Human immunodeficiency virus type 1 envelope glycoprotein gp120-mediated killing of human haematopoietic progenitors (CD34+ cells) (original) (raw)
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.
Blood, 1998
We have evaluated the susceptibility to human immunodeficiency virus (HIV)-1 infection of in vitro grown megakaryopoietic progenitors/precursors and maturing megakaryocytes (MKs), based on the following approach: (1) human hematopoietic progenitor cells (HPCs), stringently purified from peripheral blood and grown in serum-free liquid suspension culture supplemented with thrombopoietin (Tpo), generated a relatively large number of H 98% to 99% pure megakaryocytic precursors and then mature-terminal MKs; (2) at different days of culture (ie, 0, 5, 8, 10) the cells were inoculated with 0.1 to 1.0 multiplicity of infection (m.o.i.) of the lymphotropic NL4-3 or 0.1 m.o.i. of the monocytotropic BaL-1 HIV-1 strain; (3) finally, the presence of viral mRNA and proteins was analyzed by reverse transcriptase-polymerase chain reaction (RT-PCR)/in situ hybridization and antigen capture assays, respectively, on day 2 to 12 of culture. MKs derived from day 0 and day 5 BaL-1-challenged cells do not support viral replication as assessed by p24 enzyme-linked immunosorbent assay (ELISA) and RT-PCR. On the contrary, HIV transcripts and proteins were clearly detected in all NL4-3 infection experiments by RT-PCR and p24 assay, respectively, with the highest viral expression in day 5 to 8 challenged MKs. In situ hibridization studies indicate that the percentage of HIV ؉ MKs varies from at least 1% and 5% for day 0 and day 5 infected cells, respectively. Production of an infectious viral progeny, evaluated by the capability of culture supernatants from day 5 NL4-3-challenged MKs to infect C8166 T-lymphoblastoid cell line, was consistently observed (viral titer, Ϸ 5 ؋ 10 3 tissue culture infectious dose 50 /mL/10 6 cells). Exposure of MKs to saturating concentration of anti-CD4 OKT4A monoclonal antibody (MoAb), which recognizes the CD4 region binding with the gp120 envelope glycoprotein, markedly inhibited HIV infection, as indicated by a reduction of p24 content in the supernatants: because the inhibitory effect was incomplete, it is apparent that the infection is only partially CD4-dependent, suggesting that an alternative mechanism of viral entry may exist. Morphologic analysis of day 12 MKs derived from HPCs infected at day 0 showed an impaired megakaryocytic differentiation/maturation: the percentage of mature MKs was markedly reduced, in that Ϸ 80% of cells showed only one nuclear lobe and a pale cytoplasm with few granules. Conversely, megakaryocytic precursors challenged at day 5 to 8 generated fully mature day 10 to 12 MKs showing multiple nuclear segmentation. Thus, the inhibitory effect of HIV on the megakaryopoietic gene program relates to the differentiation stage of cells subjected to the viral challenge. Finally, HPCs treated with 20 or 200 ng/mL of recombinant Tat protein, analyzed at different days of culture, showed an impaired megakaryocytopoiesis comparable to that observed in HIV-infected cells, thus suggesting that Tat is a major mediator in the above described phenomena. These results shed light on the pathogenesis of HIV-related thrombocytopenia; furthermore, they provide a model to investigate the effects of HIV on megakaryocytic differentiation and function.
1995
immunodeficiency virus type 1 isolates. primary and T-cell line-passaged human sensitivity of envelope glycoproteins from Replicative function and neutralization http://jvi.asm.org/content/69/7/4413 Updated information and services can be found at: These include: CONTENT ALERTS more» cite this article), Receive: RSS Feeds, eTOCs, free email alerts (when new articles http://journals.asm.org/site/misc/reprints.xhtml Information about commercial reprint orders: http://journals.asm.org/site/subscriptions/ To subscribe to to another ASM Journal go to: on December 18, 2013 by guest http://jvi.asm.org/ Downloaded from on December 18, 2013 by guest
Blood, 1992
A number of hematologic abnormalities, including cytopenias, have been observed in patients with human immunodeficiency virus (HIV) infection. To elucidate their mechanisms, a group of 27 patients with HIV-1 infection was studied. In all patients, a marked reduction of in vitro colony formation by erythroid, granulomacrophagic, and megakaryocytic bone marrow progenitors was observed in comparison to normal donors. HIV-1 infection of marrow progenitors was investigated in studying individual colonies with the polymerase chain reaction (PCR) technique. No HIV-1 DNA could be detected in these colonies, suggesting either that marrow progenitors were not infected or that infected progenitors were not able to generate colonies in vitro. The addition of antisense oligonucleotides directed against HIV tat or nef sequences in the culture medium led to a significant increase in colony formation, suggesting that HIV replication in hematopoietic progenitors could be responsible for their defect...