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. 1998 May 1;101(9):1876–1880. doi: 10.1172/JCI2015

Blockade of CC chemokine receptor 5 (CCR5)-tropic human immunodeficiency virus-1 replication in human lymphoid tissue by CC chemokines.

L B Margolis 1, S Glushakova 1, J C Grivel 1, P M Murphy 1
PMCID: PMC508773  PMID: 9576751

Abstract

The CC chemokines MIP-1alpha, MIP-1beta, and RANTES suppress replication of certain HIV-1 strains in cultured PBMC and T cell lines by blocking interaction of gp120 with CC chemokine receptor 5 (CCR5). However, the same chemokines can enhance HIV-1 replication in cultured macrophages. The net effect of chemokines on HIV-1 infection in intact lymphoid tissue, the major reservoir of HIV-1 in vivo, is unknown and unpredictable since the tissue contains both T lymphocytes and macrophages. Here we show that exogenous MIP-1alpha, MIP-1beta, and RANTES markedly suppressed replication of CCR5-tropic HIV-1 strains in blocks of human lymphoid tissue infected ex vivo. Moreover, endogenous MIP-1alpha, MIP-1beta, and RANTES were upregulated in tissues infected ex vivo with CXC chemokine receptor 4-tropic but not CCR5-tropic HIV-1. Such an upregulation may contribute to the virus phenotype shift in the course of HIV disease in vivo.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Alkhatib G., Combadiere C., Broder C. C., Feng Y., Kennedy P. E., Murphy P. M., Berger E. A. CC CKR5: a RANTES, MIP-1alpha, MIP-1beta receptor as a fusion cofactor for macrophage-tropic HIV-1. Science. 1996 Jun 28;272(5270):1955–1958. doi: 10.1126/science.272.5270.1955. [DOI] [PubMed] [Google Scholar]
  2. Berger E. A. HIV entry and tropism: the chemokine receptor connection. AIDS. 1997;11 (Suppl A):S3–16. [PubMed] [Google Scholar]
  3. Choe H., Farzan M., Sun Y., Sullivan N., Rollins B., Ponath P. D., Wu L., Mackay C. R., LaRosa G., Newman W. The beta-chemokine receptors CCR3 and CCR5 facilitate infection by primary HIV-1 isolates. Cell. 1996 Jun 28;85(7):1135–1148. doi: 10.1016/s0092-8674(00)81313-6. [DOI] [PubMed] [Google Scholar]
  4. Cocchi F., DeVico A. L., Garzino-Demo A., Arya S. K., Gallo R. C., Lusso P. Identification of RANTES, MIP-1 alpha, and MIP-1 beta as the major HIV-suppressive factors produced by CD8+ T cells. Science. 1995 Dec 15;270(5243):1811–1815. doi: 10.1126/science.270.5243.1811. [DOI] [PubMed] [Google Scholar]
  5. Combadiere C., Ahuja S. K., Tiffany H. L., Murphy P. M. Cloning and functional expression of CC CKR5, a human monocyte CC chemokine receptor selective for MIP-1(alpha), MIP-1(beta), and RANTES. J Leukoc Biol. 1996 Jul;60(1):147–152. doi: 10.1002/jlb.60.1.147. [DOI] [PubMed] [Google Scholar]
  6. Dean M., Carrington M., Winkler C., Huttley G. A., Smith M. W., Allikmets R., Goedert J. J., Buchbinder S. P., Vittinghoff E., Gomperts E. Genetic restriction of HIV-1 infection and progression to AIDS by a deletion allele of the CKR5 structural gene. Hemophilia Growth and Development Study, Multicenter AIDS Cohort Study, Multicenter Hemophilia Cohort Study, San Francisco City Cohort, ALIVE Study. Science. 1996 Sep 27;273(5283):1856–1862. doi: 10.1126/science.273.5283.1856. [DOI] [PubMed] [Google Scholar]
