Lymphocyte activation by HIV-1 envelope glycoprotein

Kornfeld, Hardy; Cruikshank, William W.; Pyle, Stephen W.; Berman, Jeffrey S.

doi:10.1038/335445a0

Cited by 214 publications

(92 citation statements)

References 47 publications

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“…This assumption is supported by reported alterations in Ca 2 mobilization, inositol polyphosphate generation and phospholipase C activation observed in T cells from infected patients and in T cells exposed to viral proteins [7][8][9][10]. In a recent work, we found that unresponsiveness of CD4 T cells from HIV-infected individuals after engagement of the CD3 complex was associated with reduced tyrosine phosphorylation and altered levels of p56 lck and p59 fyn tyrosine kinases [11].…”

Section: Introductionsupporting

confidence: 64%

CD4+ lymphocytes from HIV-infected patients display impaired CD45-associated tyrosine phosphatase activity which is enhanced by anti-oxidants

Cayota

Vuillier

González

et al. 1996

Clinical and Experimental Immunology

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SUMMARYIt has been proposed that signal transduction defects may, at least partially, account for the functional impairment of CD4 lymphocytes during HIV-1 infection. Recently, we have demonstrated that unresponsive CD4 lymphocytes from these patients had reduced protein tyrosine phosphorylation after CD3 engagement, and that this defect was associated with constitutively altered levels of p56 lck and p59 fyn kinases. Since CD45 is essential for T cell receptor (TCR) and CD2-mediated activation of protein tyrosine kinases, we study here CD45-associated tyrosine phosphatase activity in resting and activated CD4 T cells from HIV-infected patients. We found a significant decrease in the basal and postactivation phosphatase activity of CD45 which correlated well with impairment of proliferative responses. In addition, decreased levels of cellular thiols observed in resting CD4 lymphocytes from these patients suggested a disturbed redox status. Although expression levels of CD45 were decreased in most patients, a significant recovery of phosphatase activity and proliferative responses was observed in most patients by preincubating cells with N-acetyl-L-cysteine and 2 -mercaptoethanol. In some patients, anti-oxidant treatment failed to significantly enhance phosphatase activity and proliferative responses. The low responses of purified CD4 lymphocytes from these patients were associated with a high ratio of apoptotic cell death which did not appear to be influenced by anti-oxidant treatment.

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Section: Introductionsupporting

confidence: 64%

CD4+ lymphocytes from HIV-infected patients display impaired CD45-associated tyrosine phosphatase activity which is enhanced by anti-oxidants

Cayota

Vuillier

González

et al. 1996

Clinical and Experimental Immunology

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“…Previous studies determined that HIV-1 gp120 can induce migration of bona fide CD4 ϩ and CD8 ϩ T cells. 20,21 These studies showed that this migration can be induced in a CD4-or CXCR4-dependent manner and that migration of resting CD8 ϩ T cells can be induced in a CXCR4-dependent manner. Our results suggest that interaction of gp120 with both CD4 and CXCR4 is required for migration of CD8 ϩ CD4 dim cells.…”

Section: Discussionmentioning

confidence: 99%

Activation of CD8 T cells induces expression of CD4, which functions as a chemotactic receptor

Kitchen

LaForge

Patel

et al. 2002

Blood

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IntroductionThe CD4 protein has many different functions in the development and activity of a T cell. CD4 has an important role in T-helper (Th)-cell development and response to antigen in the context of major histocompatibility complex class II (MHC II). It also serves as an adhesion molecule and a chemotactic receptor, and it has a role in cellular activation. CD4, a 58-kd transmembrane glycoprotein, is a member of the immunoglobulin family of receptors. 1 The extracellular 370-amino acid portion of CD4 is folded into 4 different domains, which are designated D1 to D4. 1 These domains are involved in a variety of interactions with other proteins, such as the T-cell receptor, MHC II,, and human immunodeficiency virus (HIV) gp120. Engagement of CD4 plays an important role in the initiation of events that lead to activation of Th cells or recruitment of those cells to sites of inflammation. The cytoplasmic tail of the CD4 protein was shown to associate noncovalently with Lck, a Src-family protein tyrosine kinase. 2,3 Cross-linking of CD4 with monoclonal antibodies (mAbs) or stimulation of CD4 by IL-16 results in Lck tyrosine phosphorylation and subsequent tyrosine phosphorylation of other cellular proteins. [4][5][6] These tyrosine phosphorylation events lead to modulation of cellular activation and functional responses. 7 CD4 expression is tightly regulated during the T-cell development process, and this control has an important role in T-cell maturation and function. The coordinate cell-surface expression of CD4 and CD8 and the subsequent down-regulation of either CD4 or CD8 are definitive markers of T-cell ontogeny. Furthermore, expression of one of these molecules on mature T cells is indicative of successful selection and commitment of these cells to either the Th or T-cytotoxic lineage. 8 However, previous ideas on the terminal differentiation of a cell into either a CD4 ϩ CD8 Ϫ Th cell or a CD4 Ϫ CD8 ϩ T-cytotoxic cell have been questioned. Several studies, including one of ours, found that activation of mature CD4 Ϫ CD8 ϩ (CD8 single-positive [SP]) T cells by costimulation 9,10 or superantigen stimulation 11 results in expression of CD4, which renders these cells susceptible to infection by HIV-1. [9][10][11] We previously found that CD45RA ϩ CD8 SP cells respond to costimulation with greater expression of CD4 than do CD45RO ϩ CD8 SP cells. 10 Thus, expression of CD4 can be modulated on T cells at more mature stages of development than was previously thought, suggesting that CD4 may be involved in mature CD8 T-cell function.The CD4 molecule was previously shown to function as a chemotactic receptor for both IL-16 and the viral surface glycoprotein HIV gp120 on CD4 ϩ Th cells. IL-16 specifically binds the D4 region, and gp120 binds the D1 region of CD4. 12,13 IL-16 is a 14-kd molecule that forms homotetramers, which are required for biologic activity. 14 This cytokine is produced by a variety of cells, including CD8 and CD4 T cells, eosinophils, mast cells, bronchial epithelial cells, synovial fibroblasts,...

