Human immunodeficiency virus type 1 envelope glycoprotein gp120-mediated killing of human haematopoietic progenitors (CD34+ cells) (original) (raw)
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Archives of Virology, 1992
The effect of increasing concentrations (from 0.01 to 10 ~tg/ml) of HIV-1 envelope glycoproteins gpl60, gpl20, gp41 and core protein p24 was evaluated on the in vitro growth of enriched hematopoietic progenitors (CD34 + cells). Both gpl20 and gpl60, at concentrations from 0.01 to 10 Ixg/ml, caused a progressive and significant (p < 0.05) decrease in viable CD34 + cell count in liquid cultures supplemented with 2 ng/ml of human recombinant (r) interleukin-3 (IL-3), evaluated by means of Trypan-blue exclusion and [3H]thymidine ([3H]TdR) incorporation. In the absence of rlL-3, no inhibitory effects were observed even at the highest gpl60 and gpl20 concentrations explored (10 ~tg/ ml). On the contrary, gp41 and p24 did not affect the number of viable CD34 + cells, either in the presence or in the absence of rIL-3. Moreover, gpl60 and gpl20, but not gp41 and p24, significantly (p < 0.05) inhibited the in vitro growth of granulomacrophage progenitors (CFU-GM) in a dose-dependent fashion. These data clearly demonstrate that HIV-1 envelope glycoproteins inhibit the growth of purified hematopoiefic progenitors. We propose that HIV-1 can impair hematopoiesis through the interaction of gp 120/gp 160 with CD34 + cell surface, independently of an infectious process.
Blood, 1994
We have recently demonstrated that the human immunodeficiency virus type 1 (HIV-1) envelope glycoprotein gp160 enhances the in vitro differentiation of hematopoietic myeloid progenitor cells derived from cord blood by inducing secretion of colony-stimulating factor(s) (CSF) in T cells, presumably through the interaction of gp160 with CD4 molecules. In this study, we investigated the gp 160-induced humoral CSFs in cord blood by enzyme-linked immunosorbent assay (ELISA) and by polymerase chain reaction on reverse-transcribed mRNA (RT-PCR). We demonstrate that gp160 can induce interleukin (IL)-3, IL-6, and granulocyte-macrophage CSF (GM-CSF) protein secretion only in purified cord-blood T cells (CB-T) and not in detectable amounts in whole cord blood cells (WCB); cytokine mRNA induction occurred in purified CB-T and WCB, but was significantly greater in the former. Treatment of gp160 with soluble CD4 (sCD4) abolished the secretion of all three cytokines in CB-T cells, which suggests th...
CD4-Independent inhibition of lymphocyte proliferation mediated by HIV-1 envelope glycoproteins
Virology, 1992
The cytopathic effects of HIV-l produced by direct infection of human T cells do not account for the disproportionate loss of CD4-positive lymphocytes during the course of HIV infection. Previous studies have demonstrated the inhibition of uninfected human T cell activation and proliferation by the HIV-l envelope glycoproteins, presumably due to gpl20-CD4 interactions. To examine the ability of HIV-l to inhibitT cell proliferation in the absence of both direct infection and gpl20-CD4 interactions, we tested the effect of HIV-1 on mouse T cell proliferation. Culture media containing HIV-l released from infected cells inhibited T lymphocyte proliferation in response to interleukin-2 (IL-2). Studies to explore the mechanism of this inhibition suggested that the decrease in proliferation resulted from interactions between HIV-l and the mouse cells, but did not involve IL-2/IL-2 receptor interactions. We used monoclonal antibodies to demonstrate that the HIV-l envelope glycoproteins were required for the inhibition of murine T cell proliferation. Anti-gpl20 antibodies completely restored proliferation, indicating that the surface protein gpl20 was primarily required for the inhibition of proliferation. However, antibodies directed against the transmembrane protein of HIV-1 (gp41) also partially restored lymphocyte proliferation. The functional significance of the HIV-l envelope protein epitopes recognized by the monoclonal antibodies is discussed.
Proceedings of the National Academy of Sciences, 1990
Envelope glycoprotein gp120 of human immunodeficiency virus type 1 (HIV-1) is known to inhibit T-cell function, but little is known about the mechanisms of this immunosuppression. Pretreatment of a CD4+ tetanus toxoid-specific T-cell clone with soluble gp120 was found to exert a dose-dependent inhibition of soluble antigen-driven or anti-CD3 monoclonal antibody-driven proliferative response, interleukin 2 (IL-2) production, and surface IL-2 receptor (IL-2R) alpha-chain expression, all of which were reversed by the addition of exogenous IL-2. mRNA for the gene encoding IL-2 was suppressed by treatment with gp120, but IL-2R gene transcription was not inhibited. Bypass activation of the T-cell clone with phorbol 12-myristate 13-acetate plus ionomycin was unaffected by gp120 pretreatment. Thus, gp120-CD4 interaction interferes with an essential role of the CD4 molecule in signal transduction through the CD3-antigen receptor (Ti) complex. Such a mechanism of gp120-induced immunosuppression, if operative in vivo, could contribute to the depressed specific immune responses associated with HIV infection.
Journal of Virology, 1996
We have used envelope recombinant viruses generated between two molecular clones of human immunodeficiency virus type 1 (HIV-1), T-cell-tropic HIV-1 SF2 and macrophage-tropic HIV-1 SF162 , to assess pathogenic potential in the human peripheral blood leukocyte-reconstituted severe combined immune deficiency mouse model. Recombinant HIV-1 SF2 viruses expressing the envelope gp120 gene of HIV-1 SF162 caused as rapid a CD4 ุ T-cell depletion as did HIV-1 SF162. The reciprocal HIV-1 SF162 recombinant virus with the HIV-1 SF2 envelope caused slower CD4 ุ T-cell loss. Although changing the V3 loop sequence of HIV-1 SF162 to that of HIV-1 SF2 did not change the rate of CD4 ุ T-cell depletion, replacing the V3 of HIV-1 SF2 with the sequence of HIV-1 SF162 resulted in virus that was poorly infectious in vivo but not in vitro. These studies suggest that the envelope gene determines properties important for pathogenesis in vivo as well as for cell tropism in vitro. HIV-1 infection in vivo may have more stringent requirements for envelope conformation.