Skip to main content
NCBI home page
The EMBO Journal logoLink to The EMBO Journal
. 1998 May 1;17(9):2699–2708. doi: 10.1093/emboj/17.9.2699

Efficient HIV-1 replication can occur in the absence of the viral matrix protein.

H Reil 1, A A Bukovsky 1, H R Gelderblom 1, H G Göttlinger 1
PMCID: PMC1170610  PMID: 9564051

Abstract

Matrix (MA), a major structural protein of retroviruses, is thought to play a critical role in several steps of the HIV-1 replication cycle, including the plasma membrane targeting of Gag, the incorporation of envelope (Env) glycoproteins into nascent particles, and the nuclear import of the viral genome in non-dividing cells. We now show that the entire MA protein is dispensable for the incorporation of HIV-1 Env glycoproteins with a shortened cytoplasmic domain. Furthermore, efficient HIV-1 replication in the absence of up to 90% of MA was observed in a cell line in which the cytoplasmic domain of Env is not required. Additional compensatory changes in Gag permitted efficient virus replication even if all of MA was replaced by a heterologous membrane targeting signal. Viruses which lacked the globular domain of MA but retained its N-terminal myristyl anchor exhibited an increased ability to form both extracellular and intracellular virus particles, consistent with a myristyl switch model of Gag membrane targeting. Pseudotyped HIV-1 particles that lacked the structurally conserved globular head of MA efficiently infected macrophages, indicating that MA is dispensable for nuclear import in terminally differentiated cells.

Full Text

The Full Text of this article is available as a PDF (439.6 KB).