  7. Deng H., Liu R., Ellmeier W., Choe S., Unutmaz D., Burkhart M., Di Marzio P., Marmon S., Sutton R. E., Hill C. M. Identification of a major co-receptor for primary isolates of HIV-1. Nature. 1996 Jun 20;381(6584):661–666. doi: 10.1038/381661a0. [DOI] [PubMed] [Google Scholar]
  8. Dragic T., Litwin V., Allaway G. P., Martin S. R., Huang Y., Nagashima K. A., Cayanan C., Maddon P. J., Koup R. A., Moore J. P. HIV-1 entry into CD4+ cells is mediated by the chemokine receptor CC-CKR-5. Nature. 1996 Jun 20;381(6584):667–673. doi: 10.1038/381667a0. [DOI] [PubMed] [Google Scholar]
  9. Fauci A. S., Pantaleo G., Stanley S., Weissman D. Immunopathogenic mechanisms of HIV infection. Ann Intern Med. 1996 Apr 1;124(7):654–663. doi: 10.7326/0003-4819-124-7-199604010-00006. [DOI] [PubMed] [Google Scholar]
  10. Feng Y., Broder C. C., Kennedy P. E., Berger E. A. HIV-1 entry cofactor: functional cDNA cloning of a seven-transmembrane, G protein-coupled receptor. Science. 1996 May 10;272(5263):872–877. doi: 10.1126/science.272.5263.872. [DOI] [PubMed] [Google Scholar]
  11. Fox C. H., Tenner-Rácz K., Rácz P., Firpo A., Pizzo P. A., Fauci A. S. Lymphoid germinal centers are reservoirs of human immunodeficiency virus type 1 RNA. J Infect Dis. 1991 Dec;164(6):1051–1057. doi: 10.1093/infdis/164.6.1051. [DOI] [PubMed] [Google Scholar]
  12. Frankel S. S., Wenig B. M., Burke A. P., Mannan P., Thompson L. D., Abbondanzo S. L., Nelson A. M., Pope M., Steinman R. M. Replication of HIV-1 in dendritic cell-derived syncytia at the mucosal surface of the adenoid. Science. 1996 Apr 5;272(5258):115–117. doi: 10.1126/science.272.5258.115. [DOI] [PubMed] [Google Scholar]
  13. Glushakova S., Baibakov B., Margolis L. B., Zimmerberg J. Infection of human tonsil histocultures: a model for HIV pathogenesis. Nat Med. 1995 Dec;1(12):1320–1322. doi: 10.1038/nm1295-1320. [DOI] [PubMed] [Google Scholar]
  14. Glushakova S., Baibakov B., Zimmerberg J., Margolis L. B. Experimental HIV infection of human lymphoid tissue: correlation of CD4+ T cell depletion and virus syncytium-inducing/non-syncytium-inducing phenotype in histocultures inoculated with laboratory strains and patient isolates of HIV type 1. AIDS Res Hum Retroviruses. 1997 Apr 10;13(6):461–471. doi: 10.1089/aid.1997.13.461. [DOI] [PubMed] [Google Scholar]
  15. Liu R., Paxton W. A., Choe S., Ceradini D., Martin S. R., Horuk R., MacDonald M. E., Stuhlmann H., Koup R. A., Landau N. R. Homozygous defect in HIV-1 coreceptor accounts for resistance of some multiply-exposed individuals to HIV-1 infection. Cell. 1996 Aug 9;86(3):367–377. doi: 10.1016/s0092-8674(00)80110-5. [DOI] [PubMed] [Google Scholar]
  16. Pantaleo G., Graziosi C., Demarest J. F., Cohen O. J., Vaccarezza M., Gantt K., Muro-Cacho C., Fauci A. S. Role of lymphoid organs in the pathogenesis of human immunodeficiency virus (HIV) infection. Immunol Rev. 1994 Aug;140:105–130. doi: 10.1111/j.1600-065x.1994.tb00867.x. [DOI] [PubMed] [Google Scholar]
  17. Raport C. J., Gosling J., Schweickart V. L., Gray P. W., Charo I. F. Molecular cloning and functional characterization of a novel human CC chemokine receptor (CCR5) for RANTES, MIP-1beta, and MIP-1alpha. J Biol Chem. 1996 Jul 19;271(29):17161–17166. doi: 10.1074/jbc.271.29.17161. [DOI] [PubMed] [Google Scholar]
