scholarly journals Envelope-Dependent Restriction of Human Immunodeficiency Virus Type 1 Spreading in CD4+ T Lymphocytes: R5 but Not X4 Viruses Replicate in the Absence of T-Cell Receptor Restimulation

1999 ◽  
Vol 73 (9) ◽  
pp. 7515-7523 ◽  
Author(s):  
Elisa Vicenzi ◽  
Paola Panina Bordignon ◽  
Priscilla Biswas ◽  
Andrea Brambilla ◽  
Chiara Bovolenta ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cell ◽  
T Lymphocytes ◽  
T Cell Receptor ◽  
Cell Receptor ◽  
Th2 Cells ◽  
Cell Clones ◽  
Immunodeficiency Virus ◽  
Hiv 1 ◽  
Th1 And Th2

ABSTRACT The human immunodeficiency virus (HIV) replicates in activated CD4+ T lymphocytes. However, only CD4+ Th2 and Th0, but not Th1, CD4+ T-cell clones have been reported to efficiently support HIV-1 replication. This dichotomous pattern was further investigated in the present study in Th1, Th2, or Th0 cell lines derived from umbilical human cord blood and in T-cell clones obtained from the peripheral blood mononuclear cells (PBMC) of healthy adults. Both primary and laboratory-adapted HIV-1 strains with CCR5 as the exclusive entry coreceptor (R5 viruses) efficiently replicated in Th1, Th2, and Th0 cells. In sharp contrast, CXCR4-dependent (X4) viruses poorly replicated in both polarized and unpolarized CD4+ T cells, including adults’ PBMC infected several days after mitogenic stimulation. Unlike the X4 HIV-1NL4-3, a chimera in which the env gene had been replaced with that of the R5 HIV-1NL(AD8), efficiently replicated in both Th1 and Th2 cells. This X4-dependent restriction of HIV replication was not explained by either the absence of functional CXCR4 on the cell surface or by the inefficient viral entry and reverse transcription. T-cell receptor stimulation by anti-CD3 monoclonal antibodies fully rescued X4 HIV-1 replication in both Th1 and Th2 cells, whereas it did not alter the extent and kinetics of R5 HIV-1 spreading. Thus, R5 HIVs show a replicative advantage in comparison to X4 viruses in their ability to efficiently propagate among suboptimally activated T lymphocytes, regardless of their polarized or unpolarized functional profiles. This observation may help to explain the absolute predominance of R5 HIVs over X4 viruses observed after viral transmission and during early-stage disease.

scholarly journals Circulating CD8 T Lymphocytes in Human Immunodeficiency Virus-Infected Individuals Have Impaired Function and Downmodulate CD3ζ, the Signaling Chain of the T-Cell Receptor Complex

Blood ◽  
1998 ◽  
Vol 91 (2) ◽  
pp. 585-594 ◽  
Author(s):  
Linda A. Trimble ◽  
Judy Lieberman
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cells ◽  
T Cell ◽  
T Lymphocytes ◽  
T Cell Receptor ◽  
Cell Receptor ◽  
Receptor Complex ◽  
Cd8 T Lymphocytes ◽  
Immunodeficiency Virus ◽  
Specific Cytotoxicity

Although human immunodeficiency virus (HIV)-infected subjects without acquired immunodeficiency syndrome have a high frequency of HIV-specific CD8 T lymphocytes, freshly isolated lymphocytes frequently lack detectable HIV-specific cytotoxicity. However, this effector function becomes readily apparent after overnight culture. To investigate reasons for T-cell dysfunction, we analyzed T-cell expression of the cytolytic protease granzyme A and of CD3ζ, the signaling component of the T-cell receptor complex. An increased proportion of CD4 and CD8 T cells from HIV-infected donors contain granzyme A, consistent with the known increased frequency of activated T cells. In 28 HIV-infected donors with mild to advanced immunodeficiency, a substantial fraction of circulating T cells downmodulated CD3ζ (fraction of T cells expressing CD3ζ, 0.74 ± 0.16 v 1.01 ± 0.07 in healthy donors; P < .0000005). CD3ζ expression is downregulated more severely in CD8 than CD4 T cells, decreases early in infection, and correlates with declining CD4 counts and disease stage. CD3ζ expression increases over 6 to 16 hours of culture in an interleukin-2–dependent manner, coincident with restoration of viral-specific cytotoxicity. Impaired T-cell receptor signaling may help explain why HIV-specific cytotoxic T lymphocytes fail to control HIV replication.

