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

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.

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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.

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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).

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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.

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Correspondence to Kathleen L Collins.

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The authors declare no competing financial interests.

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

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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

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