Skip to main content
NCBI home page
Journal of Virology logoLink to Journal of Virology
. 1997 Sep;71(9):6407–6415. doi: 10.1128/jvi.71.9.6407-6415.1997

Shared usage of the chemokine receptor CXCR4 by the feline and human immunodeficiency viruses.

B J Willett 1, L Picard 1, M J Hosie 1, J D Turner 1, K Adema 1, P R Clapham 1
PMCID: PMC191914  PMID: 9261358

Abstract

Feline immunodeficiency virus (FIV) induces a disease state in the domestic cat that is similar to AIDS in human immunodeficiency virus (HIV)-infected individuals. As with HIV, FIV can be divided into primary and cell culture-adapted isolates. Adaptation of FIV to replicate and form syncytia in the Crandell feline kidney (CrFK) cell line is accompanied by an increase in the net charge of the V3 loop of the envelope glycoprotein, mirroring the changes observed in the V3 loop of HIV gp120 with the switch from a non-syncytium-inducing phenotype to a syncytium-inducing phenotype. These data suggest a common mechanism of infection with FIV and HIV. In this study, we demonstrate that cell culture-adapted strains of FIV are able to use the alpha-chemokine receptor CXCR4 for cell fusion. Following ectopic expression of human CXCR4 on nonpermissive human cells, the cells are able to fuse with FIV-infected feline cells. Moreover, fusion between FIV-infected feline cells and CXCR4-transfected human cells is inhibited by both anti-CXCR4 and anti-FIV antibodies. cDNAs encoding the feline CXCR4 homolog were cloned from both T-lymphoblastoid and kidney cell lines. Feline CXCR4 displayed 94.9% amino acid sequence identity with human CXCR4 and was found to be expressed widely on cell lines susceptible to infection with cell culture-adapted strains FIV. Ectopic expression of feline CXCR4 on human cells rendered the cells susceptible to FIV-dependent fusion. Moreover, feline CXCR4 was found to be as efficient as human CXCR4 in supporting cell fusion between CD4-expressing murine fibroblast cells and either HIV type 1 (HIV-1) or HIV-2 Env-expressing human cells. Previous studies have demonstrated that feline cells expressing human CD4 are not susceptible to infection with HIV-1; therefore, further restrictions to HIV-1 Env-dependent fusion may exist in feline cells. As feline and human CXCR4 support both FIV- and HIV-dependent cell fusion, these results suggest a close evolutionary link between FIV and HIV and a common mechanism of infection involving an interaction between the virus and a member of the seven-transmembrane domain chemokine receptor family of molecules.

Full Text

The Full Text of this article is available as a PDF (724.2 KB).

