubject variability in the rate of progression to AIDS (1987 criteria) and decrease in CD4+ T cell numbers.
Figure 2: Association of CCL3L1-CCR5 GRG status with viral load during early disease, with AIDS-free status and with CD4+ T cell loss.
Figure 3: Viral load–independent association of CCL3L1-CCR5 GRG status with the rate and extent of CD4+ T cell loss as well as with the rate of progression to AIDS for WHMC HIV+ subjects.
Figure 4: Association of CCL3L1-CCR5 GRG status with CMI status, as assessed by DTH skin test reactivity, for WHMC HIV+ subjects before and during HAART.
Figure 5: CCL3L1-CCR5 genotypes that influence DTH responses in HIV− subjects can be used to predict HIV disease course, and Ccr5-null mice have impaired DTH responses to KLH.
Figure 6: CCL3L1 copy number and CCR5 genotype have additive effects on DTH responses and can be used to predict risk of HIV transmission, steady-state viral load and disease progression rate.

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References

  1. Douek, D.C., Picker, L.J. & Koup, R.A. T cell dynamics in HIV-1 infection. Annu. Rev. Immunol. 21, 265–304 (2003).

    Article  CAS  PubMed  Google Scholar 

  2. Li, Q. et al. Peak SIV replication in resting memory CD4+ T cells depletes gut lamina propria CD4+ T cells. Nature 434, 1148–1152 (2005).

    Article  CAS  PubMed  Google Scholar 

  3. Rodriguez, B. et al. Predictive value of plasma HIV RNA level on rate of CD4 T-cell decline in untreated HIV infection. J. Am. Med. Assoc. 296, 1498–1506 (2006).

    Article  CAS  Google Scholar 

  4. Pandrea, I. et al. Paucity of CD4+CCR5+ T cells is a typical feature of natural SIV hosts. Blood 109, 1069–1076 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Moore, J.P., Kitchen, S.G., Pugach, P. & Zack, J.A. The CCR5 and CXCR4 coreceptors–central to understanding the transmission and pathogenesis of human immunodeficiency virus type 1 infection. AIDS Res. Hum. Retroviruses 20, 111–126 (2004).

    Article  CAS  PubMed  Google Scholar 

  6. Lederman, M.M., Penn-Nicholson, A., Cho, M. & Mosier, D. Biology of CCR5 and its role in HIV infection and treatment. J. Am. Med. Assoc. 296, 815–826 (2006).

    Article  CAS  Google Scholar 

  7. Nibbs, R.J., Yang, J., Landau, N.R., Mao, J.H. & Graham, G.J. LD78beta, a non-allelic variant of human MIP-1alpha (LD78alpha), has enhanced receptor interactions and potent HIV suppressive activity. J. Biol. Chem. 274, 17478–17483 (1999).

    Article  CAS  PubMed  Google Scholar 

  8. Gonzalez, E. et al. The influence of CCL3L1 gene-containing segmental duplications on HIV-1/AIDS susceptibility. Science 307, 1434–1440 (2005).

    Article  CAS  PubMed  Google Scholar 

  9. Kaslow, R.A., Dorak, T. & Tang, J.J. Influence of host genetic variation on susceptibility to HIV type 1 infection. J. Infect. Dis. 191 Suppl 1, S68–S77 (2005).

    Article  PubMed  Google Scholar 

  10. Mummidi, S. et al. Genealogy of the CCR5 locus and chemokine system gene variants associated with altered rates of HIV-1 disease progression. Nat. Med. 4, 786–793 (1998).

    Article  CAS  PubMed  Google Scholar 

  11. Mangano, A. et al. Concordance between the CC chemokine receptor 5 genetic determinants that alter risks of transmission and disease progression in children exposed perinatally to human immunodeficiency virus. J. Infect. Dis. 183, 1574–1585 (2001).

    Article  CAS  PubMed  Google Scholar 

  12. Gonzalez, E. et al. Race-specific HIV-1 disease-modifying effects associated with CCR5 haplotypes. Proc. Natl. Acad. Sci. USA 96, 12004–12009 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Martin, M.P. et al. Genetic acceleration of AIDS progression by a promoter variant of CCR5. Science 282, 1907–1911 (1998).

    Article  CAS  PubMed  Google Scholar 

  14. Hladik, F. et al. Combined effect of CCR5-Delta32 heterozygosity and the CCR5 promoter polymorphism -2459 A/G on CCR5 expression and resistance to human immunodeficiency virus type 1 transmission. J. Virol. 79, 11677–11684 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Salkowitz, J.R. et al. CCR5 promoter polymorphism determines macrophage CCR5 density and magnitude of HIV-1 propagation in vitro. Clin. Immunol. 108, 234–240 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Taub, D.D. et al. Beta chemokines costimulate lymphocyte cytolysis, proliferation, and lymphokine production. J. Leukoc. Biol. 59, 81–89 (1996).