scholarly journals Alterations in T-Cell Receptor Vβ Repertoire of CD4 and CD8 T Lymphocytes in Human Immunodeficiency Virus-Infected Children

2003 ◽  
Vol 10 (1) ◽  
pp. 53-58 ◽  
Author(s):  
Monica Kharbanda ◽  
Thomas W. McCloskey ◽  
Rajendra Pahwa ◽  
Mei Sun ◽  
Savita Pahwa
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cells ◽  
T Cell ◽  
T Lymphocytes ◽  
T Cell Receptor ◽  
Cd8 T Cells ◽  
Chronic Phase ◽  
Cell Receptor ◽  
Cd8 T Lymphocytes ◽  
Immunodeficiency Virus

ABSTRACT Perturbations in the T-cell receptor (TCR) Vβ repertoire were assessed in the CD4 and CD8 T lymphocytes of human immunodeficiency virus (HIV)-infected children who were receiving therapy during the chronic phase of infection by flow cytometry (FC) and PCR analysis. By FC, representation of 21 TCR Vβ subfamilies was assessed for an increased or decreased percentage in CD4 and CD8 T cells, and by PCR, 22 TCR Vβ subfamilies of CD4 and CD8 T cells were analyzed by CDR3 spectratyping for perturbations and reduction in the number of peaks, loss of Gaussian distribution, or clonal dominance. The majority of the TCR Vβ subfamilies were examined by both methods and assessed for deviation from the norm by comparison with cord blood samples. The CD8-T-lymphocyte population exhibited more perturbations than the CD4 subset, and clonal dominance was present exclusively in CD8 T cells. Of the 55 total CD8-TCR Vβ families classified with clonal dominance by CDR3 spectratyping, only 18 of these exhibited increased expression by FC. Patients with high numbers of CD8-TCR Vβ families with decreased percentages had reduced percentages of total CD4 T cells. Increases in the number of CD4-TCR Vβ families with increased percentages showed a positive correlation with skewing. Overall, changes from normal were often discordant between the two methods. This study suggests that the assessment of HIV-induced alterations in TCR Vβ families at cellular and molecular levels yields different information and that our understanding of the immune response to HIV is still evolving.

scholarly journals Zeta Chain of the T-Cell Receptor Interacts with nef of Simian Immunodeficiency Virus and Human Immunodeficiency Virus Type 2

1998 ◽  
Vol 72 (12) ◽  
pp. 9827-9834 ◽  
Author(s):  
Anita Y. M. Howe ◽  
Jae U. Jung ◽  
Ronald C. Desrosiers
Keyword(s):  
Amino Acids ◽  
Human Immunodeficiency Virus ◽  
T Cell ◽  
Tyrosine Kinase ◽  
T Cell Receptor ◽  
Cell Receptor ◽  
Jurkat Cells ◽  
Zeta Chain ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT A truncated version of the nef gene of simian immunodeficiency virus SIVmac239 capable of encoding amino acids 98 to 263 was used as bait to screen a cDNA library from activated lymphocytes in a yeast two-hybrid system. The zeta chain of the T-cell receptor (TCRζ) was found to interact specifically not only with truncated SIV nef in yeast cells but also with full-length glutathione S-transferase (GST)-SIVnef fusion protein in vitro. Coimmunoprecipitation of TCRζ with full-length SIV nef was demonstrated in transfected Jurkat cells and in Cos 18 cells which express the cytoplasmic domain of TCRζ fused to the external domain of CD8 via the CD8 transmembrane domain. Using a series of nef deletion mutants, we have mapped the binding site within the central core domain of nef (amino acids 98 to 235). Binding of TCRζ was specific for nef isolated from SIVmac239, SIVsmH4, and human immunodeficiency virus (HIV)-2ST and was not detected with nef from five different HIV-1 isolates. An active tyrosine kinase was coprecipitated with nef-TCRζcomplexes from Jurkat cells but not from J.CAM1.6 cells which lack a functional Lck tyrosine kinase. These results demonstrate a specific association of SIV and HIV-2 nef, but not HIV-1 nef, with TCRζ.

scholarly journals T-Cell Receptor-Mediated Anergy of a Human Immunodeficiency Virus (HIV) gp120-Specific CD4+ Cytotoxic T-Cell Clone, Induced by a Natural HIV Type 1 Variant Peptide

