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:

HIV-1 infects multipotent progenitor cells causing cell death and establishing latent cellular reservoirs

Nature Medicine volume 16, pages 446–451 (2010)Cite this article

Subjects

Abstract

HIV causes a chronic infection characterized by depletion of CD4+ T lymphocytes and the development of opportunistic infections. Despite drugs that inhibit viral spread, HIV infection has been difficult to cure because of uncharacterized reservoirs of infected cells that are resistant to highly active antiretroviral therapy (HAART) and the immune response. Here we used CD34+ cells from infected people as well as in vitro studies of wild-type HIV to show infection and killing of CD34+ multipotent hematopoietic progenitor cells (HPCs). In some HPCs, we detected latent infection that stably persisted in cell culture until viral gene expression was activated by differentiation factors. A unique reporter HIV that directly detects latently infected cells in vitro confirmed the presence of distinct populations of active and latently infected HPCs. These findings have major implications for understanding HIV bone marrow pathology and the mechanisms by which HIV causes persistent infection.

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

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

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

Figure 1: HIV genomes.
Figure 2: HIV actively infects HPCs, leading to cell death.
Figure 3: HIV infects multipotent HPCs.
Figure 4: Induction of HIV from latency.
Figure 5: Active and latent infection in T cells and HPCs.
Figure 6: Active and inducible infection in HPCs from HIV+ people.

Similar content being viewed by others

References

  1. 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 

  2. Bailey, J.R. et al. Residual human immunodeficiency virus type 1 viremia in some patients on antiretroviral therapy is dominated by a small number of invariant clones rarely found in circulating CD4+ T cells. J. Virol. 80, 6441–6457 (2006).

    Article  CAS  Google Scholar 

  3. Neal, T.F. et al. CD34+ progenitor cells from asymptomatic patients are not a major reservoir for human immunodeficiency virus-1. Blood 86, 1749–1756 (1995).

    CAS  PubMed  Google Scholar 

  4. Weichold, F.F. et al. Neither human immunodeficiency virus-1 (HIV-1) nor HIV-2 infects most-primitive human hematopoietic stem cells as assessed in long-term bone marrow cultures. Blood 91, 907–915 (1998).

    CAS  PubMed  Google Scholar 

  5. Majka, M. et al. Bone marrow CD34+ cells and megakaryoblasts secrete β-chemokines that block infection of hematopoietic cells by M-tropic R5 HIV. J. Clin. Invest. 104, 1739–1749 (1999).

    Article  CAS  Google Scholar 

  6. Zhang, J., Scadden, D.T. & Crumpacker, C.S. Primitive hematopoietic cells resist HIV-1 infection via p21. J. Clin. Invest. 117, 473–481 (2007).

    Article  CAS  Google Scholar 

  7. Zhang, C.C., Kaba, M., Iizuka, S., Huynh, H. & Lodish, H.F. Angiopoietin-like 5 and IGFBP2 stimulate ex vivo expansion of human cord blood hematopoietic stem cells as assayed by NOD/SCID transplantation. Blood 111, 3415–3423 (2008).

    Article  CAS  Google Scholar 

  8. Collman, R. et al. An infectious molecular clone of an unusual macrophage-tropic and highly cytopathic strain of human immunodeficiency virus type 1. J. Virol. 66, 7517–7521 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Schwartz, O., Marechal, V., Le Gall, S., Lemonnier, F. & Heard, J.M. Endocytosis of major histocompatibility complex class I molecules is induced by the HIV-1 Nef protein. Nat. Med. 2, 338–342 (1996).

    Article  CAS  Google Scholar 

  10. Collins, K.L., Chen, B.K., Kalams, S.A., Walker, B.D. & Baltimore, D. HIV-1 Nef protein protects infected primary cells against killing by cytotoxic T lymphocytes. Nature 391, 397–401 (1998).

    Article  CAS  Google Scholar 

  11. Caux, C., Dezutter-Dambuyant, C., Schmitt, D. & Banchereau, J. GM-CSF and TNF-α cooperate in the generation of dendritic Langerhans cells. Nature 360, 258–261 (1992).

    Article  CAS  Google Scholar 

  12. 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. 70, 6044–6053 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Gasmi, M. et al. Requirements for efficient production and transduction of human immunodeficiency virus type 1–based vectors. J. Virol. 73, 1828–1834 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Yam, P.Y. et al. Design of HIV vectors for efficient gene delivery into human hematopoietic cells. Mol. Ther. 5, 479–484 (2002).

    Article  CAS  Google Scholar 

  15. Yamamoto, N. et al. Analysis of human immunodeficiency virus type 1 integration by using a specific, sensitive and quantitative assay based on real-time polymerase chain reaction. Virus Genes 32, 105–113 (2006).

