scholarly journals Cross-reactive TCR with alloreactivity for immunodominant HIV-1 epitope Gag TL9 with enhanced control of viral infection

2021 ◽  
Author(s):  
Yang Liu ◽  
Dan San ◽  
Lei Yin
Keyword(s):  
T Cell ◽  
Viral Infection ◽  
Structural Study ◽  
Structural Data ◽  
Escape Mutant ◽  
Cell Phenotype ◽  
Peptide Ligand ◽  
High Affinity ◽  
Functional Advantage ◽  
Hiv 1

Although both HLA B*81:01 and HLA B*42:01 are members of the B7 supertype and can present many of the same HIV-1 epitopes, the identification of a dual-reactive T cell phenotype was unexpected, since structural data suggested that TL9 peptide binds to each allele in a distinct conformation. How the dual-reactive TCR recognizes these radically distinct p-MHC surfaces is revealed by our structural study, that the introduction of TCR T18A induces a molecular switch of the TL9 peptide in B4201 to approach its conformation in B8101. Most importantly, unique docking of CDR3β towards MHC but not peptide ligand strengthens the peptide tolerance of T18A, extends the ability of TCR to adapt mutations. Moreover, the high affinity of dual active TCR for WT and escape mutant TL9 highlights the functional advantage of the alloreactive phenotype.

scholarly journals IL-21 from high-affinity CD4 T cells drives differentiation of brain-resident CD8 T cells during persistent viral infection

2020 ◽  
Vol 5 (51) ◽  
pp. eabb5590 ◽  
Author(s):  
Heather M. Ren ◽  
Elizabeth M. Kolawole ◽  
Mingqiang Ren ◽  
Ge Jin ◽  
Colleen S. Netherby-Winslow ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Viral Infection ◽  
Cd8 T Cells ◽  
Cd4 T Cells ◽  
Central Nervous System Infection ◽  
Cell Receptor ◽  
Cd4 T Cell ◽  
Persistent Viral Infection ◽  
High Affinity

Development of tissue-resident memory (TRM) CD8 T cells depends on CD4 T cells. In polyomavirus central nervous system infection, brain CXCR5hi PD-1hi CD4 T cells produce interleukin-21 (IL-21), and CD8 T cells lacking IL-21 receptors (IL21R−/−) fail to become bTRM. IL-21+ CD4 T cells exhibit elevated T cell receptor (TCR) affinity and higher TCR density. IL21R−/− brain CD8 T cells do not express CD103, depend on vascular CD8 T cells for maintenance, are antigen recall defective, and lack TRM core signature genes. CD4 T cell–deficient and IL21R−/− brain CD8 T cells show similar deficiencies in expression of genes for oxidative metabolism, and intrathecal delivery of IL-21 to CD4 T cell–depleted mice restores expression of electron transport genes in CD8 T cells to wild-type levels. Thus, high-affinity CXCR5hi PD-1hi CD4 T cells in the brain produce IL-21, which drives CD8 bTRM differentiation in response to a persistent viral infection.

scholarly journals Altered CD4+T Cell Phenotype and Function Determine the Susceptibility to Mucosal Candidiasis in Transgenic Mice Expressing HIV-1

2006 ◽  
Vol 177 (1) ◽  
pp. 479-491 ◽  
Author(s):  
Daniel Lewandowski ◽  
Miriam Marquis ◽  
Francine Aumont ◽  
Annie-Claude Lussier-Morin ◽  
Marianne Raymond ◽  
...  
Keyword(s):  
T Cell ◽  
Transgenic Mice ◽  
Cd4 T Cell ◽  
Cell Phenotype ◽  
Mucosal Candidiasis ◽  
And Function ◽  
Hiv 1

Resistance to viral infection by intraepithelial lymphocytes in HIV-1 P18-I10-specific T-cell receptor transgenic mice