  18. Samson M., Labbe O., Mollereau C., Vassart G., Parmentier M. Molecular cloning and functional expression of a new human CC-chemokine receptor gene. Biochemistry. 1996 Mar 19;35(11):3362–3367. doi: 10.1021/bi952950g. [DOI] [PubMed] [Google Scholar]
  19. Samson M., Libert F., Doranz B. J., Rucker J., Liesnard C., Farber C. M., Saragosti S., Lapoumeroulie C., Cognaux J., Forceille C. Resistance to HIV-1 infection in caucasian individuals bearing mutant alleles of the CCR-5 chemokine receptor gene. Nature. 1996 Aug 22;382(6593):722–725. doi: 10.1038/382722a0. [DOI] [PubMed] [Google Scholar]
  20. Schmidtmayerova H., Nottet H. S., Nuovo G., Raabe T., Flanagan C. R., Dubrovsky L., Gendelman H. E., Cerami A., Bukrinsky M., Sherry B. Human immunodeficiency virus type 1 infection alters chemokine beta peptide expression in human monocytes: implications for recruitment of leukocytes into brain and lymph nodes. Proc Natl Acad Sci U S A. 1996 Jan 23;93(2):700–704. doi: 10.1073/pnas.93.2.700. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Schmidtmayerova H., Sherry B., Bukrinsky M. Chemokines and HIV replication. Nature. 1996 Aug 29;382(6594):767–767. doi: 10.1038/382767a0. [DOI] [PubMed] [Google Scholar]
  22. Schuitemaker H., Koot M., Kootstra N. A., Dercksen M. W., de Goede R. E., van Steenwijk R. P., Lange J. M., Schattenkerk J. K., Miedema F., Tersmette M. Biological phenotype of human immunodeficiency virus type 1 clones at different stages of infection: progression of disease is associated with a shift from monocytotropic to T-cell-tropic virus population. J Virol. 1992 Mar;66(3):1354–1360. doi: 10.1128/jvi.66.3.1354-1360.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Simmons G., Clapham P. R., Picard L., Offord R. E., Rosenkilde M. M., Schwartz T. W., Buser R., Wells T. N., Proudfoot A. E. Potent inhibition of HIV-1 infectivity in macrophages and lymphocytes by a novel CCR5 antagonist. Science. 1997 Apr 11;276(5310):276–279. doi: 10.1126/science.276.5310.276. [DOI] [PubMed] [Google Scholar]
  24. Tersmette M., Lange J. M., de Goede R. E., de Wolf F., Eeftink-Schattenkerk J. K., Schellekens P. T., Coutinho R. A., Huisman J. G., Goudsmit J., Miedema F. Association between biological properties of human immunodeficiency virus variants and risk for AIDS and AIDS mortality. Lancet. 1989 May 6;1(8645):983–985. doi: 10.1016/s0140-6736(89)92628-7. [DOI] [PubMed] [Google Scholar]
  25. Wu L., Gerard N. P., Wyatt R., Choe H., Parolin C., Ruffing N., Borsetti A., Cardoso A. A., Desjardin E., Newman W. CD4-induced interaction of primary HIV-1 gp120 glycoproteins with the chemokine receptor CCR-5. Nature. 1996 Nov 14;384(6605):179–183. doi: 10.1038/384179a0. [DOI] [PubMed] [Google Scholar]
  26. Zimmerman P. A., Buckler-White A., Alkhatib G., Spalding T., Kubofcik J., Combadiere C., Weissman D., Cohen O., Rubbert A., Lam G. 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 Jan;3(1):23–36. [PMC free article] [PubMed] [Google Scholar]

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