Human immunodeficiency virus type 1 envelope glycoprotein gp120 produces immune defects in CD4+ T lymphocytes by inhibiting interleukin 2 mRNA.

Oyaizu, Naoki; Chirmule, Narendra; Kalyanaraman, Vaniambadi S.; Hall, William W.; Pahwa, Rajendra; Shüster, Michael; Pahwa, Savita

doi:10.1073/pnas.87.6.2379

Cited by 131 publications

(68 citation statements)

References 46 publications

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“…6), presumably by blocking HIV gp120 from binding CD4 on the surfaces of T cells. These findings are consistent with many previous reports that describe HIV gp120-mediated inhibition of T cell signaling and proliferation (37)(38)(39)(40)(41). Unlike other work, however, HIV gp120 did not induce apoptosis in DC-T cell cocultures (data not shown).…”

Section: Discussionsupporting

confidence: 83%

Decreased Stimulation of CD4+ T Cell Proliferation and IL-2 Production by Highly Enriched Populations of HIV-Infected Dendritic Cells

Kawamura

Gatanaga

Borris³

et al. 2003

The Journal of Immunology

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APC infection and dysfunction may contribute to the immunopathogenesis of HIV disease. In this study, we examined immunologic function of highly enriched populations of HIV-infected monocyte-derived dendritic cells (DC). Compared with uninfected DC, HIV-infected DC markedly down-regulated surface expression of CD4. HIV p24+ DC were then enriched by negative selection of CD4+HIV p24− DC and assessed for cytokine secretion and immunologic function. Although enriched populations of HIV-infected DC secreted increased IL-12p70 and decreased IL-10, these cells were poor stimulators of allogeneic CD4+ T cell proliferation and IL-2 production. Interestingly, HIV-infected DC secreted HIV gp120 and the addition of soluble (s) CD4 (a known ligand for HIV gp120) to DC-CD4+ T cell cocultures restored T cell proliferation in a dose-dependent manner. By contrast, addition of antiretroviral drugs did not affect CD4+ T cell proliferation. Furthermore, recombinant HIV gp120 inhibited proliferation in uninfected cocultures of allogeneic DC and CD4+ T cells, an effect that was also reversed by addition of sCD4. In summary, we show that HIV gp120 produced by DC infected by HIV in vitro impairs normal CD4+ T cell function and that sCD4 completely reverses HIV gp120-mediated immunosuppression. We hypothesize that HIV-infected DC may contribute to impaired CD4+ T cell-mediated immune responses in vivo and that agents that block this particular immunosuppression may be potential immune adjuvants in HIV-infected individuals.

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Section: Discussionsupporting

confidence: 83%

Decreased Stimulation of CD4+ T Cell Proliferation and IL-2 Production by Highly Enriched Populations of HIV-Infected Dendritic Cells

Kawamura

Gatanaga

Borris³

et al. 2003

The Journal of Immunology

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“…CD4 receptors play a crucial role in enhancing sensitivity of TCR-triggered T cell activation by interacting with MHC class II (MHC II) molecules on APCs (25,26) and by their noncovalent interaction with the src family tyrosine kinase p56 lck whose activation initiates TCR signaling progression (26)(27)(28)(29). In line with this, a plethora of in vitro studies provide experimental proof that gp120 binding to the CD4 receptor interferes with TCR-induced CD4 + T cell activation (30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43)(44)(45)(46)(47). However, the effect of noninfectious gp120-CD4 receptor interaction on CD4 + T cell activation is still a contradictory issue in the literature, and the gp120 levels measured in plasma of HIV + patients may be below those that have functional effects on cells in vitro (48).…”

mentioning

confidence: 70%

“…On the other hand, gp120 binding to CD4 + T cells was shown to reduce their activation mediated through TCR stimulation (30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43). Mechanisms to explain gp120-induced negative effects on CD4 + T cell activation are manifold: gp120-mediated cross-linking of CD4 receptors was suggested to induce CD4 receptor endocytosis (33,35,36,41,46), to prevent peptide-MHC II-CD4 receptor interaction (37,50) through interference of gp120 with the MHC II binding site on the CD4 receptor (51), to abolish proximal TCR signaling (32,34,38,40,52), or to redistribute p56 lck away from TCRs or from the immunological synapse (IS) (39,53).…”

mentioning

confidence: 99%

The Orientation of HIV-1 gp120 Binding to the CD4 Receptor Differentially Modulates CD4+ T Cell Activation

