Skip to main content
PMC home page
Journal of Virology logoLink to Journal of Virology
. 1996 Jul;70(7):4220–4227. doi: 10.1128/jvi.70.7.4220-4227.1996

Cyclophilin A is required for the replication of group M human immunodeficiency virus type 1 (HIV-1) and simian immunodeficiency virus SIV(CPZ)GAB but not group O HIV-1 or other primate immunodeficiency viruses.

D Braaten 1, E K Franke 1, J Luban 1
PMCID: PMC190352  PMID: 8676442

Abstract

The human immunodeficiency virus type 1 (HIV-1) Gag polyprotein binds to cyclophilin A and incorporates this cellular peptidyl prolyl-isomerase into virions. Disruption of cyclophilin A incorporation, either by gag mutations or by cyclosporine A, inhibits virion infectivity, indicating that cyclophilin A plays an essential role in the HIV-1 life cycle. Using assays for packaging of cyclophilin A into virions and for viral replication sensitivity to cyclosporine A, as well as information gleaned from the alignment of Gag residues encoded by representative viral isolates, we demonstrate that of the five lineages of primate immunodeficiency viruses, only HIV-1 requires cyclophilin A for replication. Cloned viral isolates from clades A, B, and D of HIV-1 group M, as well as a phylogenetically related isolate from chimpanzee, all require cyclophilin A for replication. In contrast, the replication of two outlier (group O) HIV-1 isolates is unaffected by concentrations of cyclosporine A which disrupt cyclophilin A incorporation into virions, indicating that these viruses are capable of replicating independently of cyclophilin A. These studies identify the first phenotypic difference between HIV-1 group M and group O and are consistent with phylogenetic studies suggesting that the two HIV-1 groups were introduced into human populations via separate zoonotic transmission events.

Full Text

The Full Text of this article is available as a PDF (397.7 KB).

