CD4 is expressed on a heterogeneous subset of hematopoietic progenitors, which persistently harbor CXCR4 and CCR5-tropic HIV proviral genomes in vivo

PLoS Pathogens

Dale Bixby¹  Adewunmi Onafuwa-Nuga²  Valeri Terry²  Norman Markowitz³  Ryan Yucha⁴  Lucy A. McNamara⁴  Robert A. J. Signer⁴  Sean J. Morrison⁴  Frances Taschuk⁴  Kathleen L. Collins⁵  James Riddell IV⁶  Thomas D. Zaikos⁷  Nadia T. Sebastian⁸ 

[1] Children’s Research Institute, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America;Department of Microbiology and Immunology University of Michigan, Ann Arbor, Michigan, United States of America;Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America;Division of Infectious Disease, Department of Internal Medicine University of Michigan, Ann Arbor, Michigan, United States of America;Division of Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, United States of America;Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America;Medical Scientist Training Program, University of Michigan, Ann Arbor, Michigan, United States of America;Program in Cellular and Molecular Biology, University of Michigan, Ann Arbor, Michigan, United States of America

关键词: HIV;    T cells;    Cell differentiation;    Flow cytometry;    Polymerase chain reaction;    HIV infections;    Stem cells;    Bone marrow cells;   

DOI  :  10.1371/journal.ppat.1006509

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

Latent HIV infection of long-lived cells is a barrier to viral clearance. Hematopoietic stem and progenitor cells are a heterogeneous population of cells, some of which are long-lived. CXCR4-tropic HIVs infect a broad range of HSPC subtypes, including hematopoietic stem cells, which are multi-potent and long-lived. However, CCR5-tropic HIV infection is limited to more differentiated progenitor cells with life spans that are less well understood. Consistent with emerging data that restricted progenitor cells can be long-lived, we detected persistent HIV in restricted HSPC populations from optimally treated people. Further, genotypic and phenotypic analysis of amplified env alleles from donor samples indicated that both CXCR4- and CCR5-tropic viruses persisted in HSPCs. RNA profiling confirmed expression of HIV receptor RNA in a pattern that was consistent with in vitro and in vivo results. In addition, we characterized a CD4high HSPC sub-population that was preferentially targeted by a variety of CXCR4- and CCR5-tropic HIVs in vitro. Finally, we present strong evidence that HIV proviral genomes of both tropisms can be transmitted to CD4-negative daughter cells of multiple lineages in vivo. In some cases, the transmitted proviral genomes contained signature deletions that inactivated the virus, eliminating the possibility that coincidental infection explains the results. These data support a model in which both stem and non-stem cell progenitors serve as persistent reservoirs for CXCR4- and CCR5-tropic HIV proviral genomes that can be passed to daughter cells.

【 授权许可】

CC BY