Skip to main content
PMC home page
Journal of Virology logoLink to Journal of Virology
. 1997 Aug;71(8):5713–5722. doi: 10.1128/jvi.71.8.5713-5722.1997

Mechanism of human immunodeficiency virus type 1 localization in CD4-negative thymocytes: differentiation from a CD4-positive precursor allows productive infection.

S G Kitchen 1, C H Uittenbogaart 1, J A Zack 1
PMCID: PMC191823  PMID: 9223457

Abstract

Human immunodeficiency virus (HIV) infection of the thymus could have profound effects on development of the immune response, particularly in children. We and others have established that in addition to infecting and depleting CD4-bearing thymocytes, functional HIV proviruses are found in thymocytes lacking surface CD4 expression. Using in vitro thymocyte cultures, we show that neither HIV-mediated down regulation of CD4 nor CD4-independent infection contributes to the localization of HIV in cells lacking the primary virus receptor. Rather, infection of a CD4-positive precursor cell (CD4 positive/CD8 positive) with subsequent differentiation into a mature CD4-negative phenotype results in productively infected CD4-negative cells. This novel mechanism may contribute to pathogenesis by distributing viral sequences into functional subsets of T cells typically refractory to HIV infection and could account for the presence of viral DNA in CD8-positive lymphocytes recently observed in patients.

Full Text

The Full Text of this article is available as a PDF (973.4 KB).

