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:

Replication and compartmentalization of HIV-1 in kidney epithelium of patients with HIV-associated nephropathy

Abstract

HIV-associated nephropathy is a clinicopathologic entity that includes proteinuria, focal segmental glomerulosclerosis often of the collapsing variant, and microcystic tubulointerstitial disease1,2,3,4. Increasing evidence supports a role for HIV-1 infection of renal epithelium in the pathogenesis of HIV-associated nephropathy5,6,7,8. Using in situ hybridization, we previously demonstrated HIV-1 gag and nef mRNA in renal epithelial cells of patients with HIV-associated nephropathy9. Here, to investigate whether renal epithelial cells were productively infected by HIV-1, we examined renal tissue for the presence of HIV-1 DNA and mRNA by in situ hybridization and PCR, and we molecularly characterized the HIV-1 quasispecies in the renal compartment. Infected renal epithelial cells were removed by laser-capture microdissection from biopsies of two patients, DNA was extracted, and HIV-1 V3-loop or gp120-envelope sequences were amplified from individually dissected cells by nested PCR. Phylogenetic analysis of kidney-derived sequences as well as corresponding sequences from peripheral blood mononuclear cells of the same patients revealed evidence of tissue-specific viral evolution. In phylogenetic trees constructed from V3 and gp120 sequences, kidney-derived sequences formed tissue-specific subclusters within the radiation of blood mononuclear cell-derived viral sequences from both patients. These data, along with the detection of HIV-1-specific proviral DNA and mRNA in tubular epithelium cells, argue strongly for localized replication of HIV-1 in the kidney and the existence of a renal viral reservoir.

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

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

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

Figure 1: Detection of viral nucleic acids in renal biopsies.
Figure 2: Analysis of the T-cell receptor rearrangement in microdissected tissue.
Figure 3: Quasispecies complexity of kidney and PBMC-derived from 2 patients with HIVAN.

Similar content being viewed by others

Accession codes

Accessions

GenBank/EMBL/DDBJ

References

  1. Rao, T.K., Friedman, E.A. & Nicastri, A.D. The types of renal disease in the acquired immunodeficiency syndrome. N. Engl. J. Med. 316, 1062–1068 (1987).

    Article  CAS  Google Scholar 

  2. Strauss, J. et al. Renal disease in children with the acquired immunodeficiency syndrome. N. Engl. J. Med. 321, 625–630 (1989).

    Article  CAS  Google Scholar 

  3. Winston, J.A., Burns, G.C. & Klotman, P.E. Treatment of HIV-associated nephropathy. Semin. Nephrol. 20, 293–298 (2000).

    CAS  PubMed  Google Scholar 

  4. Humphreys, M.H. Human immunodeficiency virus-associated glomerulosclerosis. Kidney Int. 48, 311–320 (1995).

    Article  CAS  Google Scholar 

  5. Dickie, P. et al. HIV-associated nephropathy in transgenic mice expressing HIV-1 genes. Virology 185, 109–119 (1991).

    Article  CAS  Google Scholar 

  6. Bruggeman, L.A. et al. Nephropathy in human immunodeficiency virus-1 transgenic mice is due to renal transgene expression. J. Clin. Invest. 100, 84–92 (1997).

    Article  CAS  Google Scholar 

  7. Cohen, A.H., Sun, N.C., Shapshak, P. & Imagawa, D.T. Demonstration of human immunodeficiency virus in renal epithelium in HIV-associated nephropathy. Mod. Pathol. 2, 125–128 (1989).

    CAS  PubMed  Google Scholar 

  8. Winston, J.A. et al. Nephropathy and establishment of a renal reservoir of HIV type 1 during primary infection. N. Engl. J. Med. 344, 1979–1984 (2001).

    Article  CAS  Google Scholar 

  9. Bruggeman, L.A. et al. Renal Epithelium is a previously unrecognized site of HIV-1 infection. J Am Soc Nephrol (2000).

  10. Cantor, E.S., Kimmel, P.L. & Bosch, J.P. Effect of race on expression of acquired immunodeficiency syndrome-associated nephropathy. Arch. Intern. Med. 151, 125–128 (1991).

    Article  CAS  Google Scholar 

  11. US Renal Data System. (National Institute Of Health, NIDDK, Bethesda, Maryland, 1997).

  12. Bourgoignie, J.J., Ortiz-Interian, C., Green, D.F. & Roth, D. Race, a cofactor in HIV-1-associated nephropathy. Transplant Proc. 21, 3899–3901 (1989).

    CAS  PubMed  Google Scholar 

  13. Deng, H. et al. Identification of a major co-receptor for primary isolates of HIV-1. Nature 381, 661–666 (1996).

    Article  CAS  Google Scholar 

  14. Hoffman, T.L., Stephens, E.B., Narayan, O. & Doms, R.W. HIV type I envelope determinants for use of the CCR2b, CCR3, STRL33, and APJ coreceptors. Proc. Natl. Acad. Sci. USA 95, 11360–1135 (1998).