Selected References

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

  1. Aiken C. Pseudotyping human immunodeficiency virus type 1 (HIV-1) by the glycoprotein of vesicular stomatitis virus targets HIV-1 entry to an endocytic pathway and suppresses both the requirement for Nef and the sensitivity to cyclosporin A. J Virol. 1997 Aug;71(8):5871–5877. doi: 10.1128/jvi.71.8.5871-5877.1997. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Bryant M., Ratner L. Myristoylation-dependent replication and assembly of human immunodeficiency virus 1. Proc Natl Acad Sci U S A. 1990 Jan;87(2):523–527. doi: 10.1073/pnas.87.2.523. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Bukrinskaya A. G., Ghorpade A., Heinzinger N. K., Smithgall T. E., Lewis R. E., Stevenson M. Phosphorylation-dependent human immunodeficiency virus type 1 infection and nuclear targeting of viral DNA. Proc Natl Acad Sci U S A. 1996 Jan 9;93(1):367–371. doi: 10.1073/pnas.93.1.367. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Bukrinsky M. I., Haggerty S., Dempsey M. P., Sharova N., Adzhubel A., Spitz L., Lewis P., Goldfarb D., Emerman M., Stevenson M. A nuclear localization signal within HIV-1 matrix protein that governs infection of non-dividing cells. Nature. 1993 Oct 14;365(6447):666–669. doi: 10.1038/365666a0. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Bukrinsky M. I., Sharova N., Dempsey M. P., Stanwick T. L., Bukrinskaya A. G., Haggerty S., Stevenson M. Active nuclear import of human immunodeficiency virus type 1 preintegration complexes. Proc Natl Acad Sci U S A. 1992 Jul 15;89(14):6580–6584. doi: 10.1073/pnas.89.14.6580. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Cannon P. M., Matthews S., Clark N., Byles E. D., Iourin O., Hockley D. J., Kingsman S. M., Kingsman A. J. Structure-function studies of the human immunodeficiency virus type 1 matrix protein, p17. J Virol. 1997 May;71(5):3474–3483. doi: 10.1128/jvi.71.5.3474-3483.1997. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Christensen A. M., Massiah M. A., Turner B. G., Sundquist W. I., Summers M. F. Three-dimensional structure of the HTLV-II matrix protein and comparative analysis of matrix proteins from the different classes of pathogenic human retroviruses. J Mol Biol. 1996 Dec 20;264(5):1117–1131. doi: 10.1006/jmbi.1996.0700. [DOI] [PubMed] [Google Scholar]
  8. Conte M. R., Klikova M., Hunter E., Ruml T., Matthews S. The three-dimensional solution structure of the matrix protein from the type D retrovirus, the Mason-Pfizer monkey virus, and implications for the morphology of retroviral assembly. EMBO J. 1997 Oct 1;16(19):5819–5826. doi: 10.1093/emboj/16.19.5819. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Cosson P. Direct interaction between the envelope and matrix proteins of HIV-1. EMBO J. 1996 Nov 1;15(21):5783–5788. [PMC free article] [PubMed] [Google Scholar]
  10. Dorfman T., Mammano F., Haseltine W. A., Göttlinger H. G. Role of the matrix protein in the virion association of the human immunodeficiency virus type 1 envelope glycoprotein. J Virol. 1994 Mar;68(3):1689–1696. doi: 10.1128/jvi.68.3.1689-1696.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Dubay J. W., Roberts S. J., Hahn B. H., Hunter E. Truncation of the human immunodeficiency virus type 1 transmembrane glycoprotein cytoplasmic domain blocks virus infectivity. J Virol. 1992 Nov;66(11):6616–6625. doi: 10.1128/jvi.66.11.6616-6625.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Fouchier R. A., Meyer B. E., Simon J. H., Fischer U., Malim M. H. HIV-1 infection of non-dividing cells: evidence that the amino-terminal basic region of the viral matrix protein is important for Gag processing but not for post-entry nuclear import. EMBO J. 1997 Aug 1;16(15):4531–4539. doi: 10.1093/emboj/16.15.4531. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Freed E. O., Englund G., Maldarelli F., Martin M. A. Phosphorylation of residue 131 of HIV-1 matrix is not required for macrophage infection. Cell. 1997 Jan 24;88(2):171–174. doi: 10.1016/s0092-8674(00)81836-x. [DOI] [PubMed] [Google Scholar]
  14. Freed E. O., Englund G., Martin M. A. Role of the basic domain of human immunodeficiency virus type 1 matrix in macrophage infection. J Virol. 1995 Jun;69(6):3949–3954. doi: 10.1128/jvi.69.6.3949-3954.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Freed E. O., Martin M. A. Virion incorporation of envelope glycoproteins with long but not short cytoplasmic tails is blocked by specific, single amino acid substitutions in the human immunodeficiency virus type 1 matrix. J Virol. 1995 Mar;69(3):1984–1989. doi: 10.1128/jvi.69.3.1984-1989.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Freed E. O., Orenstein J. M., Buckler-White A. J., Martin M. A. Single amino acid changes in the human immunodeficiency virus type 1 matrix protein block virus particle production. J Virol. 1994 Aug;68(8):5311–5320. doi: 10.1128/jvi.68.8.5311-5320.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Fäcke M., Janetzko A., Shoeman R. L., Kräusslich H. G. A large deletion in the matrix domain of the human immunodeficiency virus gag gene redirects virus particle assembly from the plasma membrane to the endoplasmic reticulum. J Virol. 1993 Aug;67(8):4972–4980. doi: 10.1128/jvi.67.8.4972-4980.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Gallay P., Hope T., Chin D., Trono D. HIV-1 infection of nondividing cells through the recognition of integrase by the importin/karyopherin pathway. Proc Natl Acad Sci U S A. 1997 Sep 2;94(18):9825–9830. doi: 10.1073/pnas.94.18.9825. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Gallay P., Swingler S., Aiken C., Trono D. HIV-1 infection of nondividing cells: C-terminal tyrosine phosphorylation of the viral matrix protein is a key regulator. Cell. 1995 Feb 10;80(3):379–388. doi: 10.1016/0092-8674(95)90488-3. [DOI] [PubMed] [Google Scholar]