Selected References

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

  1. 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]
  2. Aldrovandi G. M., Feuer G., Gao L., Jamieson B., Kristeva M., Chen I. S., Zack J. A. The SCID-hu mouse as a model for HIV-1 infection. Nature. 1993 Jun 24;363(6431):732–736. doi: 10.1038/363732a0. [DOI] [PubMed] [Google Scholar]
  3. Aldrovandi G. M., Zack J. A. Replication and pathogenicity of human immunodeficiency virus type 1 accessory gene mutants in SCID-hu mice. J Virol. 1996 Mar;70(3):1505–1511. doi: 10.1128/jvi.70.3.1505-1511.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Bonyhadi M. L., Rabin L., Salimi S., Brown D. A., Kosek J., McCune J. M., Kaneshima H. HIV induces thymus depletion in vivo. Nature. 1993 Jun 24;363(6431):728–732. doi: 10.1038/363728a0. [DOI] [PubMed] [Google Scholar]
  5. Brooks E. G., Wirt D. P., Goldblum R. M., Vaidya S., Asuncion M. T., Patterson J. C., Ware C. F., Klimpel G. R. Double-negative (CD4- CD8-) T cells with an alpha/beta T cell receptor. Non-MHC-restricted cytolytic activity and lymphokine production. J Immunol. 1990 Jun 15;144(12):4507–4512. [PubMed] [Google Scholar]
  6. Budd R. C., Mixter P. F. The origin of CD4-CD8-TCR alpha beta+ thymocytes: a model based on T-cell receptor avidity. Immunol Today. 1995 Sep;16(9):428–431. doi: 10.1016/0167-5699(95)80019-0. [DOI] [PubMed] [Google Scholar]
  7. Chen B. K., Gandhi R. T., Baltimore D. CD4 down-modulation during infection of human T cells with human immunodeficiency virus type 1 involves independent activities of vpu, env, and nef. J Virol. 1996 Sep;70(9):6044–6053. doi: 10.1128/jvi.70.9.6044-6053.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Crise B., Buonocore L., Rose J. K. CD4 is retained in the endoplasmic reticulum by the human immunodeficiency virus type 1 glycoprotein precursor. J Virol. 1990 Nov;64(11):5585–5593. doi: 10.1128/jvi.64.11.5585-5593.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Crispe I. N. CD4/CD8-negative T cells with alpha beta antigen receptors. Curr Opin Immunol. 1994 Jun;6(3):438–441. doi: 10.1016/0952-7915(94)90124-4. [DOI] [PubMed] [Google Scholar]
  10. De Maria A., Pantaleo G., Schnittman S. M., Greenhouse J. J., Baseler M., Orenstein J. M., Fauci A. S. Infection of CD8+ T lymphocytes with HIV. Requirement for interaction with infected CD4+ cells and induction of infectious virus from chronically infected CD8+ cells. J Immunol. 1991 Apr 1;146(7):2220–2226. [PubMed] [Google Scholar]
  11. Erard F., Wild M. T., Garcia-Sanz J. A., Le Gros G. Switch of CD8 T cells to noncytolytic CD8-CD4- cells that make TH2 cytokines and help B cells. Science. 1993 Jun 18;260(5115):1802–1805. doi: 10.1126/science.8511588. [DOI] [PubMed] [Google Scholar]
  12. Garcia J. V., Alfano J., Miller A. D. The negative effect of human immunodeficiency virus type 1 Nef on cell surface CD4 expression is not species specific and requires the cytoplasmic domain of CD4. J Virol. 1993 Mar;67(3):1511–1516. doi: 10.1128/jvi.67.3.1511-1516.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Garcia J. V., Miller A. D. Serine phosphorylation-independent downregulation of cell-surface CD4 by nef. Nature. 1991 Apr 11;350(6318):508–511. doi: 10.1038/350508a0. [DOI] [PubMed] [Google Scholar]
  14. Hatch W. C., Tanaka K. E., Calvelli T., Rashbaum W. K., Kress Y., Lyman W. D. Persistent productive HIV-1 infection of a CD4- human fetal thymocyte line. J Immunol. 1992 May 15;148(10):3055–3061. [PubMed] [Google Scholar]
  15. Hays E. F., Uittenbogaart C. H., Brewer J. C., Vollger L. W., Zack J. A. In vitro studies of HIV-1 expression in thymocytes from infants and children. AIDS. 1992 Mar;6(3):265–272. doi: 10.1097/00002030-199203000-00003. [DOI] [PubMed] [Google Scholar]
  16. Ho D. D., Neumann A. U., Perelson A. S., Chen W., Leonard J. M., Markowitz M. Rapid turnover of plasma virions and CD4 lymphocytes in HIV-1 infection. Nature. 1995 Jan 12;373(6510):123–126. doi: 10.1038/373123a0. [DOI] [PubMed] [Google Scholar]