2004 ◽  
Vol 316 (2) ◽  
pp. 356-363 ◽  
Author(s):  
Hideki Kuribayashi ◽  
Ayako Wakabayashi ◽  
Masumi Shimizu ◽  
Hiroshi Kaneko ◽  
Yoshihiko Norose ◽  
...  
Keyword(s):  
T Cell ◽  
Transgenic Mice ◽  
Viral Infection ◽  
T Cell Receptor ◽  
Cell Receptor ◽  
Intraepithelial Lymphocytes ◽  
Hiv 1 ◽  
Resistance To Viral Infection

scholarly journals The differential short- and long-term effects of HIV-1 latency-reversing agents on T cell function

2016 ◽  
Vol 6 (1) ◽  
Author(s):  
G. Clutton ◽  
Y. Xu ◽  
P. L. Baldoni ◽  
K. R. Mollan ◽  
J. Kirchherr ◽  
...  
Keyword(s):  
T Cell ◽  
Histone Deacetylase Inhibitors ◽  
Cell Function ◽  
Cd8 T Cell ◽  
Cell Phenotype ◽  
T Cell Function ◽  
Latently Infected ◽  
Infected Cells ◽  
Hiv 1 ◽  
Reversing Agents

Abstract Despite the extraordinary success of HIV-1 antiretroviral therapy in prolonging life, infected individuals face lifelong therapy because of a reservoir of latently-infected cells that harbor replication competent virus. Recently, compounds have been identified that can reverse HIV-1 latency in vivo. These latency- reversing agents (LRAs) could make latently-infected cells vulnerable to clearance by immune cells, including cytolytic CD8+ T cells. We investigated the effects of two leading LRA classes on CD8+ T cell phenotype and function: the histone deacetylase inhibitors (HDACis) and protein kinase C modulators (PKCms). We observed that relative to HDACis, the PKCms induced much stronger T cell activation coupled with non-specific cytokine production and T cell proliferation. When examining antigen-specific CD8+ T cell function, all the LRAs except the HDACi Vorinostat reduced, but did not abolish, one or more measurements of CD8+ T cell function. Importantly, the extent and timing of these effects differed between LRAs. Panobinostat had detrimental effects within 10 hours of drug treatment, whereas the effects of the other LRAs were observed between 48 hours and 5 days. These observations suggest that scheduling of LRA and CD8+ T cell immunotherapy regimens may be critical for optimal clearance of the HIV-1 reservoir.

scholarly journals HIV-1 infection alters CD4+memory T-cell phenotype at the site of disease in extrapulmonary tuberculosis

2011 ◽  
Vol 42 (1) ◽  
pp. 147-157 ◽  
Author(s):  
Kerryn Matthews ◽  
Mpiko Ntsekhe ◽  
Faisal Syed ◽  
Thomas Scriba ◽  
James Russell ◽  
...  
Keyword(s):  
T Cell ◽  
Extrapulmonary Tuberculosis ◽  
Cell Phenotype ◽  
Memory T Cell ◽  
Hiv 1

scholarly journals Stable Phenotypic Changes of the Host T Cells Are Essential to the Long-Term Stability of Latent HIV-1 Infection

2015 ◽  
Vol 89 (13) ◽  
pp. 6656-6672 ◽  
Author(s):  
Lillian Seu ◽  
Steffanie Sabbaj ◽  
Alexandra Duverger ◽  
Frederic Wagner ◽  
Joshua C. Anderson ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Memory T Cells ◽  
Host Cells ◽  
Cell Phenotype ◽  
Memory T Cell ◽  
Latent Hiv ◽  
The Stability ◽  
Hiv 1 ◽  
Extreme Stability