Selected References

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

  1. Ackley C. D., Yamamoto J. K., Levy N., Pedersen N. C., Cooper M. D. Immunologic abnormalities in pathogen-free cats experimentally infected with feline immunodeficiency virus. J Virol. 1990 Nov;64(11):5652–5655. doi: 10.1128/jvi.64.11.5652-5655.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. 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]
  3. Berson J. F., Long D., Doranz B. J., Rucker J., Jirik F. R., Doms R. W. A seven-transmembrane domain receptor involved in fusion and entry of T-cell-tropic human immunodeficiency virus type 1 strains. J Virol. 1996 Sep;70(9):6288–6295. doi: 10.1128/jvi.70.9.6288-6295.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Bleul C. C., Farzan M., Choe H., Parolin C., Clark-Lewis I., Sodroski J., Springer T. A. The lymphocyte chemoattractant SDF-1 is a ligand for LESTR/fusin and blocks HIV-1 entry. Nature. 1996 Aug 29;382(6594):829–833. doi: 10.1038/382829a0. [DOI] [PubMed] [Google Scholar]
  5. Brelot A., Heveker N., Pleskoff O., Sol N., Alizon M. Role of the first and third extracellular domains of CXCR-4 in human immunodeficiency virus coreceptor activity. J Virol. 1997 Jun;71(6):4744–4751. doi: 10.1128/jvi.71.6.4744-4751.1997. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Brunner D., Pedersen N. C. Infection of peritoneal macrophages in vitro and in vivo with feline immunodeficiency virus. J Virol. 1989 Dec;63(12):5483–5488. doi: 10.1128/jvi.63.12.5483-5488.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. 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]
  8. Clapham P. R., Blanc D., Weiss R. A. Specific cell surface requirements for the infection of CD4-positive cells by human immunodeficiency virus types 1 and 2 and by Simian immunodeficiency virus. Virology. 1991 Apr;181(2):703–715. doi: 10.1016/0042-6822(91)90904-P. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. 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]
  10. Dalgleish A. G., Beverley P. C., Clapham P. R., Crawford D. H., Greaves M. F., Weiss R. A. The CD4 (T4) antigen is an essential component of the receptor for the AIDS retrovirus. Nature. 1984 Dec 20;312(5996):763–767. doi: 10.1038/312763a0. [DOI] [PubMed] [Google Scholar]
  11. De Jong J. J., De Ronde A., Keulen W., Tersmette M., Goudsmit J. Minimal requirements for the human immunodeficiency virus type 1 V3 domain to support the syncytium-inducing phenotype: analysis by single amino acid substitution. J Virol. 1992 Nov;66(11):6777–6780. doi: 10.1128/jvi.66.11.6777-6780.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Dean G. A., Reubel G. H., Moore P. F., Pedersen N. C. Proviral burden and infection kinetics of feline immunodeficiency virus in lymphocyte subsets of blood and lymph node. J Virol. 1996 Aug;70(8):5165–5169. doi: 10.1128/jvi.70.8.5165-5169.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Dean G. A., Reubel G. H., Pedersen N. C. Simian immunodeficiency virus infection of CD8+ lymphocytes in vivo. J Virol. 1996 Aug;70(8):5646–5650. doi: 10.1128/jvi.70.8.5646-5650.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. 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]
  15. Devereux J., Haeberli P., Smithies O. A comprehensive set of sequence analysis programs for the VAX. Nucleic Acids Res. 1984 Jan 11;12(1 Pt 1):387–395. doi: 10.1093/nar/12.1part1.387. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Doranz B. J., Rucker J., Yi Y., Smyth R. J., Samson M., Peiper S. C., Parmentier M., Collman R. G., Doms R. W. A dual-tropic primary HIV-1 isolate that uses fusin and the beta-chemokine receptors CKR-5, CKR-3, and CKR-2b as fusion cofactors. Cell. 1996 Jun 28;85(7):1149–1158. doi: 10.1016/s0092-8674(00)81314-8. [DOI] [PubMed] [Google Scholar]