  20. Gallay P., Swingler S., Song J., Bushman F., Trono D. HIV nuclear import is governed by the phosphotyrosine-mediated binding of matrix to the core domain of integrase. Cell. 1995 Nov 17;83(4):569–576. doi: 10.1016/0092-8674(95)90097-7. [DOI] [PubMed] [Google Scholar]
  21. Gamble T. R., Yoo S., Vajdos F. F., von Schwedler U. K., Worthylake D. K., Wang H., McCutcheon J. P., Sundquist W. I., Hill C. P. Structure of the carboxyl-terminal dimerization domain of the HIV-1 capsid protein. Science. 1997 Oct 31;278(5339):849–853. doi: 10.1126/science.278.5339.849. [DOI] [PubMed] [Google Scholar]
  22. Gelderblom H. R. Assembly and morphology of HIV: potential effect of structure on viral function. AIDS. 1991 Jun;5(6):617–637. [PubMed] [Google Scholar]
  23. Gitti R. K., Lee B. M., Walker J., Summers M. F., Yoo S., Sundquist W. I. Structure of the amino-terminal core domain of the HIV-1 capsid protein. Science. 1996 Jul 12;273(5272):231–235. doi: 10.1126/science.273.5272.231. [DOI] [PubMed] [Google Scholar]
  24. Göttlinger H. G., Sodroski J. G., Haseltine W. A. Role of capsid precursor processing and myristoylation in morphogenesis and infectivity of human immunodeficiency virus type 1. Proc Natl Acad Sci U S A. 1989 Aug;86(15):5781–5785. doi: 10.1073/pnas.86.15.5781. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Heinzinger N. K., Bukrinsky M. I., Haggerty S. A., Ragland A. M., Kewalramani V., Lee M. A., Gendelman H. E., Ratner L., Stevenson M., Emerman M. The Vpr protein of human immunodeficiency virus type 1 influences nuclear localization of viral nucleic acids in nondividing host cells. Proc Natl Acad Sci U S A. 1994 Jul 19;91(15):7311–7315. doi: 10.1073/pnas.91.15.7311. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Helseth E., Kowalski M., Gabuzda D., Olshevsky U., Haseltine W., Sodroski J. Rapid complementation assays measuring replicative potential of human immunodeficiency virus type 1 envelope glycoprotein mutants. J Virol. 1990 May;64(5):2416–2420. doi: 10.1128/jvi.64.5.2416-2420.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Hill C. P., Worthylake D., Bancroft D. P., Christensen A. M., Sundquist W. I. Crystal structures of the trimeric human immunodeficiency virus type 1 matrix protein: implications for membrane association and assembly. Proc Natl Acad Sci U S A. 1996 Apr 2;93(7):3099–3104. doi: 10.1073/pnas.93.7.3099. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Kräusslich H. G., Welker R. Intracellular transport of retroviral capsid components. Curr Top Microbiol Immunol. 1996;214:25–63. doi: 10.1007/978-3-642-80145-7_2. [DOI] [PubMed] [Google Scholar]
  29. Lee P. P., Linial M. L. Efficient particle formation can occur if the matrix domain of human immunodeficiency virus type 1 Gag is substituted by a myristylation signal. J Virol. 1994 Oct;68(10):6644–6654. doi: 10.1128/jvi.68.10.6644-6654.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Lee Y. H., Schwartz M. D., Panganiban A. T. The HIV-1 matrix domain of Gag is required for Vpu responsiveness during particle release. Virology. 1997 Oct 13;237(1):46–55. doi: 10.1006/viro.1997.8711. [DOI] [PubMed] [Google Scholar]
  31. Lewis P., Hensel M., Emerman M. Human immunodeficiency virus infection of cells arrested in the cell cycle. EMBO J. 1992 Aug;11(8):3053–3058. doi: 10.1002/j.1460-2075.1992.tb05376.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Mammano F., Kondo E., Sodroski J., Bukovsky A., Göttlinger H. G. Rescue of human immunodeficiency virus type 1 matrix protein mutants by envelope glycoproteins with short cytoplasmic domains. J Virol. 1995 Jun;69(6):3824–3830. doi: 10.1128/jvi.69.6.3824-3830.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Massiah M. A., Starich M. R., Paschall C., Summers M. F., Christensen A. M., Sundquist W. I. Three-dimensional structure of the human immunodeficiency virus type 1 matrix protein. J Mol Biol. 1994 Nov 25;244(2):198–223. doi: 10.1006/jmbi.1994.1719. [DOI] [PubMed] [Google Scholar]
  34. Matthews S., Barlow P., Boyd J., Barton G., Russell R., Mills H., Cunningham M., Meyers N., Burns N., Clark N. Structural similarity between the p17 matrix protein of HIV-1 and interferon-gamma. Nature. 1994 Aug 25;370(6491):666–668. doi: 10.1038/370666a0. [DOI] [PubMed] [Google Scholar]