    Article  CAS  PubMed  Google Scholar 

  17. Karpus, W.J. et al. Differential CC chemokine-induced enhancement of T helper cell cytokine production. J. Immunol. 158, 4129–4136 (1997).

    CAS  PubMed  Google Scholar 

  18. Zou, W. et al. Macrophage-derived dendritic cells have strong Th1-polarizing potential mediated by beta-chemokines rather than IL-12. J. Immunol. 165, 4388–4396 (2000).

    Article  CAS  PubMed  Google Scholar 

  19. Pinto, L.A., Williams, M.S., Dolan, M.J., Henkart, P.A. & Shearer, G.M. Beta-chemokines inhibit activation-induced death of lymphocytes from HIV-infected individuals. Eur. J. Immunol. 30, 2048–2055 (2000).

    Article  CAS  PubMed  Google Scholar 

  20. Luther, S.A. & Cyster, J.G. Chemokines as regulators of T cell differentiation. Nat. Immunol. 2, 102–107 (2001).

    Article  CAS  PubMed  Google Scholar 

  21. Moser, B. & Loetscher, P. Lymphocyte traffic control by chemokines. Nat. Immunol. 2, 123–128 (2001).

    Article  CAS  PubMed  Google Scholar 

  22. Lillard, J.W., Jr. et al. MIP-1alpha and MIP-1beta differentially mediate mucosal and systemic adaptive immunity. Blood 101, 807–814 (2003).

    Article  CAS  PubMed  Google Scholar 

  23. Molon, B. et al. T cell costimulation by chemokine receptors. Nat. Immunol. 6, 465–471 (2005).

    Article  CAS  PubMed  Google Scholar 

  24. Castellino, F. et al. Chemokines enhance immunity by guiding naive CD8+ T cells to sites of CD4+ T cell–dendritic cell interaction. Nature 440, 890–895 (2006).

    Article  CAS  PubMed  Google Scholar 

  25. Amella, C.A., Sherry, B., Shepp, D.H. & Schmidtmayerova, H. Macrophage inflammatory protein 1alpha inhibits postentry steps of human immunodeficiency virus type 1 infection via suppression of intracellular cyclic AMP. J. Virol. 79, 5625–5631 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Zhang, Z.Q. et al. The impact of early immune destruction on the kinetics of postacute viral replication in rhesus monkey infected with the simian-human immunodeficiency virus 89.6P. Virology 320, 75–84 (2004).

    Article  CAS  PubMed  Google Scholar 

  27. Bonhoeffer, S., Funk, G.A., Gunthard, H.F., Fischer, M. & Muller, V. Glancing behind virus load variation in HIV-1 infection. Trends Microbiol. 11, 499–504 (2003).

    Article  CAS  PubMed  Google Scholar 

  28. Mellors, J.W. et al. Plasma viral load and CD4+ lymphocytes as prognostic markers of HIV-1 infection. Ann. Intern. Med. 126, 946–954 (1997).

    Article  CAS  PubMed  Google Scholar 

  29. Mellors, J.W. et al. Prognosis in HIV-1 infection predicted by the quantity of virus in plasma. Science 272, 1167–1170 (1996).

    Article  CAS  PubMed  Google Scholar 

  30. Migueles, S.A. et al. HLA B*5701 is highly associated with restriction of virus replication in a subgroup of HIV-infected long term nonprogressors. Proc. Natl. Acad. Sci. USA 97, 2709–2714 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Altfeld, M. et al. Influence of HLA-B57 on clinical presentation and viral control during acute HIV-1 infection. AIDS 17, 2581–2591 (2003).

    Article  CAS  PubMed  Google Scholar 

  32. Betts, M.R. et al. HIV nonprogressors preferentially maintain highly functional HIV-specific CD8+ T cells. Blood 107, 4781–4789 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Kim, S. et al. Both serum HIV type 1 RNA levels and CD4+ lymphocyte counts predict clinical outcome in HIV type 1-infected subjects with 200 to 500 CD4+ cells per cubic millimeter. AIDS Clinical Trials Group Study 175 Virology Study Team. AIDS Res. Hum. Retroviruses 16, 645–653 (2000).