  17. Dow S. W., Poss M. L., Hoover E. A. Feline immunodeficiency virus: a neurotropic lentivirus. J Acquir Immune Defic Syndr. 1990;3(7):658–668. [PubMed] [Google Scholar]
  18. 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]
  19. Endres M. J., Clapham P. R., Marsh M., Ahuja M., Turner J. D., McKnight A., Thomas J. F., Stoebenau-Haggarty B., Choe S., Vance P. J. CD4-independent infection by HIV-2 is mediated by fusin/CXCR4. Cell. 1996 Nov 15;87(4):745–756. doi: 10.1016/s0092-8674(00)81393-8. [DOI] [PubMed] [Google Scholar]
  20. English R. V., Johnson C. M., Gebhard D. H., Tompkins M. B. In vivo lymphocyte tropism of feline immunodeficiency virus. J Virol. 1993 Sep;67(9):5175–5186. doi: 10.1128/jvi.67.9.5175-5186.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. 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]
  22. Fuerst T. R., Niles E. G., Studier F. W., Moss B. Eukaryotic transient-expression system based on recombinant vaccinia virus that synthesizes bacteriophage T7 RNA polymerase. Proc Natl Acad Sci U S A. 1986 Nov;83(21):8122–8126. doi: 10.1073/pnas.83.21.8122. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Henikoff S., Henikoff J. G. Amino acid substitution matrices from protein blocks. Proc Natl Acad Sci U S A. 1992 Nov 15;89(22):10915–10919. doi: 10.1073/pnas.89.22.10915. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Hirsch V. M., Martin J. E., Dapolito G., Elkins W. R., London W. T., Goldstein S., Johnson P. R. Spontaneous substitutions in the vicinity of the V3 analog affect cell tropism and pathogenicity of simian immunodeficiency virus. J Virol. 1994 Apr;68(4):2649–2661. doi: 10.1128/jvi.68.4.2649-2661.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Hosie M. J., Dunsford T. H., de Ronde A., Willett B. J., Cannon C. A., Neil J. C., Jarrett O. Suppression of virus burden by immunization with feline immunodeficiency virus Env protein. Vaccine. 1996 Apr;14(5):405–411. doi: 10.1016/0264-410x(95)00193-5. [DOI] [PubMed] [Google Scholar]
  26. Hosie M. J., Willett B. J., Dunsford T. H., Jarrett O., Neil J. C. A monoclonal antibody which blocks infection with feline immunodeficiency virus identifies a possible non-CD4 receptor. J Virol. 1993 Mar;67(3):1667–1671. doi: 10.1128/jvi.67.3.1667-1671.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Hwang S. S., Boyle T. J., Lyerly H. K., Cullen B. R. Identification of the envelope V3 loop as the primary determinant of cell tropism in HIV-1. Science. 1991 Jul 5;253(5015):71–74. doi: 10.1126/science.1905842. [DOI] [PubMed] [Google Scholar]
  28. Ikeda Y., Tomonaga K., Kawaguchi Y., Kohmoto M., Inoshima Y., Tohya Y., Miyazawa T., Kai C., Mikami T. Feline immunodeficiency virus can infect a human cell line (MOLT-4) but establishes a state of latency in the cells. J Gen Virol. 1996 Aug;77(Pt 8):1623–1630. doi: 10.1099/0022-1317-77-8-1623. [DOI] [PubMed] [Google Scholar]
  29. Kirchhoff F., Mori K., Desrosiers R. C. The "V3" domain is a determinant of simian immunodeficiency virus cell tropism. J Virol. 1994 Jun;68(6):3682–3692. doi: 10.1128/jvi.68.6.3682-3692.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Klatzmann D., Champagne E., Chamaret S., Gruest J., Guetard D., Hercend T., Gluckman J. C., Montagnier L. T-lymphocyte T4 molecule behaves as the receptor for human retrovirus LAV. Nature. 1984 Dec 20;312(5996):767–768. doi: 10.1038/312767a0. [DOI] [PubMed] [Google Scholar]
  31. Livingstone W. J., Moore M., Innes D., Bell J. E., Simmonds P. Frequent infection of peripheral blood CD8-positive T-lymphocytes with HIV-1. Edinburgh Heterosexual Transmission Study Group. Lancet. 1996 Sep 7;348(9028):649–654. doi: 10.1016/s0140-6736(96)02091-0. [DOI] [PubMed] [Google Scholar]
