Abstract
Human immunodeficiency virus type 1 (HIV-1) infection of the human thymus results in depletion of CD4-bearing thymocytes. This depletion is initially manifested in the immature CD4+/CD8+ thymocyte subset. To determine cellular factors involved in HIV infection in the thymus, we examined the expression of the recently identified viral coreceptor, CXCR4, on fresh human thymocytes and on human cells from SCID-hu (Thy/Liv) mice. CXCR4 is a member of the chemokine receptor family which is required along with CD4 for entry into the cell of syncytium-inducing (SI) HIV-1 strains. Our analyses show that CXCR4 expression is modulated during T-lymphoid differentiation such that immature thymocytes display an increased frequency and higher surface density of the coreceptor than do more mature cells. In addition, using an SI strain of HIV-1 which directs expression of a reporter protein on the surface of infected cells, we have found that the immature CD4+/CD8+ thymocytes that express the highest levels of both CD4 and CXCR4 are the cells that are preferentially infected and depleted by the virus in vitro. Thus, high levels of both primary receptor and coreceptor may allow efficient infection of the thymus by certain HIV-1 strains. This in part may explain the rapid disease progression seen in some HIV-infected children, where the thymus is actively involved in the production of new T lymphocytes.
Full Text
The Full Text of this article is available as a PDF (193.9 KB).
Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- 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]
- 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]
- 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]
- Alvarez-Vallina L., González A., Gambón F., Kreisler M., Díaz-Espada F. Delimitation of the proliferative stages in the human thymus indicates that cell expansion occurs before the expression of CD3 (T cell receptor). J Immunol. 1993 Jan 1;150(1):8–16. [PubMed] [Google Scholar]
- Baggiolini M., Dewald B., Moser B. Interleukin-8 and related chemotactic cytokines--CXC and CC chemokines. Adv Immunol. 1994;55:97–179. [PubMed] [Google Scholar]
- 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]
- 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]
- Bleul C. C., Wu L., Hoxie J. A., Springer T. A., Mackay C. R. The HIV coreceptors CXCR4 and CCR5 are differentially expressed and regulated on human T lymphocytes. Proc Natl Acad Sci U S A. 1997 Mar 4;94(5):1925–1930. doi: 10.1073/pnas.94.5.1925. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 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]
- Carroll R. G., Riley J. L., Levine B. L., Feng Y., Kaushal S., Ritchey D. W., Bernstein W., Weislow O. S., Brown C. R., Berger E. A. Differential regulation of HIV-1 fusion cofactor expression by CD28 costimulation of CD4+ T cells. Science. 1997 Apr 11;276(5310):273–276. doi: 10.1126/science.276.5310.273. [DOI] [PubMed] [Google Scholar]
- 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]
- 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]
- 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]
- 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]
- 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]
- Federsppiel B., Melhado I. G., Duncan A. M., Delaney A., Schappert K., Clark-Lewis I., Jirik F. R. Molecular cloning of the cDNA and chromosomal localization of the gene for a putative seven-transmembrane segment (7-TMS) receptor isolated from human spleen. Genomics. 1993 Jun;16(3):707–712. doi: 10.1006/geno.1993.1251. [DOI] [PubMed] [Google Scholar]
- 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]
- 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]
- 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]
- 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]
- 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]
- Kaneshima H., Su L., Bonyhadi M. L., Connor R. I., Ho D. D., McCune J. M. Rapid-high, syncytium-inducing isolates of human immunodeficiency virus type 1 induce cytopathicity in the human thymus of the SCID-hu mouse. J Virol. 1994 Dec;68(12):8188–8192. doi: 10.1128/jvi.68.12.8188-8192.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kitchen S. G., Uittenbogaart C. H., Zack J. A. Mechanism of human immunodeficiency virus type 1 localization in CD4-negative thymocytes: differentiation from a CD4-positive precursor allows productive infection. J Virol. 1997 Aug;71(8):5713–5722. doi: 10.1128/jvi.71.8.5713-5722.1997. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kollmann T. R., Kim A., Pettoello-Mantovani M., Hachamovitch M., Rubinstein A., Goldstein M. M., Goldstein H. Divergent effects of chronic HIV-1 infection on human thymocyte maturation in SCID-hu mice. J Immunol. 1995 Jan 15;154(2):907–921. [PubMed] [Google Scholar]
- Kraft D. L., Weissman I. L., Waller E. K. Differentiation of CD3-4-8- human fetal thymocytes in vivo: characterization of a CD3-4+8- intermediate. J Exp Med. 1993 Jul 1;178(1):265–277. doi: 10.1084/jem.178.1.265. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Krowka J. F., Sarin S., Namikawa R., McCune J. M., Kaneshima H. Human T cells in the SCID-hu mouse are phenotypically normal and functionally competent. J Immunol. 1991 Jun 1;146(11):3751–3756. [PubMed] [Google Scholar]
- Lapham C. K., Ouyang J., Chandrasekhar B., Nguyen N. Y., Dimitrov D. S., Golding H. Evidence for cell-surface association between fusin and the CD4-gp120 complex in human cell lines. Science. 1996 Oct 25;274(5287):602–605. doi: 10.1126/science.274.5287.602. [DOI] [PubMed] [Google Scholar]
- Loetscher M., Geiser T., O'Reilly T., Zwahlen R., Baggiolini M., Moser B. Cloning of a human seven-transmembrane domain receptor, LESTR, that is highly expressed in leukocytes. J Biol Chem. 1994 Jan 7;269(1):232–237. [PubMed] [Google Scholar]
- 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]
- Namikawa R., Kaneshima H., Lieberman M., Weissman I. L., McCune J. M. Infection of the SCID-hu mouse by HIV-1. Science. 1988 Dec 23;242(4886):1684–1686. doi: 10.1126/science.3201256. [DOI] [PubMed] [Google Scholar]
- 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]
- 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]
- Rosenzweig M., Clark D. P., Gaulton G. N. Selective thymocyte depletion in neonatal HIV-1 thymic infection. AIDS. 1993 Dec;7(12):1601–1605. doi: 10.1097/00002030-199312000-00009. [DOI] [PubMed] [Google Scholar]
- Schall T. J., Bacon K. B. Chemokines, leukocyte trafficking, and inflammation. Curr Opin Immunol. 1994 Dec;6(6):865–873. doi: 10.1016/0952-7915(94)90006-x. [DOI] [PubMed] [Google Scholar]
- 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]
- 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]
- 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]
- 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]
- 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]
- 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]
- 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]
- Zack J. A., Haislip A. M., Krogstad P., Chen I. S. Incompletely reverse-transcribed human immunodeficiency virus type 1 genomes in quiescent cells can function as intermediates in the retroviral life cycle. J Virol. 1992 Mar;66(3):1717–1725. doi: 10.1128/jvi.66.3.1717-1725.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]