    Article  CAS  PubMed  Google Scholar 

  34. Gandhi, R.T. & Walker, B.D. Immunologic control of HIV-1. Annu. Rev. Med. 53, 149–172 (2002).

    Article  CAS  PubMed  Google Scholar 

  35. Birx, D.L. et al. The prognostic utility of delayed-type hypersensitivity skin testing in the evaluation of HIV-infected patients. Military Medical Consortium for Applied Retroviral Research. J. Acquir. Immune Defic. Syndr. 6, 1248–1257 (1993).

    CAS  PubMed  Google Scholar 

  36. Blatt, S.P. et al. Delayed-type hypersensitivity skin testing predicts progression to AIDS in HIV-infected patients. Ann. Intern. Med. 119, 177–184 (1993).

    Article  CAS  PubMed  Google Scholar 

  37. Dolan, M.J. et al. In vitro T cell function, delayed-type hypersensitivity skin testing, and CD4+ T cell subset phenotyping independently predict survival time in patients infected with human immunodeficiency virus. J. Infect. Dis. 172, 79–87 (1995).

    Article  CAS  PubMed  Google Scholar 

  38. Kniker, W.T., Anderson, C.T., McBryde, J.L., Roumiantzeff, M. & Lesourd, B. Multitest CMI for standardized measurement of delayed cutaneous hypersensitivity and cell-mediated immunity. Normal values and proposed scoring system for healthy adults in the U.S.A. Ann. Allergy 52, 75–82 (1984).

    CAS  PubMed  Google Scholar 

  39. Maas, J.J. et al. In vivo delayed-type hypersensitivity skin test anergy in human immunodeficiency virus type 1 infection is associated with T cell nonresponsiveness in vitro. J. Infect. Dis. 178, 1024–1029 (1998).

    Article  CAS  PubMed  Google Scholar 

  40. Gordin, F.M. et al. Delayed-type hypersensitivity skin tests are an independent predictor of human immunodeficiency virus disease progression. Department of Veterans Affairs Cooperative Study Group. J. Infect. Dis. 169, 893–897 (1994).

    Article  CAS  PubMed  Google Scholar 

  41. Smith, A. et al. Does genotype mask the relationship between psychological factors and immune function? Brain Behav. Immun. 19, 147–152 (2005).

    Article  CAS  PubMed  Google Scholar 

  42. Mummidi, S. et al. Evolution of human and non-human primate CC chemokine receptor 5 gene and mRNA. Potential roles for haplotype and mRNA diversity, differential haplotype-specific transcriptional activity, and altered transcription factor binding to polymorphic nucleotides in the pathogenesis of HIV-1 and simian immunodeficiency virus. J. Biol. Chem. 275, 18946–18961 (2000).

    Article  CAS  PubMed  Google Scholar 

  43. Brenchley, J.M., Price, D.A. & Douek, D.C. HIV disease: fallout from a mucosal catastrophe? Nat. Immunol. 7, 235–239 (2006).

    Article  CAS  PubMed  Google Scholar 

  44. Gilbert, P.B. et al. What constitutes efficacy for a human immunodeficiency virus vaccine that ameliorates viremia: issues involving surrogate end points in phase 3 trials. J. Infect. Dis. 188, 179–193 (2003).

    Article  PubMed  Google Scholar 

  45. Abel, L. & Casanova, J.L. Human genetics of infectious diseases: Fundamental insights from clinical studies. Semin. Immunol. 18, 327–329 (2006).

    Article  PubMed  Google Scholar 

  46. Koning, F.A. et al. Low-level CD4+ T cell activation is associated with low susceptibility to HIV-1 infection. J. Immunol. 175, 6117–6122 (2005).

    Article  CAS  PubMed  Google Scholar 

  47. van Asten, L. et al. Pre-seroconversion immune status predicts the rate of CD4 T cell decline following HIV infection. AIDS 18, 1885–1893 (2004).

    Article  PubMed  Google Scholar 

  48. Martin, M.P. et al. Innate partnership of HLA-B and KIR3DL1 subtypes against HIV-1. Nat. Genet. 39, 733–740 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Dunham, R. et al. The AIDS resistance of naturally SIV-infected sooty mangabeys is independent of cellular immunity to the virus. Blood 108, 209–217 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Duggal, P. et al. The effect of RANTES chemokine genetic variants on early HIV-1 plasma RNA among African American injection drug users. J. Acquir. Immune Defic. Syndr. 38, 584–589 (2005).

    Article  CAS  PubMed  Google Scholar 

  51. Qi, Y. et al. KIR/HLA pleiotropism: protection against both HIV and opportunistic infections. PLoS Pathog 2, e79 (2006).