    Article  CAS  Google Scholar 

  15. Choe, H. et al. The orphan seven-transmembrane receptor apj supports the entry of primary T-cell-line-tropic and dualtropic human immunodeficiency virus type 1. J. Virol. 72, 6113–6118 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Owman, C. et al. The leukotriene B4 receptor functions as a novel type of coreceptor mediating entry of primary HIV-1 isolates into CD4-positive cells. Proc. Natl. Acad. Sci. USA 95, 9530–9534 (1998).

    Article  CAS  Google Scholar 

  17. Moore, J.P. Coreceptors: Implications for HIV pathogenesis and therapy. Science 276, 51–52 (1997).

    Article  CAS  Google Scholar 

  18. Eitner, F. et al. Chemokine receptor CCR5 and CXCR4 expression in HIV-associated kidney disease. J. Am. Soc. Nephrol. 11, 856–867 (2000).

    CAS  PubMed  Google Scholar 

  19. Conaldi, P.G. et al. HIV-1 kills renal tubular epithelial cells in vitro by triggering an apoptotic pathway involving caspase activation and Fas upregulation. J. Clin. Invest. 102, 2041–2049 (1998).

    Article  CAS  Google Scholar 

  20. Mack, M. et al. Transfer of the chemokine receptor CCR5 between cells by membrane-derived microparticles: A mechanism for cellular human immunodeficiency virus 1 infection. Nature Med. 6, 769–775 (2000).

    Article  CAS  Google Scholar 

  21. Meng, G. et al. Primary intestinal epithelial cells selectively transfer R5 HIV-1 to CCR5+ cells. Nature Med. 8, 150–156 (2002).

    Article  CAS  Google Scholar 

  22. Lagaye, S. et al. Cell-to-cell contact results in a selective translocation of maternal human immunodeficiency virus type 1 quasispecies across a trophoblastic barrier by both transcytosis and infection. J. Virol. 75, 4780–4791 (2001).

    Article  CAS  Google Scholar 

  23. Chun, T.W. et al. Presence of an inducible HIV-1 latent reservoir during highly active antiretroviral therapy. Proc. Natl. Acad. Sci. USA 94, 13193–13197 (1997).

    Article  CAS  Google Scholar 

  24. Bukrinsky, M.I., Stanwick, T.L., Dempsey, M.P. & Stevenson, M. Quiescent T lymphocytes as an inducible virus reservoir in HIV-1 infection. Science 254, 423–427 (1991).

    Article  CAS  Google Scholar 

  25. Tanji, N. Effect of tissue processing on the ability to recover nucleic acid from specific renal tissue compartment. Exp Nephrol. (2000).

  26. Emmert-Buck, M.R. et al. Laser capture microdissection. Science 274, 998–1001 (1996).

    Article  CAS  Google Scholar 

  27. Bottaro, M., Berti, E., Biondi, A., Migone, N. & Crosti, L. Heteroduplex analysis of T-cell receptor γ gene rearrangements for diagnosis and monitoring of cutaneous T-cell lymphomas. Blood 83, 3271–3278 (1994).

    CAS  PubMed  Google Scholar 

  28. Higgins, D.G., Thompson, J.D. & Gibson, T.J. Using CLUSTAL for multiple sequence alignments. Meth. Enzymol. 266, 383–402 (1996).

    Article  CAS  Google Scholar 

  29. Faulkner, D.V. & Jurka, J. Multiple aligned sequence editor (MASE). Trends Biochem. Sci. 13, 321–322 (1988).

    Article  CAS  Google Scholar 

  30. Kimura, M. A simple method for estimating evolutionary rates of base substitutions through comparative studies of nucleotide sequences. J. Mol. Evol. 16, 111–120 (1980).

    CAS  Google Scholar 

  31. Saitou, N. & Nei, M. The neighbor-joining method: A new method for reconstructing phylogenetic trees. Mol. Biol. Evol. 4, 406–425 (1987).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank I. Gelman for critical review of the manuscript and W. Abbott for artwork preparation. This work was supported by grants from the National Institute of Health P01 DK50795, P01 DK56492, N01 AI85338 and P20AI27767, and the National Science Foundation (to G.B.) CCR-0073081 and DBI-0090789.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Daniele Marras.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Marras, D., Bruggeman, L., Gao, F. et al. Replication and compartmentalization of HIV-1 in kidney epithelium of patients with HIV-associated nephropathy. Nat Med 8, 522–526 (2002). https://doi.org/10.1038/nm0502-522

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm0502-522

This article is cited by

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