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

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.

Cytotoxic T lymphocytes and viral evolution in primary HIV-1 infection*

1999 ◽  
Vol 97 (6) ◽  
pp. 707-718 ◽  
Author(s):  
David A. PRICE ◽  
Chris A. O'CALLAGHAN ◽  
Joseph A. WHELAN ◽  
Philippa J. EASTERBROOK ◽  
Rodney E. PHILLIPS
Keyword(s):  
T Lymphocytes ◽  
Cytotoxic T Lymphocytes ◽  
T Lymphocyte ◽  
Cytotoxic T Lymphocyte ◽  
Viral Evolution ◽  
Case Series ◽  
Effector Cells ◽  
Lymphocyte Responses ◽  
Hiv 1

Efforts to develop immune-based therapies for HIV infection have been impeded by incomplete definition of the immunological correlates of protection. Despite many precedents demonstrating that CD8+ cytotoxic T lymphocytes are key mediators of protective anti-viral immunity in non-human animal models, direct evidence that these effector cells control viral replication in HIV-1 infection has remained elusive. The first part of this paper describes a detailed immunological and genetic study founded on evolutionary considerations. Following infection with HIV-1, virus variants which escaped recognition by autologous cytotoxic T lymphocytes were shown to possess a selection advantage within the host environment. Cytotoxic T lymphocytes therefore exert anti-viral pressure in vivo. This observation provides compelling evidence that cytotoxic T lymphocytes comprise a significant element of anti-retroviral immunity. Subsequently, the quantification of peripheral cytotoxic T lymphocyte frequencies utilizing peptide–(human leucocyte antigen class I) tetrameric complexes is described. Five patients with qualitatively similar immunodominant cytotoxic T lymphocyte responses during symptomatic primary HIV-1 infection were studied longitudinally. Expansions of virus-specific CD8+ lymphocytes comprising up to 2% of the total CD8+ T cell population were observed in the acute phase of infection. Antigenic load was identified as an important determinant of circulating HIV-1-specific CD8+ lymphocyte levels; however, significant numbers of such cells were also found to persist following prolonged therapeutic suppression of plasma viraemia. In addition, an analysis of antigenic sequence variation with time in this case series suggests that the early administration of combination anti-retroviral therapy may limit HIV-1 mutational escape from host cytolytic specificities. The implications of these preliminary data are discussed. The data presented suggest that vaccination protocols should aim to elicit vigorous cytotoxic T lymphocyte responses to HIV-1. Attempts to stimulate polyvalent responses to mutationally intolerant epitopes are likely to be most effective. Optimal management of HIV-1 infection requires an understanding of dynamic host–virus interactions, and may involve strategies designed to enhance cytotoxic T lymphocyte activity following periods of anti-retroviral drug therapy.

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.

In vivo persistence of a HIV-1-encoded HLA-B27-restricted cytotoxic T lymphocyte epitope despite specificin vitro reactivity

1991 ◽  
Vol 21 (10) ◽  
pp. 2637-2640 ◽  
Author(s):  
Andreas Meyerhans ◽  
Gilles Dadaglio ◽  
Jean-Pierre Vartanian ◽  
Pierre Langlade-Demoyen ◽  
Ronald Frank ◽  
...  
Keyword(s):  
T Lymphocyte ◽  
Cytotoxic T Lymphocyte ◽  
Hla B27 ◽  
Hiv 1

Cytotoxic T lymphocyte recognition of HLA-B*5101-restricted HIV-1 Rev epitope which is naturally processed in HIV-1-infected cells

AIDS ◽  
1999 ◽  
Vol 13 (7) ◽  
pp. 861 ◽  
Author(s):  
Hiroko Tomiyama ◽  
Yoshitomo Chujoh ◽  
Tatsuo Shioda ◽  
Kiyoshi Miwa ◽  
Shin-ichi Oka ◽  
...  
Keyword(s):  
T Lymphocyte ◽  
Cytotoxic T Lymphocyte ◽  
Infected Cells ◽  
Hiv 1

scholarly journals Evaluation of CD8 T cell killing models with computer simulations of 2-photon imaging experiments

2019 ◽  
Author(s):  
Ananya Rastogi ◽  
Philippe Robert ◽  
Stephan Halle ◽  
Michael Meyer-Hermann
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Lymphocyte ◽  
Cytotoxic T Lymphocyte ◽  
Cytotoxic T Cells ◽  
Signal Integration ◽  
Agent Based ◽  
Killing Activity ◽  
Infected Cells

AbstractIn vivo imaging of cytotoxic T lymphocyte (CTL) killing activity revealed that infected cells have a higher observed probability of dying after multiple contacts with CTLs, suggesting memory effect in CTLs or infected cells. We developed a three-dimensional agent-based model of CTL killing activity to discriminate different hypotheses about how infected cells get killed based on quantitative 2-photon in vivo observations. We compared a constant CTL killing probability with mechanisms of signal integration in CTL or infected cells. The most likely scenario implied increased susceptibility of infected cells with increasing number of CTL contacts where the total number of contacts was a critical factor as opposed to signal integration over many contacts. However, when allowing in silico T cells to interact with apoptotic target cells (zombie contacts), a contact history independent killing mechanism was also in agreement with the experimental datasets. We showed that contacts that take place between CTLs and dying infected cells impact the observed killing dynamics because even in absence of modulation of cell properties, we saw an increase of the observed probability of killing infected cells with more interactions. The duration taken by an infected cell to die and the per capita killing rate (PCKR) of CTLs, parameters hard to measure directly, were determined from the model and turned out predictive to distinguish the different CTL killing models in future experiments. The comparison of observed datasets to simulation results, revealed limitations in interpreting 2-photon data, and provided prediction for additional measurements to distinguish CTL killing models.HighlightsKilling of infected cells by cytotoxic T cells typically involves more than a single contact.Cytotoxic T cells or infected cells integrate signals from multiple interactions.T cell contacts with dying infected cells have a major impact on in vivo data interpretation.Significance StatementDespite having a clear understanding of cytotoxic T lymphocyte (CTL) mediated cytotoxicity mechanisms, the quantitative dynamics remain unexplored at a cellular level. We developed an agent-based model to compare different hypotheses for mechanisms of CTL mediated cytotoxicity that could lead to an increase in observed probability of killing infected cells at higher interactions with CTLs as seen in vivo. We showed that this behaviour can be explained by modulation of properties by infected cells or CTLs with increasing number of contacts. For the modulation, we compared two modes of signal integration and showed that time is not a relevant parameter in signal integration. We also studied the impact of contacts between CTLs and apoptotic infected cells on observed killing properties.

scholarly journals T Cell Affinity Maturation by Selective Expansion during Infection

1999 ◽  
Vol 189 (4) ◽  
pp. 701-710 ◽  
Author(s):  
Dirk H. Busch ◽  
Eric G. Pamer
Keyword(s):  
T Cell ◽  
T Lymphocyte ◽  
Cytotoxic T Lymphocyte ◽  
Affinity Maturation ◽  
Cell Populations ◽  
Mhc Molecules ◽  
Infected Cells ◽  
Peptide Complexes ◽  
The Impact

T lymphocyte recognition of infected cells is mediated by T cell receptors (TCRs) interacting with their ligands, self–major histocompatibility complex (MHC) molecules complexed with pathogen-derived peptides. Serial TCR interactions with potentially small numbers of MHC/ peptide complexes on infected cells transmit signals that result in T lymphocyte expansion and activation of effector functions. The impact of TCR affinity for MHC/peptide complexes on the rate or extent of in vivo T cell expansion is not known. Here we show that in vivo expansion of complex T cell populations after bacterial infection is accompanied by an increase in their overall affinity for antigen. T cell populations that have undergone additional rounds of in vivo expansion express a narrower range of TCRs, have increased sensitivity for antigen in cytotoxic T lymphocyte assays, and bind MHC/peptide complexes with greater affinity. The selective expansion of higher affinity T cells provides an in vivo mechanism for optimizing the early detection of infected cells.

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