Selected References

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

  1. Aberham C., Weber S., Phares W. Spontaneous mutations in the human immunodeficiency virus type 1 gag gene that affect viral replication in the presence of cyclosporins. J Virol. 1996 Jun;70(6):3536–3544. doi: 10.1128/jvi.70.6.3536-3544.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Adachi A., Gendelman H. E., Koenig S., Folks T., Willey R., Rabson A., Martin M. A. Production of acquired immunodeficiency syndrome-associated retrovirus in human and nonhuman cells transfected with an infectious molecular clone. J Virol. 1986 Aug;59(2):284–291. doi: 10.1128/jvi.59.2.284-291.1986. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Baker E. K., Colley N. J., Zuker C. S. The cyclophilin homolog NinaA functions as a chaperone, forming a stable complex in vivo with its protein target rhodopsin. EMBO J. 1994 Oct 17;13(20):4886–4895. doi: 10.1002/j.1460-2075.1994.tb06816.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Bartz S. R., Hohenwalter E., Hu M. K., Rich D. H., Malkovsky M. Inhibition of human immunodeficiency virus replication by nonimmunosuppressive analogs of cyclosporin A. Proc Natl Acad Sci U S A. 1995 Jun 6;92(12):5381–5385. doi: 10.1073/pnas.92.12.5381. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Billich A., Hammerschmid F., Peichl P., Wenger R., Zenke G., Quesniaux V., Rosenwirth B. Mode of action of SDZ NIM 811, a nonimmunosuppressive cyclosporin A analog with activity against human immunodeficiency virus (HIV) type 1: interference with HIV protein-cyclophilin A interactions. J Virol. 1995 Apr;69(4):2451–2461. doi: 10.1128/jvi.69.4.2451-2461.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Braaten D., Franke E. K., Luban J. Cyclophilin A is required for an early step in the life cycle of human immunodeficiency virus type 1 before the initiation of reverse transcription. J Virol. 1996 Jun;70(6):3551–3560. doi: 10.1128/jvi.70.6.3551-3560.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Charneau P., Borman A. M., Quillent C., Guétard D., Chamaret S., Cohen J., Rémy G., Montagnier L., Clavel F. Isolation and envelope sequence of a highly divergent HIV-1 isolate: definition of a new HIV-1 group. Virology. 1994 Nov 15;205(1):247–253. doi: 10.1006/viro.1994.1640. [DOI] [PubMed] [Google Scholar]
  8. Chattopadhyay S. K., Oliff A. I., Linemeyer D. L., Lander M. R., Lowy D. R. Genomes of murine leukemia viruses isolated from wild mice. J Virol. 1981 Sep;39(3):777–791. doi: 10.1128/jvi.39.3.777-791.1981. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Coffin J. M. HIV population dynamics in vivo: implications for genetic variation, pathogenesis, and therapy. Science. 1995 Jan 27;267(5197):483–489. doi: 10.1126/science.7824947. [DOI] [PubMed] [Google Scholar]
  10. Fischer G., Schmid F. X. The mechanism of protein folding. Implications of in vitro refolding models for de novo protein folding and translocation in the cell. Biochemistry. 1990 Mar 6;29(9):2205–2212. doi: 10.1021/bi00461a001. [DOI] [PubMed] [Google Scholar]
  11. Franke E. K., Yuan H. E., Luban J. Specific incorporation of cyclophilin A into HIV-1 virions. Nature. 1994 Nov 24;372(6504):359–362. doi: 10.1038/372359a0. [DOI] [PubMed] [Google Scholar]
  12. Fruman D. A., Burakoff S. J., Bierer B. E. Immunophilins in protein folding and immunosuppression. FASEB J. 1994 Apr 1;8(6):391–400. doi: 10.1096/fasebj.8.6.7513288. [DOI] [PubMed] [Google Scholar]
  13. Fultz P. N., Gordon T. P., Anderson D. C., McClure H. M. Prevalence of natural infection with simian immunodeficiency virus and simian T-cell leukemia virus type I in a breeding colony of sooty mangabey monkeys. AIDS. 1990 Jul;4(7):619–625. doi: 10.1097/00002030-199007000-00002. [DOI] [PubMed] [Google Scholar]
  14. Gething M. J., Sambrook J. Protein folding in the cell. Nature. 1992 Jan 2;355(6355):33–45. doi: 10.1038/355033a0. [DOI] [PubMed] [Google Scholar]
  15. Gürtler L. G., Hauser P. H., Eberle J., von Brunn A., Knapp S., Zekeng L., Tsague J. M., Kaptue L. A new subtype of human immunodeficiency virus type 1 (MVP-5180) from Cameroon. J Virol. 1994 Mar;68(3):1581–1585. doi: 10.1128/jvi.68.3.1581-1585.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Haendler B., Hofer-Warbinek R., Hofer E. Complementary DNA for human T-cell cyclophilin. EMBO J. 1987 Apr;6(4):947–950. doi: 10.1002/j.1460-2075.1987.tb04843.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Handschumacher R. E., Harding M. W., Rice J., Drugge R. J., Speicher D. W. Cyclophilin: a specific cytosolic binding protein for cyclosporin A. Science. 1984 Nov 2;226(4674):544–547. doi: 10.1126/science.6238408. [DOI] [PubMed] [Google Scholar]