  35. Momany C., Kovari L. C., Prongay A. J., Keller W., Gitti R. K., Lee B. M., Gorbalenya A. E., Tong L., McClure J., Ehrlich L. S. Crystal structure of dimeric HIV-1 capsid protein. Nat Struct Biol. 1996 Sep;3(9):763–770. doi: 10.1038/nsb0996-763. [DOI] [PubMed] [Google Scholar]
  36. Morikawa Y., Kishi T., Zhang W. H., Nermut M. V., Hockley D. J., Jones I. M. A molecular determinant of human immunodeficiency virus particle assembly located in matrix antigen p17. J Virol. 1995 Jul;69(7):4519–4523. doi: 10.1128/jvi.69.7.4519-4523.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Nelle T. D., Wills J. W. A large region within the Rous sarcoma virus matrix protein is dispensable for budding and infectivity. J Virol. 1996 Apr;70(4):2269–2276. doi: 10.1128/jvi.70.4.2269-2276.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Parent L. J., Wilson C. B., Resh M. D., Wills J. W. Evidence for a second function of the MA sequence in the Rous sarcoma virus Gag protein. J Virol. 1996 Feb;70(2):1016–1026. doi: 10.1128/jvi.70.2.1016-1026.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Saggioro D., Panozzo M., Chieco-Bianchi L. Human T-lymphotropic virus type I transcriptional regulation by methylation. Cancer Res. 1990 Aug 15;50(16):4968–4973. [PubMed] [Google Scholar]
  40. Stein B. S., Gowda S. D., Lifson J. D., Penhallow R. C., Bensch K. G., Engleman E. G. pH-independent HIV entry into CD4-positive T cells via virus envelope fusion to the plasma membrane. Cell. 1987 Jun 5;49(5):659–668. doi: 10.1016/0092-8674(87)90542-3. [DOI] [PubMed] [Google Scholar]
  41. Wang C. T., Zhang Y., McDermott J., Barklis E. Conditional infectivity of a human immunodeficiency virus matrix domain deletion mutant. J Virol. 1993 Dec;67(12):7067–7076. doi: 10.1128/jvi.67.12.7067-7076.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Weinberg J. B., Matthews T. J., Cullen B. R., Malim M. H. Productive human immunodeficiency virus type 1 (HIV-1) infection of nonproliferating human monocytes. J Exp Med. 1991 Dec 1;174(6):1477–1482. doi: 10.1084/jem.174.6.1477. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Wilk T., Pfeiffer T., Bosch V. Retained in vitro infectivity and cytopathogenicity of HIV-1 despite truncation of the C-terminal tail of the env gene product. Virology. 1992 Jul;189(1):167–177. doi: 10.1016/0042-6822(92)90692-i. [DOI] [PubMed] [Google Scholar]
  44. Willey R. L., Smith D. H., Lasky L. A., Theodore T. S., Earl P. L., Moss B., Capon D. J., Martin M. A. In vitro mutagenesis identifies a region within the envelope gene of the human immunodeficiency virus that is critical for infectivity. J Virol. 1988 Jan;62(1):139–147. doi: 10.1128/jvi.62.1.139-147.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Wiskerchen M., Muesing M. A. Human immunodeficiency virus type 1 integrase: effects of mutations on viral ability to integrate, direct viral gene expression from unintegrated viral DNA templates, and sustain viral propagation in primary cells. J Virol. 1995 Jan;69(1):376–386. doi: 10.1128/jvi.69.1.376-386.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Yee J. K., Friedmann T., Burns J. C. Generation of high-titer pseudotyped retroviral vectors with very broad host range. Methods Cell Biol. 1994;43(Pt A):99–112. doi: 10.1016/s0091-679x(08)60600-7. [DOI] [PubMed] [Google Scholar]
  47. Yu X., Yu Q. C., Lee T. H., Essex M. The C terminus of human immunodeficiency virus type 1 matrix protein is involved in early steps of the virus life cycle. J Virol. 1992 Sep;66(9):5667–5670. doi: 10.1128/jvi.66.9.5667-5670.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Yu X., Yuan X., Matsuda Z., Lee T. H., Essex M. The matrix protein of human immunodeficiency virus type 1 is required for incorporation of viral envelope protein into mature virions. J Virol. 1992 Aug;66(8):4966–4971. doi: 10.1128/jvi.66.8.4966-4971.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Yuan X., Yu X., Lee T. H., Essex M. Mutations in the N-terminal region of human immunodeficiency virus type 1 matrix protein block intracellular transport of the Gag precursor. J Virol. 1993 Nov;67(11):6387–6394. doi: 10.1128/jvi.67.11.6387-6394.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Zhou W., Parent L. J., Wills J. W., Resh M. D. Identification of a membrane-binding domain within the amino-terminal region of human immunodeficiency virus type 1 Gag protein which interacts with acidic phospholipids. J Virol. 1994 Apr;68(4):2556–2569. doi: 10.1128/jvi.68.4.2556-2569.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. Zhou W., Resh M. D. Differential membrane binding of the human immunodeficiency virus type 1 matrix protein. J Virol. 1996 Dec;70(12):8540–8548. doi: 10.1128/jvi.70.12.8540-8548.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  52. von Schwedler U., Kornbluth R. S., Trono D. The nuclear localization signal of the matrix protein of human immunodeficiency virus type 1 allows the establishment of infection in macrophages and quiescent T lymphocytes. Proc Natl Acad Sci U S A. 1994 Jul 19;91(15):6992–6996. doi: 10.1073/pnas.91.15.6992. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from The EMBO Journal are provided here courtesy of Nature Publishing Group

RESOURCES