    Article  CAS  Google Scholar 

  16. Zufferey, R. et al. Self-inactivating lentivirus vector for safe and efficient in vivo gene delivery. J. Virol. 72, 9873–9880 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Davis, T.A. et al. Phorbol esters induce differentiation of human CD34+ hemopoietic progenitors to dendritic cells: evidence for protein kinase C–mediated signaling. J. Immunol. 160, 3689–3697 (1998).

    CAS  PubMed  Google Scholar 

  18. Kuroda, H., Kutner, R.H., Bazan, N.G. & Reiser, J. Simplified lentivirus vector production in protein-free media using polyethylenimine-mediated transfection. J. Virol. Methods 157, 113–121 (2008).

    Article  Google Scholar 

  19. Kohno, T. et al. A new improved method for the concentration of HIV-1 infective particles. J. Virol. Methods 106, 167–173 (2002).

    Article  CAS  Google Scholar 

  20. Yamamoto, N. et al. Analysis of human immunodeficiency virus type 1 integration by using a specific, sensitive and quantitative assay based on real-time polymerase chain reaction. Virus Genes 32, 105–113 (2006).

    Article  CAS  Google Scholar 

  21. Clouse, K.A. et al. Monokine regulation of human immunodeficiency virus-1 expression in a chronically infected human T cell clone. J. Immunol. 142, 431–438 (1989).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was funded by US National Institutes of Health grant RO1 AI051192, MO1-RR000042, the Burroughs Wellcome Foundation, the University of Michigan Molecular Mechanisms in Microbial Pathogenesis Training Grant (C.C.C.), the Rackham Predoctoral Fellowship (C.C.C.), a US National Science Foundation predoctoral fellowship (L.A.M.) and a Bernard Maas Fellowship (L.A.M.). We thank C. van de Ven (University of Michigan) for umbilical cord blood and C. McIntyre-Ramm for assistance with human studies. The following reagents were obtained through the AIDS Research and Reference Reagent Program, Division of AIDS, National Institute of Allergy and Infectious Diseases, US National Institutes of Health: p89.6 from R.G. Collman (University of Pennsylvania), pNL4-3 from M. Martin (Viral Pathogenesis and Vaccine Section at the US National Institute of Allergy and Infectious Diseases), p94UG–114.1 and pYU-2 from B. Hahn (University of Alabama at Birmingham) and pMJ4 from T. Ndung'u (Nelson Mandela School of Medicine), B. Renjifo (Harvard School of Public Health) and M. Essex (Harvard School of Public Health). pCMV-G was from N. Hopkins, (Massachusetts Institute of Technology), pCMV-HIV-1 and pHIV-7/SF-GFP were from S.-J.-K. Yee (City of Hope National Medical Center) and pEGFP-N2-LAMP1 was from N. Andrews (Yale University).

Author information

Author notes

  1. Michael R Savona

    Present address: Current address: Division of Hematology, Blood and Bone Marrow Transplantation, San Antonio Military Medical Center, Department of Internal Medicine, University of Texas Health Science Center, San Antonio, Texas, USA.,

  2. Christoph C Carter and Adewunmi Onafuwa-Nuga: These authors contributed equally to this work.

Authors and Affiliations

  1. Graduate Program in Cellular and Molecular Biology, University of Michigan, Ann Arbor, Michigan, USA

    Christoph C Carter & Kathleen L Collins

  2. Medical Scientist Training Program, University of Michigan, Ann Arbor, Michigan, USA

    Christoph C Carter & Kathleen L Collins

  3. Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA

    Adewunmi Onafuwa-Nuga, James Riddell IV, Dale Bixby, Michael R Savona & Kathleen L Collins

  4. Department of Microbiology and Immunology, University of Michigan, Ann Arbor, Michigan, USA

    Lucy A McNamara & Kathleen L Collins

  5. Department of Epidemiology, University of Michigan, Ann Arbor, Michigan, USA

    Lucy A McNamara

Authors
  1. Christoph C Carter
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Adewunmi Onafuwa-Nuga
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Lucy A McNamara
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. James Riddell IV
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Dale Bixby
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Michael R Savona
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Kathleen L Collins
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

C.C.C., L.A.M. and A.O.-N. conducted in vitro experiments and data analysis and assisted with writing the manuscript. J.R. IV assisted with human subjects. M.R.S. and D.B. obtained bone marrow aspirates and assisted with human subjects. K.L.C. supervised the project and wrote the manuscript.

Corresponding author

Correspondence to Kathleen L Collins.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–7 and Supplementary Table 1 (PDF 709 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Carter, C., Onafuwa-Nuga, A., McNamara, L. et al. HIV-1 infects multipotent progenitor cells causing cell death and establishing latent cellular reservoirs. Nat Med 16, 446–451 (2010). https://doi.org/10.1038/nm.2109

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm.2109

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