Intrinsic Human Immunodeficiency Virus Type 1 Resistance of Hematopoietic Stem Cells Despite Coreceptor Expression

Abstract

Interactions of human immunodeficiency virus type 1 (HIV-1) with hematopoietic stem cells may define restrictions on immune reconstitution following effective antiretroviral therapy and affect stem cell gene therapy strategies for AIDS. In the present study, we demonstrated mRNA and cell surface expression of HIV-1 receptors CD4 and the chemokine receptors CCR-5 and CXCR-4 in fractionated cells representing multiple stages of hematopoietic development. Chemokine receptor function was documented in subsets of cells by calcium flux in response to a cognate ligand. Productive infection by HIV-1 via these receptors was observed with the notable exception of stem cells, in which case the presence of CD4, CXCR-4, and CCR-5, as documented by single-cell analysis for expression and function, was insufficient for infection. Neither productive infection, transgene expression, nor virus entry was detectable following exposure of stem cells to either wild-type HIV-1 or lentivirus constructs pseudotyped in HIV-1 envelopes of macrophage-tropic, T-cell-tropic, or dualtropic specificity. Successful entry into stem cells of a vesicular stomatitis virus G protein-pseudotyped HIV-1 construct demonstrated that the resistance to HIV-1 was mediated at the level of virus-cell membrane fusion and entry. These data define the hematopoietic stem cell as a sanctuary cell which is resistant to HIV-1 infection by a mechanism independent of receptor and coreceptor expression that suggests a novel means of cellular protection from HIV-1.

Effect of ABC transporters on HIV‐1 infection: inhibition of virus production by theMDR1transporter

“…However, the effect of inhibitors of substrate binding suggests that an active hydrophobic binding domain in P-gp may be at least partially responsible for this phenotype. Our observations could explain a recent report (26) that hematopoietic stem cells are resistant to HIV-1 infection although they express the HIV-1 receptor CD4 and coreceptor CXCR4, since these cells are known to express P-gp (27). These data are also consistent with another recent observation indicating that P-gp overexpressing cells are resistant to other enveloped viruses that enter via the plasma membrane (Y. Raviv, A. Puri, and R. Blumenthal, unpublished results).…”

HIV and SIV infection: the role of cellular restriction and immune responses in viral replication and pathogenesis

“…It has been shown that the block to HIV infection of HSCs occurs at viral fusion and entry. This block to infection can be overridden experimentally, using pseudotyped virus containing the envelope of vesicular stomatis virus G‐type underscoring the role of envelope fusion and entry as a restrictive factor (65). In addition to fusion and viral entry, p21 within the HSC has been shown to play a role in inhibiting infection.…”

Susceptibility of hematopoietic stem cells to pathogens: role in virus/bacteria tropism and pathogenesis

“…Weichold et al [13] have shown that HIV does not infect HSCs in vitro with any signi¢cant frequency, and that infected cells are not represented within long-term bone marrow cultures. In addition, Shen et al have shown that neither productive infection, transgene expression, nor virus entry was detectable following exposure of stem cells to HIV-1 [14]. They postulated that HSC is an example of a primary cell type uniquely protected from HIV-1 infection by endogenous mechanisms.…”