2000 ◽  
Vol 74 (5) ◽  
pp. 2121-2130 ◽  
Author(s):  
Latifa Bouhdoud ◽  
Patricia Villain ◽  
Abderrazzak Merzouki ◽  
Maximilian Arella ◽  
Clément Couture
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Cell Receptor ◽  
Cytotoxic T Cell ◽  
Ctl Response ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT Human immunodeficiency virus type 1 (HIV-1) infection triggers a cytotoxic T-lymphocyte (CTL) response mediated by CD8+ and perhaps CD4+ CTLs. The mechanisms by which HIV-1 escapes from this CTL response are only beginning to be understood. However, it is already clear that the extreme genetic variability of the virus is a major contributing factor. Because of the well-known ability of altered peptide ligands (APL) to induce a T-cell receptor (TCR)-mediated anergic state in CD4+ helper T cells, we investigated the effects of HIV-1 sequence variations on the proliferation and cytotoxic activation of a human CD4+ CTL clone (Een217) specific for an epitope composed of amino acids 410 to 429 of HIV-1 gp120. We report that a natural variant of this epitope induced a functional anergic state rendering the T cells unable to respond to their antigenic ligand and preventing the proliferation and cytotoxic activation normally induced by the original antigenic peptide. Furthermore, the stimulation of Een217 cells with this APL generated altered TCR-proximal signaling events that have been associated with the induction of T-cell anergy in CD4+ T cells. Importantly, the APL-induced anergic state of the Een217 T cells could be prevented by the addition of interleukin 2, which restored their ability to respond to their nominal antigen. Our data therefore suggest that HIV-1 variants can induce a state of anergy in HIV-specific CD4+ CTLs. Such a mechanism may allow a viral variant to not only escape the CTL response but also facilitate the persistence of other viral strains that may otherwise be recognized and eliminated by HIV-specific CTLs.

scholarly journals Human Immunodeficiency Virus Type 1 Envelope gp120-Induced Partial T-Cell Receptor Signaling Creates an F-Actin-Depleted Zone in the Virological Synapse

2009 ◽  
Vol 83 (21) ◽  
pp. 11341-11355 ◽  
Author(s):  
Gaia Vasiliver-Shamis ◽  
Michael W. Cho ◽  
Catarina E. Hioe ◽  
Michael L. Dustin
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cell ◽  
Infected Cell ◽  
T Cell Receptor ◽  
Cell Receptor ◽  
Cd4 T Cell ◽  
Virological Synapse ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT Cell-to-cell transmission of human immunodeficiency virus type 1 (HIV-1) occurs via a virological synapse (VS), a tight cell-cell junction formed between HIV-infected cells and target cells in which the HIV-1-infected cell polarizes and releases virions toward the noninfected target cell in a gp120- and intercellular adhesion molecule 1 (ICAM-1)-dependent process. The response of the target cell has been less studied. We utilized supported planar bilayers presenting gp120 and ICAM-1 as a reductionist model for the infected-cell membrane and investigated its effect on the target CD4 T cell. This study shows that HIV-1 gp120 interaction with its receptors is initially organized into microclusters that undergo F-actin-dependent consolidation into a central supramolecular activation complex (cSMAC). Src kinases are active in both gp120 microclusters and in the VS cSMAC. The early T-cell receptor (TCR) signaling machinery is partially activated at the VS, and signaling does not propagate to trigger Ca2+ elevation or increase CD69 expression. However, these partial TCR signals act locally to create an F-actin-depleted zone. We propose a model in which the F-actin-depleted zone formed within the target CD4 T cell enhances the reception of virions by releasing the physical barrier for HIV-1 entry and facilitating postentry events.

scholarly journals Random T-Cell Receptor Recruitment in Human Immunodeficiency Virus Type 1 (HIV-1)-Specific CD8+ T Cells from Genetically Identical Twins Infected with the Same HIV-1 Strain

2007 ◽  
Vol 81 (22) ◽  
pp. 12666-12669 ◽  
Author(s):  
Xu G. Yu ◽  
Mathias Lichterfeld ◽  
Katie L. Williams ◽  
Javier Martinez-Picado ◽  
Bruce D. Walker
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Cell Receptor ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT Human immunodeficiency virus type 1 (HIV-1) cytotoxic T-lymphocyte escape mutations represent both a major reason for loss of HIV immune control and a considerable challenge for HIV-1 vaccine design. Previous data suggest that initial HIV-1-specific CD8+ T-cell responses are determined largely by viral and host genetics, but the mechanisms influencing the subsequent viral evolution are unclear. Here, we show a random recruitment of T-cell receptor (TCR) alpha and beta clonotypes of the initial HIV-1-specific CD8+ T cells during primary infection in two genetically identical twins infected simultaneously with the same virus, suggesting that stochastic TCR recruitment of HIV-1-specific CD8+ T cells contributes to the diverse and unpredictable HIV-1 sequence evolution.