  32. Maddon P. J., Dalgleish A. G., McDougal J. S., Clapham P. R., Weiss R. A., Axel R. The T4 gene encodes the AIDS virus receptor and is expressed in the immune system and the brain. Cell. 1986 Nov 7;47(3):333–348. doi: 10.1016/0092-8674(86)90590-8. [DOI] [PubMed] [Google Scholar]
  33. McKnight A., Clapham P. R., Weiss R. A. HIV-2 and SIV infection of nonprimate cell lines expressing human CD4: restrictions to replication at distinct stages. Virology. 1994 May 15;201(1):8–18. doi: 10.1006/viro.1994.1260. [DOI] [PubMed] [Google Scholar]
  34. McKnight A., Wilkinson D., Simmons G., Talbot S., Picard L., Ahuja M., Marsh M., Hoxie J. A., Clapham P. R. Inhibition of human immunodeficiency virus fusion by a monoclonal antibody to a coreceptor (CXCR4) is both cell type and virus strain dependent. J Virol. 1997 Feb;71(2):1692–1696. doi: 10.1128/jvi.71.2.1692-1696.1997. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Miyazawa T., Furuya T., Itagaki S., Tohya Y., Takahashi E., Mikami T. Establishment of a feline T-lymphoblastoid cell line highly sensitive for replication of feline immunodeficiency virus. Arch Virol. 1989;108(1-2):131–135. doi: 10.1007/BF01313750. [DOI] [PubMed] [Google Scholar]
  36. Needleman S. B., Wunsch C. D. A general method applicable to the search for similarities in the amino acid sequence of two proteins. J Mol Biol. 1970 Mar;48(3):443–453. doi: 10.1016/0022-2836(70)90057-4. [DOI] [PubMed] [Google Scholar]
  37. Norimine J., Miyazawa T., Kawaguchi Y., Tomonaga K., Shin Y. S., Toyosaki T., Kohmoto M., Niikura M., Tohya Y., Mikami T. Feline CD4 molecules expressed on feline non-lymphoid cell lines are not enough for productive infection of highly lymphotropic feline immunodeficiency virus isolates. Arch Virol. 1993;130(1-2):171–178. doi: 10.1007/BF01319005. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Novotney C., English R. V., Housman J., Davidson M. G., Nasisse M. P., Jeng C. R., Davis W. C., Tompkins M. B. Lymphocyte population changes in cats naturally infected with feline immunodeficiency virus. AIDS. 1990 Dec;4(12):1213–1218. doi: 10.1097/00002030-199012000-00005. [DOI] [PubMed] [Google Scholar]
  39. Nussbaum O., Broder C. C., Berger E. A. Fusogenic mechanisms of enveloped-virus glycoproteins analyzed by a novel recombinant vaccinia virus-based assay quantitating cell fusion-dependent reporter gene activation. J Virol. 1994 Sep;68(9):5411–5422. doi: 10.1128/jvi.68.9.5411-5422.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Oberlin E., Amara A., Bachelerie F., Bessia C., Virelizier J. L., Arenzana-Seisdedos F., Schwartz O., Heard J. M., Clark-Lewis I., Legler D. F. The CXC chemokine SDF-1 is the ligand for LESTR/fusin and prevents infection by T-cell-line-adapted HIV-1. Nature. 1996 Aug 29;382(6594):833–835. doi: 10.1038/382833a0. [DOI] [PubMed] [Google Scholar]
  41. Olmsted R. A., Barnes A. K., Yamamoto J. K., Hirsch V. M., Purcell R. H., Johnson P. R. Molecular cloning of feline immunodeficiency virus. Proc Natl Acad Sci U S A. 1989 Apr;86(7):2448–2452. doi: 10.1073/pnas.86.7.2448. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Osborne R., Rigby M., Siebelink K., Neil J. C., Jarrett O. Virus neutralization reveals antigenic variation among feline immunodeficiency virus isolates. J Gen Virol. 1994 Dec;75(Pt 12):3641–3645. doi: 10.1099/0022-1317-75-12-3641. [DOI] [PubMed] [Google Scholar]
  43. Pancino G., Castelot S., Sonigo P. Differences in feline immunodeficiency virus host cell range correlate with envelope fusogenic properties. Virology. 1995 Feb 1;206(2):796–806. doi: 10.1006/viro.1995.1002. [DOI] [PubMed] [Google Scholar]