  18. Harding M. W., Handschumacher R. E., Speicher D. W. Isolation and amino acid sequence of cyclophilin. J Biol Chem. 1986 Jun 25;261(18):8547–8555. [PubMed] [Google Scholar]
  19. Hirsch V. M., Dapolito G. A., Goldstein S., McClure H., Emau P., Fultz P. N., Isahakia M., Lenroot R., Myers G., Johnson P. R. A distinct African lentivirus from Sykes' monkeys. J Virol. 1993 Mar;67(3):1517–1528. doi: 10.1128/jvi.67.3.1517-1528.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Huet T., Cheynier R., Meyerhans A., Roelants G., Wain-Hobson S. Genetic organization of a chimpanzee lentivirus related to HIV-1. Nature. 1990 May 24;345(6273):356–359. doi: 10.1038/345356a0. [DOI] [PubMed] [Google Scholar]
  21. Johnson P. R., Fomsgaard A., Allan J., Gravell M., London W. T., Olmsted R. A., Hirsch V. M. Simian immunodeficiency viruses from African green monkeys display unusual genetic diversity. J Virol. 1990 Mar;64(3):1086–1092. doi: 10.1128/jvi.64.3.1086-1092.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Joshi A., Jeang K. T. Reduction in growth temperature minimizes instability of large plasmids containing HIV-1 proviral genomes. Biotechniques. 1993 Jun;14(6):880, 884-6. [PubMed] [Google Scholar]
  23. Kanki P. J., Kurth R., Becker W., Dreesman G., McLane M. F., Essex M. Antibodies to simian T-lymphotropic retrovirus type III in African green monkeys and recognition of STLV-III viral proteins by AIDS and related sera. Lancet. 1985 Jun 8;1(8441):1330–1332. doi: 10.1016/s0140-6736(85)92818-1. [DOI] [PubMed] [Google Scholar]
  24. Karpas A., Lowdell M., Jacobson S. K., Hill F. Inhibition of human immunodeficiency virus and growth of infected T cells by the immunosuppressive drugs cyclosporin A and FK 506. Proc Natl Acad Sci U S A. 1992 Sep 1;89(17):8351–8355. doi: 10.1073/pnas.89.17.8351. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Lodish H. F., Kong N. Cyclosporin A inhibits an initial step in folding of transferrin within the endoplasmic reticulum. J Biol Chem. 1991 Aug 15;266(23):14835–14838. [PubMed] [Google Scholar]
  26. Loussert-Ajaka I., Chaix M. L., Korber B., Letourneur F., Gomas E., Allen E., Ly T. D., Brun-Vézinet F., Simon F., Saragosti S. Variability of human immunodeficiency virus type 1 group O strains isolated from Cameroonian patients living in France. J Virol. 1995 Sep;69(9):5640–5649. doi: 10.1128/jvi.69.9.5640-5649.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Luban J., Bossolt K. L., Franke E. K., Kalpana G. V., Goff S. P. Human immunodeficiency virus type 1 Gag protein binds to cyclophilins A and B. Cell. 1993 Jun 18;73(6):1067–1078. doi: 10.1016/0092-8674(93)90637-6. [DOI] [PubMed] [Google Scholar]
  28. Matouschek A., Rospert S., Schmid K., Glick B. S., Schatz G. Cyclophilin catalyzes protein folding in yeast mitochondria. Proc Natl Acad Sci U S A. 1995 Jul 3;92(14):6319–6323. doi: 10.1073/pnas.92.14.6319. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Myers G., MacInnes K., Korber B. The emergence of simian/human immunodeficiency viruses. AIDS Res Hum Retroviruses. 1992 Mar;8(3):373–386. doi: 10.1089/aid.1992.8.373. [DOI] [PubMed] [Google Scholar]
  30. Myers G. Tenth anniversary perspectives on AIDS. HIV: between past and future. AIDS Res Hum Retroviruses. 1994 Nov;10(11):1317–1324. doi: 10.1089/aid.1994.10.1317. [DOI] [PubMed] [Google Scholar]
  31. Nara P. L., Fischinger P. J. Quantitative infectivity assay for HIV-1 and-2. Nature. 1988 Mar 31;332(6163):469–470. doi: 10.1038/332469a0. [DOI] [PubMed] [Google Scholar]
  32. Nkengasong J. N., Janssens W., Heyndrickx L., Fransen K., Ndumbe P. M., Motte J., Leonaers A., Ngolle M., Ayuk J., Piot P. Genotypic subtypes of HIV-1 in Cameroon. AIDS. 1994 Oct;8(10):1405–1412. doi: 10.1097/00002030-199410000-00006. [DOI] [PubMed] [Google Scholar]
  33. Ohta Y., Masuda T., Tsujimoto H., Ishikawa K., Kodama T., Morikawa S., Nakai M., Honjo S., Hayami M. Isolation of simian immunodeficiency virus from African green monkeys and seroepidemiologic survey of the virus in various non-human primates. Int J Cancer. 1988 Jan 15;41(1):115–122. doi: 10.1002/ijc.2910410121. [DOI] [PubMed] [Google Scholar]
  34. Peden K., Emerman M., Montagnier L. Changes in growth properties on passage in tissue culture of viruses derived from infectious molecular clones of HIV-1LAI, HIV-1MAL, and HIV-1ELI. Virology. 1991 Dec;185(2):661–672. doi: 10.1016/0042-6822(91)90537-l. [DOI] [PubMed] [Google Scholar]