scholarly journals Circulating CD8 T Lymphocytes in Human Immunodeficiency Virus-Infected Individuals Have Impaired Function and Downmodulate CD3ζ, the Signaling Chain of the T-Cell Receptor Complex

Blood ◽  
1998 ◽  
Vol 91 (2) ◽  
pp. 585-594 ◽  
Author(s):  
Linda A. Trimble ◽  
Judy Lieberman
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cells ◽  
T Cell ◽  
T Lymphocytes ◽  
T Cell Receptor ◽  
Cell Receptor ◽  
Receptor Complex ◽  
Cd8 T Lymphocytes ◽  
Immunodeficiency Virus ◽  
Specific Cytotoxicity

Abstract Although human immunodeficiency virus (HIV)-infected subjects without acquired immunodeficiency syndrome have a high frequency of HIV-specific CD8 T lymphocytes, freshly isolated lymphocytes frequently lack detectable HIV-specific cytotoxicity. However, this effector function becomes readily apparent after overnight culture. To investigate reasons for T-cell dysfunction, we analyzed T-cell expression of the cytolytic protease granzyme A and of CD3ζ, the signaling component of the T-cell receptor complex. An increased proportion of CD4 and CD8 T cells from HIV-infected donors contain granzyme A, consistent with the known increased frequency of activated T cells. In 28 HIV-infected donors with mild to advanced immunodeficiency, a substantial fraction of circulating T cells downmodulated CD3ζ (fraction of T cells expressing CD3ζ, 0.74 ± 0.16 v 1.01 ± 0.07 in healthy donors; P < .0000005). CD3ζ expression is downregulated more severely in CD8 than CD4 T cells, decreases early in infection, and correlates with declining CD4 counts and disease stage. CD3ζ expression increases over 6 to 16 hours of culture in an interleukin-2–dependent manner, coincident with restoration of viral-specific cytotoxicity. Impaired T-cell receptor signaling may help explain why HIV-specific cytotoxic T lymphocytes fail to control HIV replication.

scholarly journals Downregulation of the T-Cell Receptor by Human Immunodeficiency Virus Type 2 Nef Does Not Protect against Disease Progression

2009 ◽  
Vol 83 (24) ◽  
pp. 12968-12972 ◽  
Author(s):  
Jérôme Feldmann ◽  
Aleksandra Leligdowicz ◽  
Assan Jaye ◽  
Tao Dong ◽  
Hilton Whittle ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cell ◽  
T Cell Receptor ◽  
Immune Activation ◽  
Cell Receptor ◽  
Hla Dr ◽  
Immunodeficiency Virus ◽  
Marked Disparity ◽  
Normal Life Span ◽  
Hiv 1

ABSTRACT Chronic immune activation is thought to play a major role in human immunodeficiency virus (HIV) pathogenesis, but the relative contributions of multiple factors to immune activation are not known. One proposed mechanism to protect against immune activation is the ability of Nef proteins from some HIV and simian immunodeficiency virus strains to downregulate the T-cell receptor (TCR)-CD3 complex of the infected cell, thereby reducing the potential for deleterious activation. HIV type 1 (HIV-1) Nef has lost this property. In contrast to HIV-1, HIV-2 infection is characterized by a marked disparity in the disease course, with most individuals maintaining a normal life span. In this study, we examined the relationship between the ability of HIV-2 Nef proteins to downregulate the TCR and immune activation, comparing progressors and nonprogressors. Representative Nef variants were isolated from 28 HIV-2-infected individuals. We assessed their abilities to downregulate the TCR from the surfaces of CD4 T cells. In the same individuals, the activation of peripheral lymphocytes was evaluated by measurement of the expression levels of HLA-DR and CD38. We observed a striking correlation of the TCR downregulation efficiency of HIV-2 Nef variants with immune activation in individuals with a low viral load. This strongly suggests that Nef expression can influence the activation state of the immune systems of infected individuals. However, the efficiency of TCR downregulation by Nef was not reduced in progressing individuals, showing that TCR downregulation does not protect against progression in HIV-2 infection.

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