Zimmermann

Liechti

Haas

et al. 2015

The Journal of Immunology

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Progressive quantitative and qualitative decline of CD4+ T cell responses is one hallmark of HIV-1 infection and likely depends on several factors, including a possible contribution by the HIV-1 envelope glycoprotein gp120, which binds with high affinity to the CD4 receptor. Besides virion-associated and cell-expressed gp120, considerable amounts of soluble gp120 are found in plasma or lymphoid tissue, predominantly in the form of gp120–anti-gp120 immune complexes (ICs). Because the functional consequences of gp120 binding to CD4+ T cells are controversially discussed, we investigated how gp120 affects TCR-mediated activation of human CD4+ T cells by agonistic anti-CD3 mAb or by HLA class II–presented peptide Ags. We show that the spatial orientation of gp120–CD4 receptor binding relative to the site of TCR engagement differentially affects TCR signaling efficiency and hence CD4+ T cell activation. Whereas spatially and temporally linked CD4 and TCR triggering at a defined site promotes CD4+ T cell activation by exceeding local thresholds for signaling propagation, CD4 receptor engagement by gp120-containing ICs all around the CD4+ T cell undermine its capacity in supporting proximal TCR signaling. In vitro, gp120 ICs are efficiently captured by CD4+ T cells and thereby render them hyporesponsive to TCR stimulation. Consistent with these in vitro results we show that CD4+ T cells isolated from HIV+ individuals are covered with ICs, which at least partially contain gp120, and suggest that IC binding to CD4 receptors might contribute to the progressive decline of CD4+ T cell function during HIV-1 infection.

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“…55 The present data on the inhibition of T-cell production of OPG by three strains of HIV-1 gp120 proteins ( Figure 5) add another candidate molecule to the factors suppressed by these glycoproteins. Surprisingly, the HIV-1 96ZM651 gp120 was the only gp120, among the four tested, that has no effect on the OPG production by CD4 þ T cells (Figure 5b), a result also obtained with the whole population of T cells (Figure 5a).…”

Section: Discussionmentioning

confidence: 99%

Normal human primary CD4+ T lymphocytes synthesize and release functional osteoprotegerin in vitro

Chakravarti

Marceau

Flamand

et al. 2008

Laboratory Investigation

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Osteoprotegerin (OPG) acts as a decoy receptor for receptor activator of nuclear factor-kB ligand (RANKL) and TNF-related apoptosis-inducing ligand (TRAIL). OPG regulates bone remodeling and the immune response. The primary objective was to decipher, among human peripheral blood mononuclear leukocytes (PBML) that produce OPG, the subset(s) responsible for this synthesis and its regulation. To this end, normal human PBML and CD4-, 8-, 19-, 14-enriched subpopulations were studied in vitro for OPG synthesis. PBML were subjected to adherence and immunomagnetic separation, and OPG expression was analyzed by PCR, northern and western blotting, and ELISA. The antiapoptotic effects of OPG were studied on TRAIL-stimulated RPMI 8226 myeloma cells. OPG was time-dependently produced by primary CD4 þ T lymphocytes exclusively. OPG secretion was upregulated by anti-CD3 antibody stimulation or incubation with interleukin (IL)-4, IL-1b, TNF-a, GM-CSF, and vitamin D 3 . In contrast, IL-10 inhibited the basal and IL-4-induced production of OPG by T cells. Conditioned media from activated T lymphocytes decreased TRAIL-induced apoptosis of RPMI 8226 cells. This effect was reversed by addition of RANKL to the T-cell conditioned media. As human immunodeficiency virus-1 (HIV-1) targets CD4 þ T cells, we evaluated the effects of recombinant HIV-1 gp120 proteins on OPG synthesis. The gp120 from three different HIV-1 strains significantly reduced the basal output of OPG from T cells. Furthermore, all four protease inhibitors (PIs) used in highly active antiretroviral therapy decreased OPG synthesis by human blood T cells, nelfinavir being the most efficient PI. The simultaneous presence of an HIV-1 gp120 and a PI abrogated the basal output of OPG. In conclusion, these results highlight a new role for T lymphocytes involved in pathologies. Activated CD4 þ T cells could, through OPG release, have a paracrine effect on adjacent cells and contribute to reduce the local process of bone remodeling and cellular apoptosis.

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Human immunodeficiency virus type 1 envelope glycoprotein gp120 produces immune defects in CD4+ T lymphocytes by inhibiting interleukin 2 mRNA.

Cited by 131 publications

References 46 publications

Decreased Stimulation of CD4+ T Cell Proliferation and IL-2 Production by Highly Enriched Populations of HIV-Infected Dendritic Cells

Decreased Stimulation of CD4+ T Cell Proliferation and IL-2 Production by Highly Enriched Populations of HIV-Infected Dendritic Cells

The Orientation of HIV-1 gp120 Binding to the CD4 Receptor Differentially Modulates CD4+ T Cell Activation

Normal human primary CD4+ T lymphocytes synthesize and release functional osteoprotegerin in vitro

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