  44. Randall R. E., Young D. F. Humoral and cytotoxic T cell immune responses to internal and external structural proteins of simian virus 5 induced by immunization with solid matrix-antibody-antigen complexes. J Gen Virol. 1988 Oct;69(Pt 10):2505–2516. doi: 10.1099/0022-1317-69-10-2505. [DOI] [PubMed] [Google Scholar]
  45. Reeves J. D., Schulz T. F. 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 Feb;71(2):1453–1465. doi: 10.1128/jvi.71.2.1453-1465.1997. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Schwartz O., Alizon M., Heard J. M., Danos O. Impairment of T cell receptor-dependent stimulation in CD4+ lymphocytes after contact with membrane-bound HIV-1 envelope glycoprotein. Virology. 1994 Jan;198(1):360–365. doi: 10.1006/viro.1994.1042. [DOI] [PubMed] [Google Scholar]
  47. Shioda T., Levy J. A., Cheng-Mayer C. Macrophage and T cell-line tropisms of HIV-1 are determined by specific regions of the envelope gp120 gene. Nature. 1991 Jan 10;349(6305):167–169. doi: 10.1038/349167a0. [DOI] [PubMed] [Google Scholar]
  48. Shioda T., Levy J. A., Cheng-Mayer C. Small amino acid changes in the V3 hypervariable region of gp120 can affect the T-cell-line and macrophage tropism of human immunodeficiency virus type 1. Proc Natl Acad Sci U S A. 1992 Oct 15;89(20):9434–9438. doi: 10.1073/pnas.89.20.9434. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Siebelink K. H., Karlas J. A., Rimmelzwaan G. F., Osterhaus A. D., Bosch M. L. A determinant of feline immunodeficiency virus involved in Crandell feline kidney cell tropism. Vet Immunol Immunopathol. 1995 May;46(1-2):61–69. doi: 10.1016/0165-2427(94)07006-s. [DOI] [PubMed] [Google Scholar]
  50. Simmons G., Wilkinson D., Reeves J. D., Dittmar M. T., Beddows S., Weber J., Carnegie G., Desselberger U., Gray P. W., Weiss R. A. Primary, syncytium-inducing human immunodeficiency virus type 1 isolates are dual-tropic and most can use either Lestr or CCR5 as coreceptors for virus entry. J Virol. 1996 Dec;70(12):8355–8360. doi: 10.1128/jvi.70.12.8355-8360.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. Trkola A., Dragic T., Arthos J., Binley J. M., Olson W. C., Allaway G. P., Cheng-Mayer C., Robinson J., Maddon P. J., Moore J. P. CD4-dependent, antibody-sensitive interactions between HIV-1 and its co-receptor CCR-5. Nature. 1996 Nov 14;384(6605):184–187. doi: 10.1038/384184a0. [DOI] [PubMed] [Google Scholar]
  52. Verschoor E. J., Boven L. A., Blaak H., van Vliet A. L., Horzinek M. C., de Ronde A. A single mutation within the V3 envelope neutralization domain of feline immunodeficiency virus determines its tropism for CRFK cells. J Virol. 1995 Aug;69(8):4752–4757. doi: 10.1128/jvi.69.8.4752-4757.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  53. Willett B. J., Hosie M. J., Dunsford T. H., Neil J. C., Jarrett O. Productive infection of T-helper lymphocytes with feline immunodeficiency virus is accompanied by reduced expression of CD4. AIDS. 1991 Dec;5(12):1469–1475. doi: 10.1097/00002030-199112000-00009. [DOI] [PubMed] [Google Scholar]
  54. Willett B. J., Hosie M. J., Neil J. C., Turner J. D., Hoxie J. A. Common mechanism of infection by lentiviruses. Nature. 1997 Feb 13;385(6617):587–587. doi: 10.1038/385587a0. [DOI] [PubMed] [Google Scholar]
  55. Willett B. J., Neil J. C. cDNA cloning and eukaryotic expression of feline CD9. Mol Immunol. 1995 Apr;32(6):417–423. doi: 10.1016/0161-5890(95)00008-3. [DOI] [PubMed] [Google Scholar]
  56. Willett B., Hosie M., Shaw A., Neil J. Inhibition of feline immunodeficiency virus infection by CD9 antibody operates after virus entry and is independent of virus tropism. J Gen Virol. 1997 Mar;78(Pt 3):611–618. doi: 10.1099/0022-1317-78-3-611. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Virology are provided here courtesy of American Society for Microbiology (ASM)

RESOURCES