Latent HIV-1 infection occurs in multiple subsets of hematopoietic progenitor cells and is reversed by NF-κB activation.
The ability of HIV-1 to establish a latent infection presents a barrier to curing HIV. The best-studied reservoir of latent virus in vivo is resting memory CD4(+) T cells, but it has recently been shown that CD34(+) hematopoietic progenitor cells (HPCs) can also become latently infected by HIV-1 in vitro and in vivo. CD34(+) cells are not homogenous, however, and it is not yet known which types of CD34(+) cells support a latent infection. Furthermore, the mechanisms through which latency is established in this cell type are not yet known. Here we report the development of a primary cell model for latent HIV-1 infection in HPCs. We demonstrate that in this model, latent infection can be established in all subsets of HPCs examined, including HPCs with cell surface markers consistent with immature hematopoietic stem and progenitor cells. We further show that the establishment of latent infection in these cells can be reversed by tumor necrosis factor alpha (TNF-α) through an NF-κB-dependent mechanism. In contrast, we do not find evidence for a role of positive transcription elongation factor b (P-TEFb) in the establishment of latent infection in HPCs. Finally, we demonstrate that prostratin and suberoylanilide hydroxamic acid (SAHA), but not hexamethylene bisacetamide (HMBA) or 5-aza-2'-deoxycytidine (Aza-CdR), reactivate latent HIV-1 in HPCs. These findings illuminate the mechanisms through which latent infection can be established in HPCs and suggest common pathways through which latent virus could be reactivated in both HPCs and resting memory T cells to eliminate latent reservoirs of HIV-1.
Department of Microbiology and Immunology, University of Michigan, Ann Arbor, Michigan, USA.
Lucy A
LA
McNamara
Janani A
JA
Ganesh
Kathleen L
KL
Collins
D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism / Q000821:virology; D002460:Cell Line; D002478:Cells, Cultured; D015658:HIV Infections / Q000235:genetics / Q000378:metabolism* / Q000821:virology*; D015497:HIV-1 / Q000502:physiology*; D006412:Hematopoietic Stem Cells / Q000378:metabolism / Q000821:virology*; D006801:Humans; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D017735:Virus Latency
D016328:NF-kappa B