  35. Peeters M., Fransen K., Delaporte E., Van den Haesevelde M., Gershy-Damet G. M., Kestens L., van der Groen G., Piot P. Isolation and characterization of a new chimpanzee lentivirus (simian immunodeficiency virus isolate cpz-ant) from a wild-captured chimpanzee. AIDS. 1992 May;6(5):447–451. doi: 10.1097/00002030-199205000-00002. [DOI] [PubMed] [Google Scholar]
  36. Peeters M., Honoré C., Huet T., Bedjabaga L., Ossari S., Bussi P., Cooper R. W., Delaporte E. Isolation and partial characterization of an HIV-related virus occurring naturally in chimpanzees in Gabon. AIDS. 1989 Oct;3(10):625–630. doi: 10.1097/00002030-198910000-00001. [DOI] [PubMed] [Google Scholar]
  37. Preston B. D., Poiesz B. J., Loeb L. A. Fidelity of HIV-1 reverse transcriptase. Science. 1988 Nov 25;242(4882):1168–1171. doi: 10.1126/science.2460924. [DOI] [PubMed] [Google Scholar]
  38. Roberts J. D., Bebenek K., Kunkel T. A. The accuracy of reverse transcriptase from HIV-1. Science. 1988 Nov 25;242(4882):1171–1173. doi: 10.1126/science.2460925. [DOI] [PubMed] [Google Scholar]
  39. Rosenwirth B., Billich A., Datema R., Donatsch P., Hammerschmid F., Harrison R., Hiestand P., Jaksche H., Mayer P., Peichl P. Inhibition of human immunodeficiency virus type 1 replication by SDZ NIM 811, a nonimmunosuppressive cyclosporine analog. Antimicrob Agents Chemother. 1994 Aug;38(8):1763–1772. doi: 10.1128/aac.38.8.1763. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Schreiber S. L., Crabtree G. R. The mechanism of action of cyclosporin A and FK506. Immunol Today. 1992 Apr;13(4):136–142. doi: 10.1016/0167-5699(92)90111-J. [DOI] [PubMed] [Google Scholar]
  41. Stamnes M. A., Rutherford S. L., Zuker C. S. Cyclophilins: a new family of proteins involved in intracellular folding. Trends Cell Biol. 1992 Sep;2(9):272–276. doi: 10.1016/0962-8924(92)90200-7. [DOI] [PubMed] [Google Scholar]
  42. Steinmann B., Bruckner P., Superti-Furga A. Cyclosporin A slows collagen triple-helix formation in vivo: indirect evidence for a physiologic role of peptidyl-prolyl cis-trans-isomerase. J Biol Chem. 1991 Jan 15;266(2):1299–1303. [PubMed] [Google Scholar]
  43. Sykes K., Gething M. J., Sambrook J. Proline isomerases function during heat shock. Proc Natl Acad Sci U S A. 1993 Jun 15;90(12):5853–5857. doi: 10.1073/pnas.90.12.5853. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Talbott R. L., Sparger E. E., Lovelace K. M., Fitch W. M., Pedersen N. C., Luciw P. A., Elder J. H. Nucleotide sequence and genomic organization of feline immunodeficiency virus. Proc Natl Acad Sci U S A. 1989 Aug;86(15):5743–5747. doi: 10.1073/pnas.86.15.5743. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Thali M., Bukovsky A., Kondo E., Rosenwirth B., Walsh C. T., Sodroski J., Göttlinger H. G. Functional association of cyclophilin A with HIV-1 virions. Nature. 1994 Nov 24;372(6504):363–365. doi: 10.1038/372363a0. [DOI] [PubMed] [Google Scholar]
  46. Tsujimoto H., Hasegawa A., Maki N., Fukasawa M., Miura T., Speidel S., Cooper R. W., Moriyama E. N., Gojobori T., Hayami M. Sequence of a novel simian immunodeficiency virus from a wild-caught African mandrill. Nature. 1989 Oct 12;341(6242):539–541. doi: 10.1038/341539a0. [DOI] [PubMed] [Google Scholar]
  47. Vanden Haesevelde M., Decourt J. L., De Leys R. J., Vanderborght B., van der Groen G., van Heuverswijn H., Saman E. Genomic cloning and complete sequence analysis of a highly divergent African human immunodeficiency virus isolate. J Virol. 1994 Mar;68(3):1586–1596. doi: 10.1128/jvi.68.3.1586-1596.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Wainberg M. A., Dascal A., Blain N., Fitz-Gibbon L., Boulerice F., Numazaki K., Tremblay M. The effect of cyclosporine A on infection of susceptible cells by human immunodeficiency virus type 1. Blood. 1988 Dec;72(6):1904–1910. [PubMed] [Google Scholar]
  49. Walsh C. T., Zydowsky L. D., McKeon F. D. Cyclosporin A, the cyclophilin class of peptidylprolyl isomerases, and blockade of T cell signal transduction. J Biol Chem. 1992 Jul 5;267(19):13115–13118. [PubMed] [Google Scholar]
  50. Weisman R., Creanor J., Fantes P. A multicopy suppressor of a cell cycle defect in S. pombe encodes a heat shock-inducible 40 kDa cyclophilin-like protein. EMBO J. 1996 Feb 1;15(3):447–456. [PMC free article] [PubMed] [Google Scholar]
  51. Weiss A., Wiskocil R. L., Stobo J. D. The role of T3 surface molecules in the activation of human T cells: a two-stimulus requirement for IL 2 production reflects events occurring at a pre-translational level. J Immunol. 1984 Jul;133(1):123–128. [PubMed] [Google Scholar]

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

RESOURCES