scholarly journals T cell receptor usage and fine specificity of human immunodeficiency virus 1-specific cytotoxic T lymphocyte clones: analysis of quasispecies recognition reveals a dominant response directed against a minor in vivo variant.

1996 ◽  
Vol 183 (4) ◽  
pp. 1669-1679 ◽  
Author(s):  
S A Kalams ◽  
R P Johnson ◽  
M J Dynan ◽  
K E Hartman ◽  
T Harrer ◽  
...  
Keyword(s):  
T Cell Receptor ◽  
T Lymphocyte ◽  
Cytotoxic T Lymphocyte ◽  
Cell Receptor ◽  
Ctl Response ◽  
Immunodeficiency Virus ◽  
Hla Type ◽  
A Minor ◽  
Hiv 1

Numerous virus-specific, class I-restricted cytotoxic T lymphocyte (CTL) epitopes have been identified, yet little information is available regarding the specificity of the CTL response in persons of the same human histocompatibility leukocyte antigen (HLA) type. In this study, the human immunodeficiency virus (HIV) 1 envelope-specific CTL response was evaluated in five HLA-B14-positive persons. CTL responses specific for a previously described nine-amino acid epitope in gp41 (aa 584-592, ERYLKDQQL) could be identified in all subjects, and CTL clones specific for this epitope could be isolated from four persons. Despite heterogeneous T cell receptor usage, the fine specificity of the clones was similar, as defined by recognition of alanine-substituted peptides as well as peptides representing natural HIV-1 sequence variants. Correlation with in vivo virus sequences revealed that the dominant species in two of the subjects represented poorly recognized variants, with a K-->Q substitution at amino acid 588, whereas no variants were observed in the other two subjects. Although clonal type-specific responses to these dominant variants could be identified, the magnitude of these responses remained small, and the dominant CTL response was directed at the minor in vivo variant. These studies indicate that despite similar epitope-specific immunologic pressure in persons of the same HLA type, the in vivo quasispecies may differ, and that the major in vivo immune response to a given CTL epitope can be directed at a minor variant.

scholarly journals Longitudinal analysis of T cell receptor (TCR) gene usage by human immunodeficiency virus 1 envelope-specific cytotoxic T lymphocyte clones reveals a limited TCR repertoire.

1994 ◽  
Vol 179 (4) ◽  
pp. 1261-1271 ◽  
Author(s):  
S A Kalams ◽  
R P Johnson ◽  
A K Trocha ◽  
M J Dynan ◽  
H S Ngo ◽  
...  
Keyword(s):  
T Cell Receptor ◽  
T Lymphocyte ◽  
Cytotoxic T Lymphocyte ◽  
Cell Receptor ◽  
Effector Cells ◽  
Immunodeficiency Virus ◽  
Gene Usage ◽  
Hiv 1 ◽  
Human Immunodeficiency Virus 1 ◽  
Ctl Activity

Human immunodeficiency virus 1 (HIV-1) infection is associated with a vigorous cellular immune response that allows detection of cytotoxic T lymphocyte (CTL) activity using freshly isolated peripheral blood mononuclear cells (PBMC). Although restricting class I antigens and epitopes recognized by HIV-1-specific CTL have been defined, the effector cells mediating this vigorous response have been characterized less well. Specifically, no studies have addressed the breadth and duration of response to a defined epitope. In the present study, a longitudinal analysis of T cell receptor (TCR) gene usage by CTL clones was performed in a seropositive person using TCR gene sequences as a means of tracking responses to a well-defined epitope in the glycoprotein 41 transmembrane protein. 10 CTL clones specific for this human histocompatibility leukocyte antigen-B14-restricted epitope were isolated at multiple time points over a 31-mo period. All clones were derived from a single asymptomatic HIV-1-infected individual with a vigorous response to this epitope that was detectable using unstimulated PBMC. Polymerase chain reaction amplification using V alpha and V beta family-specific primers was performed on each clone, followed by DNA sequencing of the V-D-J regions. All 10 clones utilized V alpha 14 and V beta 4 genes. Sequence analysis of the TCR revealed the first nine clones isolated to also be identical at the nucleotide level. The TCR-alpha junctional region sequence of the tenth clone was identical to the junctional region sequences of the other nine, but this clone utilized distinct D beta and J beta gene segments. This study provides evidence that the observed high degree of HIV-1-specific CTL activity may be due to monoclonal or oligoclonal expansion of specific effector cells, and that progeny of a particular CTL clone may persist for prolonged periods in vivo in the presence of a chronic productive viral infection. The observed limited TCR diversity against an immunodominant epitope may limit recognition of virus variants with mutations in regions interacting with the TCR, thereby facilitating immune escape.

scholarly journals Levels of Human Immunodeficiency Virus Type 1-Specific Cytotoxic T-Lymphocyte Effector and Memory Responses Decline after Suppression of Viremia with Highly Active Antiretroviral Therapy

1999 ◽  
Vol 73 (8) ◽  
pp. 6721-6728 ◽  
Author(s):  
Spyros A. Kalams ◽  
Philip J. Goulder ◽  
Amy K. Shea ◽  
Norman G. Jones ◽  
Alicja K. Trocha ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Immune Responses ◽  
T Lymphocyte ◽  
Highly Active Antiretroviral Therapy ◽  
Cytotoxic T Lymphocyte ◽  
Highly Active ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT Therapeutic suppression of human immunodeficiency virus type 1 (HIV-1) replication may help elucidate interactions between the host cellular immune responses and HIV-1 infection. We performed a detailed longitudinal evaluation of two subjects before and after the start of highly active antiretroviral therapy (HAART). Both subjects had evidence of in vivo-activated and memory cytotoxic T-lymphocyte precursor (CTLp) activity against multiple HIV-1 gene products. After the start of therapy, both subjects had declines in the levels of in vivo-activated HIV-1-specific CTLs and had immediate increases in circulating HIV-1-specific CTL memory cells. With continued therapy, and continued suppression of viral load, levels of memory CTLps declined. HLA A*0201 peptide tetramer staining demonstrated that declining levels of in vivo-activated CTL activity were associated with a decrease in the expression of the CD38+ activation marker. Transient increases in viral load during continued therapy were associated with increases in the levels of virus-specific CTLps in both individuals. The results were confirmed by measuring CTL responses to discrete optimal epitopes. These studies illustrate the dynamic equilibrium between the host immune response and levels of viral antigen burden and suggest that efforts to augment HIV-1-specific immune responses in subjects on HAART may decrease the incidence of virologic relapse.

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 Elicitation of High-Frequency Cytotoxic T-Lymphocyte Responses against both Dominant and Subdominant Simian-Human Immunodeficiency Virus Epitopes by DNA Vaccination of Rhesus Monkeys

2001 ◽  
Vol 75 (5) ◽  
pp. 2462-2467 ◽  
Author(s):  
Dan H. Barouch ◽  
Abie Craiu ◽  
Sampa Santra ◽  
Michael A. Egan ◽  
Jörn E. Schmitz ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Lymphocyte ◽  
Plasmid Dna ◽  
High Frequency ◽  
Rhesus Monkeys ◽  
Cytotoxic T Lymphocyte ◽  
Ctl Response ◽  
Immunodeficiency Virus ◽  
Hiv 1 ◽  
Ctl Responses

ABSTRACT Increasing evidence suggests that the generation of cytotoxic T-lymphocyte (CTL) responses specific for a diversity of viral epitopes will be needed for an effective human immunodeficiency virus type 1 (HIV-1) vaccine. Here, we determine the frequencies of CTL responses specific for the simian immunodeficiency virus Gag p11C and HIV-1 Env p41A epitopes in simian-human immunodeficiency virus (SHIV)-infected and vaccinated rhesus monkeys. The p11C-specific CTL response was high frequency and dominant and the p41A-specific CTL response was low frequency and subdominant in both SHIV-infected monkeys and in monkeys vaccinated with recombinant modified vaccinia virus Ankara vectors expressing these viral antigens. Interestingly, we found that plasmid DNA vaccination led to high-frequency CTL responses specific for both of these epitopes. These data demonstrate that plasmid DNA may be useful in eliciting a broad CTL response against multiple epitopes.

scholarly journals SARS-CoV-2 may affect the immune response via direct inhibition of T cell receptor: Mechanistic hypothesis and rationale

2021 ◽  
Author(s):  
Alexander B Sigalov
Keyword(s):  
T Cell ◽  
T Cell Receptor ◽  
Cell Receptor ◽  
T Cell Receptor Signaling ◽  
Immunodeficiency Virus ◽  
T Cell Lymphopenia ◽  
Host Cell Entry ◽  
Hiv 1

During co-evolution with their hosts, many viruses have evolved a membrane fusion mechanism to facilitate host cell entry. Examples include human immunodeficiency virus type 1 (HIV-1) and severe acute respiratory syndrome coronaviruses 1 and 2 (SARS-CoV-1 and SARS-CoV-2). These viruses can also infect immune cells (e.g., T cells), providing one of the possible mechanisms for the T cell lymphopenia observed in patients with these infections. Previously, we hypothesized and confirmed in vivo that like HIV-1, SARS-CoV-1 can use its fusion domain not only to enter the T cell but also to directly inhibit T cell receptor signaling. Here, based on the analysis of available structural and clinical data, we hypothesize that SARS-CoV-2 may use a similar "disarm the alarm" strategy to suppress immune responses. We also discuss the implications of this hypothesis for better understanding coronavirus disease 2019 (COVID-19) pathology, developing effective COVID-19 vaccines and improving clinical outcomes for COVID-19 patients.

scholarly journals Inefficient Cytotoxic T Lymphocyte–Mediated Killing of HIV-1–Infected Cells In Vivo

PLoS Biology ◽  
2006 ◽  
Vol 4 (4) ◽  
pp. e90 ◽  
Author(s):  
Becca Asquith ◽  
Charles T. T Edwards ◽  
Marc Lipsitch ◽  
Angela R McLean
Keyword(s):  
T Lymphocyte ◽  
Cytotoxic T Lymphocyte ◽  
Infected Cells ◽  
Hiv 1
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