  17. Jabbar M. A., Nayak D. P. Intracellular interaction of human immunodeficiency virus type 1 (ARV-2) envelope glycoprotein gp160 with CD4 blocks the movement and maturation of CD4 to the plasma membrane. J Virol. 1990 Dec;64(12):6297–6304. doi: 10.1128/jvi.64.12.6297-6304.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Jamieson B. D., Aldrovandi G. M., Planelles V., Jowett J. B., Gao L., Bloch L. M., Chen I. S., Zack J. A. Requirement of human immunodeficiency virus type 1 nef for in vivo replication and pathogenicity. J Virol. 1994 Jun;68(6):3478–3485. doi: 10.1128/jvi.68.6.3478-3485.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Jamieson B. D., Pang S., Aldrovandi G. M., Zha J., Zack J. A. In vivo pathogenic properties of two clonal human immunodeficiency virus type 1 isolates. J Virol. 1995 Oct;69(10):6259–6264. doi: 10.1128/jvi.69.10.6259-6264.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Jowett J. B., Planelles V., Poon B., Shah N. P., Chen M. L., Chen I. S. The human immunodeficiency virus type 1 vpr gene arrests infected T cells in the G2 + M phase of the cell cycle. J Virol. 1995 Oct;69(10):6304–6313. doi: 10.1128/jvi.69.10.6304-6313.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Koyanagi Y., Miles S., Mitsuyasu R. T., Merrill J. E., Vinters H. V., Chen I. S. Dual infection of the central nervous system by AIDS viruses with distinct cellular tropisms. Science. 1987 May 15;236(4803):819–822. doi: 10.1126/science.3646751. [DOI] [PubMed] [Google Scholar]
  22. Landolfi M. M., Van Houten N., Russell J. Q., Scollay R., Parnes J. R., Budd R. C. CD2-CD4-CD8- lymph node T lymphocytes in MRL lpr/lpr mice are derived from a CD2+CD4+CD8+ thymic precursor. J Immunol. 1993 Jul 15;151(2):1086–1096. [PubMed] [Google Scholar]
  23. Langston C., Lewis D. E., Hammill H. A., Popek E. J., Kozinetz C. A., Kline M. W., Hanson I. C., Shearer W. T. Excess intrauterine fetal demise associated with maternal human immunodeficiency virus infection. J Infect Dis. 1995 Dec;172(6):1451–1460. doi: 10.1093/infdis/172.6.1451. [DOI] [PubMed] [Google Scholar]
  24. Levy J. A. Pathogenesis of human immunodeficiency virus infection. Microbiol Rev. 1993 Mar;57(1):183–289. doi: 10.1128/mr.57.1.183-289.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Littman D. R., Gettner S. N. Unusual intron in the immunoglobulin domain of the newly isolated murine CD4 (L3T4) gene. 1987 Jan 29-Feb 4Nature. 325(6103):453–455. doi: 10.1038/325453a0. [DOI] [PubMed] [Google Scholar]
  26. 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]
  27. Lusso P., Malnati M. S., Garzino-Demo A., Crowley R. W., Long E. O., Gallo R. C. Infection of natural killer cells by human herpesvirus 6. Nature. 1993 Apr 1;362(6419):458–462. doi: 10.1038/362458a0. [DOI] [PubMed] [Google Scholar]
  28. Mackall C. L., Fleisher T. A., Brown M. R., Andrich M. P., Chen C. C., Feuerstein I. M., Horowitz M. E., Magrath I. T., Shad A. T., Steinberg S. M. Age, thymopoiesis, and CD4+ T-lymphocyte regeneration after intensive chemotherapy. N Engl J Med. 1995 Jan 19;332(3):143–149. doi: 10.1056/NEJM199501193320303. [DOI] [PubMed] [Google Scholar]
  29. McCune J. M., Namikawa R., Kaneshima H., Shultz L. D., Lieberman M., Weissman I. L. The SCID-hu mouse: murine model for the analysis of human hematolymphoid differentiation and function. Science. 1988 Sep 23;241(4873):1632–1639. doi: 10.1126/science.241.4873.1632. [DOI] [PubMed] [Google Scholar]
  30. Mercure L., Phaneuf D., Wainberg M. A. Detection of unintegrated human immunodeficiency virus type 1 DNA in persistently infected CD8+ cells. J Gen Virol. 1993 Oct;74(Pt 10):2077–2083. doi: 10.1099/0022-1317-74-10-2077. [DOI] [PubMed] [Google Scholar]
  31. Namikawa R., Weilbaecher K. N., Kaneshima H., Yee E. J., McCune J. M. Long-term human hematopoiesis in the SCID-hu mouse. J Exp Med. 1990 Oct 1;172(4):1055–1063. doi: 10.1084/jem.172.4.1055. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Papiernik M., Brossard Y., Mulliez N., Roume J., Brechot C., Barin F., Goudeau A., Bach J. F., Griscelli C., Henrion R. Thymic abnormalities in fetuses aborted from human immunodeficiency virus type 1 seropositive women. Pediatrics. 1992 Feb;89(2):297–301. [PubMed] [Google Scholar]
  33. Planelles V., Haislip A., Withers-Ward E. S., Stewart S. A., Xie Y., Shah N. P., Chen I. S. A new reporter system for detection of retroviral infection. Gene Ther. 1995 Aug;2(6):369–376. [PubMed] [Google Scholar]
  34. Rhee S. S., Marsh J. W. Human immunodeficiency virus type 1 Nef-induced down-modulation of CD4 is due to rapid internalization and degradation of surface CD4. J Virol. 1994 Aug;68(8):5156–5163. doi: 10.1128/jvi.68.8.5156-5163.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Schmid I., Krall W. J., Uittenbogaart C. H., Braun J., Giorgi J. V. Dead cell discrimination with 7-amino-actinomycin D in combination with dual color immunofluorescence in single laser flow cytometry. Cytometry. 1992;13(2):204–208. doi: 10.1002/cyto.990130216. [DOI] [PubMed] [Google Scholar]