    Article  PubMed  PubMed Central  Google Scholar 

  52. Fellay, J. et al. A whole-genome association study of major determinants for host control of HIV-1. Science 317, 944–947 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Kuziel, W.A. et al. CCR5 deficiency is not protective in the early stages of atherogenesis in apoE knockout mice. Atherosclerosis 167, 25–32 (2003).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The people and funding agencies that made this work possible are in the Supplementary Note online.

Author information

Author notes

  1. Matthew J Dolan and Hemant Kulkarni: These authors contributed equally to this work.

Authors and Affiliations

  1. Infectious Disease Clinical Research Program, Wilford Hall United States Air Force Medical Center, Lackland Air Force Base, 78236, Texas, USA

    Matthew J Dolan, Vincent Marconi, Stephanie A Anderson, Judith Delmar, Robert J O'Connell & Brian K Agan

  2. Infectious Diseases Service, Wilford Hall United States Air Force Medical Center, Lackland Air Force Base, 78236, Texas, USA

    Matthew J Dolan, Vincent Marconi, Stephanie A Anderson, Judith Delmar, Robert J O'Connell & Brian K Agan

  3. Henry M. Jackson Foundation, Wilford Hall United States Air Force Medical Center, Lackland Air Force Base, 78236, Texas, USA

    Matthew J Dolan, Stephanie A Anderson & Brian K Agan

  4. and Department of Medicine, Veterans Administration Research Center for AIDS and HIV-1 Infection, South Texas Veterans Health Care System, University of Texas Health Science Center at San Antonio, San Antonio, 78229, Texas, USA

    Hemant Kulkarni, Jose F Camargo, Weijing He, Manju Mamtani, Robert A Clark, Seema S Ahuja & Sunil K Ahuja

  5. School of Psychology, University of Western Sydney, Penrith Sth, 1797, New South Wales, Australia

    Alison Smith

  6. Cellular Biology and Immunogenetics Unit, Corporación para Investigaciones Biologicas–University of Rosario, Cra 72 78-B-141, Medellin, Colombia

    Juan-Manuel Anaya

  7. Partners AIDS Research Center, Massachusetts General Hospital, Boston, 02114, Massachusetts, USA

    Toshiyuki Miura, Florencia Pereyra & Bruce D Walker

  8. Division of AIDS, Harvard Medical School, Boston, 02114, Massachusetts, USA

    Toshiyuki Miura, Florencia Pereyra & Bruce D Walker

  9. Howard Hughes Medical Institute, Chevy Chase, 20815, Maryland, USA

    Toshiyuki Miura, Florencia Pereyra & Bruce D Walker

  10. Department of Medicine, University of California, and San Francisco General Hospital, San Francisco, 94110, California, USA

    Frederick M Hecht & Steven G Deeks

  11. Laboratorio de Biología Celular y Retrovirus, Hospital de Pediatría “J.P. Garrahan”, Buenos Aires, 1245, Argentina

    Andrea Mangano & Luisa Sen

  12. Servicio de Infectología, Hospital de Pediatría “J.P. Garrahan”, Buenos Aires, 1245, Argentina

    Rosa Bologna

  13. School of Medical Sciences, University of New South Wales, Sydney, 2052, New South Wales, Australia

    Andrew Lloyd

  14. Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, 94107, California, USA

    Jeffrey Martin

  15. Department of Microbiology & Immunology and Department of Biochemistry, University of Texas Health Science Center at San Antonio, San Antonio, 78229, Texas, USA

    Sunil K Ahuja

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  1. Matthew J Dolan
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Contributions

M.J.D., H.K. and S.K.A. conceptualized the research, conducted statistical analyses, analyzed the data and wrote the manuscript. J.F.C., W.H., A.S., J.-M.A., T.M., F.M.H., M.M. and F.P. made substantial and equivalent contributions to experimental data, analysis of data, preparation of the manuscript and/or cohort data. V.M., A.M., L.S., R.B., R.A.C., S.A.A., J.D., R.J.O., A.L., J.M., S.S.A., B.K.A., B.D.W. and S.G.D. also provided cohorts and data, important conceptual ideas and contributed to the preparation of the manuscript. M.J.D. and S.K.A. directed the study and obtained the funding for the genetic work.

Corresponding authors

Correspondence to Matthew J Dolan or Sunil K Ahuja.

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Dolan, M., Kulkarni, H., Camargo, J. et al. CCL3L1 and CCR5 influence cell-mediated immunity and affect HIV-AIDS pathogenesis via viral entry-independent mechanisms. Nat Immunol 8, 1324–1336 (2007). https://doi.org/10.1038/ni1521

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