Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

CCR5- and CXCR4-tropic HIV-1 are equally cytopathic for their T-cell targets in human lymphoid tissue

Nature Medicine volume 5, pages 344–346 (1999)Cite this article

Abstract

A rapid decline in T-cell counts and the progression to AIDS is often associated with a switch from CCR5-tropic (R5) HIV-1 to CXCR4–tropic (X4) HIV-1 or R5/X4 HIV-1 variants1,2. Experimental infection with R5 HIV-1 causes less T-cell depletion than infection with X4 or R5/X4 variants in T-cell cultures3, in ex vivo infected human lymphoid tissue4,5 and in SCID/hu mice6, despite similar replication levels. Experimental genetic changes in those sequences in gp120 that transform R5 HIV-1 variants into otherwise isogenic X4 viruses make them highly cytopathic6,7. Thus, it is now believed that R5 variants are less cytopathic for T cells than are X4 variants. However, it is not known why CCR5-mediated HIV-1 infection does not lead to a massive CD4+ T-cell depletion, as occurs in CXCR4-mediated HIV-1 infection. Here we demonstrate that R5 HIV-1 isolates are indeed highly cytopathic, but only for CCR5+/CD4+ T cells. Because these cells constitute only a small fraction of CD4+ T cells, their depletion does not substantially change the total CD4+ T-cell count. These results may explain why the clinical stage of HIV disease correlates with viral tropism.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Distribution of CXCR4- and CCR5-expressing cells among CD4+ T lymphocytes.
Figure 2: Depletion of CCR5+ and CXCR4+ subsets of CD4+ T lymphocytes in HIV-infected human lymphoid tissue ex vivo.

Similar content being viewed by others

References

  1. Tersmette, M. et al. Association between biological properties of human immunodeficiency virus variants and risk for AIDS and AIDS mortality. Lancet 1, 983–985 (1989).

    Article  CAS  Google Scholar 

  2. Scarlatti, G. et al. In vivo evolution of HIV-1 co-receptor usage and sensitivity to chemokine-mediated suppression. Nature Med. 3, 1259–1265 (1997).

    Article  CAS  Google Scholar 

  3. Berger, E.A. HIV entry and tropism: the chemokine receptor connection. AIDS 11, S3–S16 (1997).

    Google Scholar 

  4. Glushakova, S., Baibakov, B., Margolis, L.B. & Zimmerberg, J. Infection of human tonsil histocultures: a model for HIV pathogenesis. Nature Med. 1, 1320–1322 (1995).

    Article  CAS  Google Scholar 

  5. Glushakova, S. et al. Evidence for the HIV-1 phenotype switch as a causal factor in acquired immunodeficiency. Nature Med. 4, 346–349 (1998).

    Article  CAS  Google Scholar 

  6. Picchio, G.R., Gulizia, R.J., Wehrly, K., Chesebro, B. & Mosier, D.E. The cell tropism of human immunodeficiency virus type 1 determines the kinetics of plasma viremia in SCID mice reconstituted with human peripheral blood leukocytes. J. Virol. 72, 2002–2009 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Penn, M.L., Grivel, J.-C, Shramm, B., Godsmith, M.A. & Margolis, L.B. CXCR4 utilization is sufficient to trigger CD4+ T cell depletion in HIV-1- infected human lymphoid tissue. Proc. Natl. Acad. Sci. USA 96, 663–668 (1999).

    Article  CAS  Google Scholar 

  8. 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. USA 94, 1925–1930 (1997).

    Article  CAS  Google Scholar 

  9. Zaitseva, M. et al. Expression and function of CCR5 and CXCR4 on human Langerhans cells and macrophages: implications for HIV primary infection. Nature Med. 3, 1369–1375 (1997).

    Article  CAS  Google Scholar 

  10. Glushakova, S., Baibakov, B., Zimmerberg, J. & Margolis, L. Experimental HIV infection of human lymphoid tissue: Correlation of CD4+ T cell depletion and virus syncytium-inducing/non-syncytium-inducing phenotype in histoculture inoculated with laboratory strains and patient isolates of HIV type 1. AIDS Res. Retroviruses 13, 461–471 (1997).

    Article  CAS  Google Scholar 

  11. Haase, A.T. et al. Quantitative image analysis of HIV-1 infection in lymphoid tissue. Science 274, 985–989 (1996).

    Article  CAS  Google Scholar 

  12. Casella, C.R. & Finkel, T.H. Mechanisms of lymphocyte killing by HIV. Curr. Opin. Hematol. 4, 24–31 (1997).

    Article  CAS  Google Scholar 

  13. Bjorndal, A. et al. Coreceptor usage of primary human immunodeficiency virus type 1 isolates varies according to biological phenotype. J. Virol. 71, 7478–7487 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Herbein, G. et al. Apoptosis of CD8+ T cells is mediated by macrophages through interaction of HIV gp120 with chemokine receptor CXCR4. Nature 395, 189–194 (1998).

    Article  CAS  Google Scholar 

  15. McDermott, D.H. et al. CCR5 promoter polymorphism and HIV-1 disease progression. Lancet 352, 866–870 (1998).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The authors thank P. Murphy and J. Zimmerberg for many discussions, encouragement and support. This work was supported in part by the NASA/NIH Center for Three-Dimensional Tissue Culture.

Author information

Authors and Affiliations

  1. Laboratory of Molecular and Cellular Biophysics, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, 20892, Maryland, USA

    Jean-Charles Grivel & Leonid B. Margolis

Authors
  1. Jean-Charles Grivel
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Leonid B. Margolis
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Leonid B. Margolis.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Grivel, JC., Margolis, L. CCR5- and CXCR4-tropic HIV-1 are equally cytopathic for their T-cell targets in human lymphoid tissue. Nat Med 5, 344–346 (1999). https://doi.org/10.1038/6565

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/6565

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing