TY - JOUR
T1 - HIV-1 utilizes the CXCR4 chemokine receptor to infect multipotent hematopoietic stem and progenitor cells
AU - Carter, Christoph C.
AU - McNamara, Lucy A.
AU - Onafuwa-Nuga, Adewunmi
AU - Shackleton, Mark
AU - Riddell IV, James
AU - Bixby, Dale
AU - Savona, Michael R.
AU - Morrison, Sean J.
AU - Collins, Kathleen L.
N1 - Funding Information:
This work was funded by US National Institutes of Health grant RO1 AI051192, MO1-RR000042, the Burroughs Wellcome Foundation, the Rackham Predoctoral Fellowship (C.C.C.), Medical Scientist Training Grant to the University of Michigan (C.C.C.), the Molecular Mechanisms in Microbial Pathogenesis Training Grant to the University of Michigan (C.C.C.), a US National Science Foundation Predoctoral Fellowship (L.A.M.), and a Bernard Maas Fellowship (L.A.M.). M.S. was supported by the Australian National Health and Medical Research Council, the Human Frontiers Science Program. S.M. is an Investigator of the Howard Hughes Medical Institute. We are grateful to the University of Michigan flow cytometry core and the University of Michigan DNA sequencing core for their services. We thank Cosmos van de Ven and the University of Michigan Department of Obstetrics surgical staff for umbilical cord blood. We are indebted to Carole McIntyre-Ramm for assistance with recruitment of donors to our study and for help with human subjects regulatory documentation. 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: pNL4-3 from M. Martin (Viral Pathogenesis and Vaccine Section at the US National Institute of Allergy and Infectious Diseases); p89.6 from R.G. Collman (University of Pennsylvania); p94UG–114.1, pCRII-92HT593.1, and pYU-2 from B. Hahn (University of Alabama, Birmingham); pHXB2-env from Kathleen Page and Dan Littman; HIV-1 clone BaL.01 (Cat #11445) from John Mascola; CEM.NKR-CCR5 from Alexandra Trkola; bicyclam JM-2987 (hydrobromide salt of AMD-3100) and maraviroc (Cat #11580) pCMV-HIV-1 and pHIV-7/SF-GFP were gifts of S.-J.-K. Yee (City of Hope National Medical Center). The YU2 env expression plasmid was a kind gift of Joseph Sodroski.
PY - 2011/3/17
Y1 - 2011/3/17
N2 - HIV infection is characterized by gradual immune system collapse and hematopoietic dysfunction. We recently showed that HIV enters multipotent hematopoietic progenitor cells and establishes both active cytotoxic and latent infections that can be reactivated by myeloid differentiation. However, whether these multipotent progenitors include long-lived hematopoietic stem cells (HSCs) that could establish viral reservoirs for the life of the infected person remains unknown. Here we provide direct evidence that HIV targets long-lived HSCs and show that infected HSCs yield stable, multilineage engraftment in a xenograft model. Furthermore, we establish that the capacity to use the chemokine receptor CXCR4 for entry determines whether a virus will enter multipotent versus differentiated progenitor cells. Because HSCs live for the life span of the infected person and are crucial for hematopoietic health, these data may explain the poor prognosis associated with CXCR4-tropic HIV infection and suggest HSCs as long-lived cellular reservoirs of latent HIV.
AB - HIV infection is characterized by gradual immune system collapse and hematopoietic dysfunction. We recently showed that HIV enters multipotent hematopoietic progenitor cells and establishes both active cytotoxic and latent infections that can be reactivated by myeloid differentiation. However, whether these multipotent progenitors include long-lived hematopoietic stem cells (HSCs) that could establish viral reservoirs for the life of the infected person remains unknown. Here we provide direct evidence that HIV targets long-lived HSCs and show that infected HSCs yield stable, multilineage engraftment in a xenograft model. Furthermore, we establish that the capacity to use the chemokine receptor CXCR4 for entry determines whether a virus will enter multipotent versus differentiated progenitor cells. Because HSCs live for the life span of the infected person and are crucial for hematopoietic health, these data may explain the poor prognosis associated with CXCR4-tropic HIV infection and suggest HSCs as long-lived cellular reservoirs of latent HIV.
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U2 - 10.1016/j.chom.2011.02.005
DO - 10.1016/j.chom.2011.02.005
M3 - Article
C2 - 21402361
AN - SCOPUS:79952653986
SN - 1931-3128
VL - 9
SP - 223
EP - 234
JO - Cell Host and Microbe
JF - Cell Host and Microbe
IS - 3
ER -