  36. Schwartz O., Dautry-Varsat A., Goud B., Maréchal V., Subtil A., Heard J. M., Danos O. Human immunodeficiency virus type 1 Nef induces accumulation of CD4 in early endosomes. J Virol. 1995 Jan;69(1):528–533. doi: 10.1128/jvi.69.1.528-533.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Semenzato G., Agostini C., Ometto L., Zambello R., Trentin L., Chieco-Bianchi L., De Rossi A. CD8+ T lymphocytes in the lung of acquired immunodeficiency syndrome patients harbor human immunodeficiency virus type 1. Blood. 1995 May 1;85(9):2308–2314. [PubMed] [Google Scholar]
  38. Stanley S. K., McCune J. M., Kaneshima H., Justement J. S., Sullivan M., Boone E., Baseler M., Adelsberger J., Bonyhadi M., Orenstein J. Human immunodeficiency virus infection of the human thymus and disruption of the thymic microenvironment in the SCID-hu mouse. J Exp Med. 1993 Oct 1;178(4):1151–1163. doi: 10.1084/jem.178.4.1151. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Su L., Kaneshima H., Bonyhadi M., Salimi S., Kraft D., Rabin L., McCune J. M. HIV-1-induced thymocyte depletion is associated with indirect cytopathogenicity and infection of progenitor cells in vivo. Immunity. 1995 Jan;2(1):25–36. doi: 10.1016/1074-7613(95)90076-4. [DOI] [PubMed] [Google Scholar]
  40. Terstappen L. W., Huang S., Picker L. J. Flow cytometric assessment of human T-cell differentiation in thymus and bone marrow. Blood. 1992 Feb 1;79(3):666–677. [PubMed] [Google Scholar]
  41. Ueno Y., Boone T., Uittenbogaart C. H. Selective stimulation of human thymocyte subpopulations by recombinant IL-4 and IL-3. Cell Immunol. 1989 Feb;118(2):382–393. doi: 10.1016/0008-8749(89)90386-9. [DOI] [PubMed] [Google Scholar]
  42. Ueno Y., Hays E. F., Hultin L., Uittenbogaart C. H. Human thymocytes do not respond to interleukin-2 after removal of mature "bright" CD5 positive cells. Cell Immunol. 1989 Dec;124(2):239–251. doi: 10.1016/0008-8749(89)90128-7. [DOI] [PubMed] [Google Scholar]
  43. Uittenbogaart C. H., Anisman D. J., Jamieson B. D., Kitchen S., Schmid I., Zack J. A., Hays E. F. Differential tropism of HIV-1 isolates for distinct thymocyte subsets in vitro. AIDS. 1996 Jun;10(7):F9–16. doi: 10.1097/00002030-199606001-00001. [DOI] [PubMed] [Google Scholar]
  44. Uittenbogaart C. H., Anisman D. J., Zack J. A., Economides A., Schmid I., Hays E. F. Effects of cytokines on HIV-1 production by thymocytes. Thymus. 1994;23(3-4):155–175. [PubMed] [Google Scholar]
  45. Uittenbogaart C. H., Higashitani S., Schmid I., Vollger L. W., Boone T., Clement L. T. Interleukin-4 induces expression of the CD45RA antigen on human thymocyte subpopulations. Int Immunol. 1990;2(12):1179–1187. doi: 10.1093/intimm/2.12.1179. [DOI] [PubMed] [Google Scholar]
  46. Valentin H., Nugeyre M. T., Vuillier F., Boumsell L., Schmid M., Barré-Sinoussi F., Pereira R. A. Two subpopulations of human triple-negative thymic cells are susceptible to infection by human immunodeficiency virus type 1 in vitro. J Virol. 1994 May;68(5):3041–3050. doi: 10.1128/jvi.68.5.3041-3050.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Wei X., Ghosh S. K., Taylor M. E., Johnson V. A., Emini E. A., Deutsch P., Lifson J. D., Bonhoeffer S., Nowak M. A., Hahn B. H. Viral dynamics in human immunodeficiency virus type 1 infection. Nature. 1995 Jan 12;373(6510):117–122. doi: 10.1038/373117a0. [DOI] [PubMed] [Google Scholar]
  48. Willey R. L., Maldarelli F., Martin M. A., Strebel K. Human immunodeficiency virus type 1 Vpu protein induces rapid degradation of CD4. J Virol. 1992 Dec;66(12):7193–7200. doi: 10.1128/jvi.66.12.7193-7200.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Wu L., Pearse M., Egerton M., Petrie H., Scollay R. CD4-CD8- thymocytes that express the T cell receptor may have previously expressed CD8. Int Immunol. 1990;2(1):51–56. doi: 10.1093/intimm/2.1.51. [DOI] [PubMed] [Google Scholar]
  50. Zack J. A., Arrigo S. J., Weitsman S. R., Go A. S., Haislip A., Chen I. S. HIV-1 entry into quiescent primary lymphocytes: molecular analysis reveals a labile, latent viral structure. Cell. 1990 Apr 20;61(2):213–222. doi: 10.1016/0092-8674(90)90802-l. [DOI] [PubMed] [Google Scholar]

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

RESOURCES