Primitive hematopoietic cells resist HIV-1 infection via p21Waf1/Cip1/Sdi1

Abstract

Hematopoietic stem cells are resistant to HIV-1 infection. Here, we report a novel mechanism by which the cyclin-dependent kinase inhibitor (CKI) p21 Waf1/Cip1/Sdi1 (p21), a known regulator of stem cell pool size, restricts HIV-1 infection of primitive hematopoietic cells. Modifying p21 expression altered HIV-1 infection prior to changes in cell cycling and was selective for p21 since silencing the related CKIs, p27 Kip1 and p18 INK4C , had no effect on HIV-1. We show that p21 blocked viral infection by complexing with HIV-1 integrase and aborting chromosomal integration. A closely related lentivirus with a distinct integrase, SIVmac-251, and the other cellintrinsic inhibitors of HIV-1, Trim5α, PML, Murr1, and IFN-α, were unaffected by p21. Therefore, p21 is an endogenous cellular component in stem cells that provides a unique molecular barrier to HIV-1 infection and may explain how these cells remain an uninfected "sanctuary" in HIV disease.

HIV-1 Pathogenesis: The Virus

“…Cite this article as Cold Spring Harb Perspect Med 2012;2:a007443 www.perspectivesinmedicine.org they are relatively difficult to infect in culture (Shen et al 1999;Zhang et al 2007). More recently, interest in this phenomenon has focused on potential pathogenic outcomes such as anemia (Redd et al 2007), or as a source of long-lived virus making up part of the HIV-1 latent reservoir (Carter et al 2010).…”

Hematopoietic stem and progenitor cells in HIV/AIDS and immune reconstitution

“…As HSCs represent only 0.5-3% of mononuclear cells in human bone marrow, researchers have used CD34 + primary bone marrow cells without a further selection of the CD38 marker nor test of cell function with long-term culture-initiating cell assay (LTC-IC) [1][2][3][4][10][11][12][13]. These CD34 + primary hematopoietic stem and progenitor cells are dubbed HSPC [1][2][3][4][10][11][12][13]. The multipotent progenitor cells, however, are named MPPs, and these cells possess multipotentiality but have a function for limited self-renewal ( Figure 1).…”

“…The pseudo-viruses have no difficulty in entering HPCs following the spin infection and they accomplish this more easily than a routine infection with the HIV-1 virus [1][2][3][4][5][6][7]. The HIV-1 Gag in the pseudo-viruses can be easily detected with flow cytometry without a further expression of gag gene from the pseudo-viruses in the cell.…”

“…HIV-1 infects human immune cells, specifically CD4 + lymphocytes, which leads to AIDS and undermines reconstitution of immunity. The unique challenges of HIV/AIDS have triggered multidisciplinary investigators to study the virology of the pathogen and the biology of the host cells, especially the interactions of HIV-1 with T-lymphocytes, macrophages, and hematopoietic stem and progenitor cells (HSPC) [1][2][3][4][5][6][7][8].…”

Gene therapy approaches for stem cell protection

“…36,37,39 Furthermore, the subset of nucleated bone marrow cells known to contain totipotential lymphohematopoietic stem cells is difficult to isolate without pushing their differentiation, or overcoming resistance to viral vectors or other transfection methods. 42 Transient overexpression of antioxidant genes in hematopoietic progenitor cells confers protection against ionizing irradiation, TNFa and growth factor deprivation. 11 MnSOD transgene overexpression in bone marrow and esophageal stem cell subsets has been achieved using plasmid liposome transfection and has been shown to confer radiation protection.…”