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“…It has been suggested that HIV gp120 also facilitates replication in suboptimally activated cells (12)(13)(14)(15). Gp120 transduces near-simultaneous signals through CD4 (16), a component of the T cell receptor complex, and CCR5, a chemokine receptor (17)(18)(19).…”

mentioning

confidence: 99%

HIV envelope induces a cascade of cell signals in non-proliferating target cells that favor virus replication

Cicala

Arthos

Selig

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

153

147

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Certain HIV-encoded proteins modify host-cell gene expression in a manner that facilitates viral replication. These activities may contribute to low-level viral replication in nonproliferating cells. Through the use of oligonucleotide microarrays and high-throughput Western blotting we demonstrate that one of these proteins, gp120, induces the expression of cytokines, chemokines, kinases, and transcription factors associated with antigen-specific T cell activation in the absence of cellular proliferation. Examination of transcriptional changes induced by gp120 in freshly isolated peripheral blood mononuclear cells and monocyte-derivedmacrophages reveals a broad and complex transcriptional program conducive to productive infection with HIV. Observations include the induction of nuclear factor of activated T cells, components of the RNA polymerase II complex including TFII D, proteins localized to the plasma membrane, including several syntaxins, and members of the Rho protein family, including Cdc 42. These observations provide evidence that envelope-mediated signaling contributes to the productive infection of HIV in suboptimally activated T cells.H IV preferentially replicates in proliferating CD4 ϩ T cells(1). However recent evidence suggests that, in vivo, resting and suboptimally activated T cells may serve as targets for low-level productive infection in the absence of cellular proliferation (2-5). Infection in this manner may contribute to the establishment and͞or maintenance of persistent viral reservoirs that currently prevent the eradication of virus. To productively infect suboptimally activated CD4 ϩ T cells, HIV must overcome post-entry barriers to replication (6-8).DNA microarrays have been used to characterize the effect of HIV on target cell transcription (9, 10); in one microarray-based study, HIV Nef was shown to diminish barriers to viral replication by mimicking antigen-specific T cell proliferation signals (11,12). It has been suggested that HIV gp120 also facilitates replication in suboptimally activated cells (12-15). Gp120 transduces near-simultaneous signals through CD4 (16), a component of the T cell receptor complex, and CCR5, a chemokine receptor (17)(18)(19). In vivo concentrations of gp120 (20, 21) fall within the range required to induce signaling in vitro (17)(18)(19)22). To provide a more complete picture of the complex cascade of signals induced by gp120, we treated freshly isolated peripheral blood mononuclear cells (PBMCs) and monocyte-derived macrophages (MDMs) with an envelope derived from a CCR5-using virus and measured temporal changes in the levels of mRNA by using Affymetrix (Santa Clara, CA) U95A oligonucleotide microarrays that include probes encompassing Ϸ12,600 genes. In addition, we used a high-throughput Western blot analysis that allowed us to screen protein lysates with 800 monoclonal antibodies. The gp120 used was derived from JR-FL, a CCR5-tropic molecular clone obtained from a minimally passaged viral isolate (23). We used concentrations of envelope near or bel...

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Lymphocyte activation by HIV-1 envelope glycoprotein

Cited by 214 publications

References 47 publications

CD4+ lymphocytes from HIV-infected patients display impaired CD45-associated tyrosine phosphatase activity which is enhanced by anti-oxidants

CD4+ lymphocytes from HIV-infected patients display impaired CD45-associated tyrosine phosphatase activity which is enhanced by anti-oxidants

Activation of CD8 T cells induces expression of CD4, which functions as a chemotactic receptor

HIV envelope induces a cascade of cell signals in non-proliferating target cells that favor virus replication

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