ABSTRACTThe extreme stability of the latent HIV-1 reservoir in the CD4+memory T cell population prevents viral eradication with current antiretroviral therapy. It has been demonstrated that homeostatic T cell proliferation and clonal expansion of latently infected T cells due to viral integration into specific genes contribute to this extraordinary reservoir stability. Nevertheless, given the constant exposure of the memory T cell population to specific antigen or bystander activation, this reservoir stability seems remarkable, unless it is assumed that latent HIV-1 resides exclusively in memory T cells that recognize rare antigens. Another explanation for the stability of the reservoir could be that the latent HIV-1 reservoir is associated with an unresponsive T cell phenotype. We demonstrate here that host cells of latent HIV-1 infection events were functionally altered in ways that are consistent with the idea of an anergic, unresponsive T cell phenotype. Manipulations that induced or mimicked an anergic T cell state promoted latent HIV-1 infection. Kinome analysis data reflected this altered host cell phenotype at a system-wide level and revealed how the stable kinase activity changes networked to stabilize latent HIV-1 infection. Protein-protein interaction networks generated from kinome data could further be used to guide targeted genetic or pharmacological manipulations that alter the stability of latent HIV-1 infection. In summary, our data demonstrate that stable changes to the signal transduction and transcription factor network of latently HIV-1 infected host cells are essential to the ability of HIV-1 to establish and maintain latent HIV-1 infection status.IMPORTANCEThe extreme stability of the latent HIV-1 reservoir allows the infection to persist for the lifetime of a patient, despite completely suppressive antiretroviral therapy. This extreme reservoir stability is somewhat surprising, since the latently HIV-1 infected CD4+memory T cells that form the structural basis of the viral reservoir should be exposed to cognate antigen over time. Antigen exposure would trigger a recall response and should deplete the reservoir, likely over a relatively short period. Our data demonstrate that stable and system-wide phenotypic changes to host cells are a prerequisite for the establishment and maintenance of latent HIV-1 infection events. The changes observed are consistent with an unresponsive, anergy-like T cell phenotype of latently HIV-1 infected host cells. An anergy-like, unresponsive state of the host cells of latent HIV-1 infection events would explain the stability of the HIV-1 reservoir in the face of continuous antigen exposure.

scholarly journals Rapid Viral Escape at an Immunodominant Simian-Human Immunodeficiency Virus Cytotoxic T-Lymphocyte Epitope Exacts a Dramatic Fitness Cost

2005 ◽  
Vol 79 (9) ◽  
pp. 5721-5731 ◽  
Author(s):  
Caroline S. Fernandez ◽  
Ivan Stratov ◽  
Robert De Rose ◽  
Katrina Walsh ◽  
C. Jane Dale ◽  
...  
Keyword(s):  
T Cell ◽  
T Lymphocyte ◽  
Cytotoxic T Lymphocyte ◽  
Fitness Cost ◽  
Escape Mutation ◽  
Escape Mutant ◽  
Wild Type ◽  
Immunodeficiency Virus ◽  
Hiv 1 ◽  
Pigtail Macaques

ABSTRACT Escape from specific T-cell responses contributes to the progression of human immunodeficiency virus type 1 (HIV-1) infection. T-cell escape viral variants are retained following HIV-1 transmission between major histocompatibility complex (MHC)-matched individuals. However, reversion to wild type can occur following transmission to MHC-mismatched hosts in the absence of cytotoxic T-lymphocyte (CTL) pressure, due to the reduced fitness of the escape mutant virus. We estimated both the strength of immune selection and the fitness cost of escape variants by studying the rates of T-cell escape and reversion in pigtail macaques. Near-complete replacement of wild-type with T-cell escape viral variants at an immunodominant simian immunodeficiency virus Gag epitope KP9 occurred rapidly (over 7 days) following infection of pigtail macaques with SHIVSF162P3. Another challenge virus, SHIVmn229, previously serially passaged through pigtail macaques, contained a KP9 escape mutation in 40/44 clones sequenced from the challenge stock. When six KP9-responding animals were infected with this virus, the escape mutation was maintained. By contrast, in animals not responding to KP9, rapid reversion of the K165R mutation occurred over 2 weeks after infection. The rapidity of reversion to the wild-type sequence suggests a significant fitness cost of the T-cell escape mutant. Quantifying both the selection pressure exerted by CTL and the fitness costs of escape mutation has important implications for the development of CTL-based vaccine strategies.

scholarly journals Characteristics and determinants of T-cell phenotype normalization in HIV-1-infected individuals receiving long-term antiretroviral therapy

HIV Medicine ◽  
2013 ◽  
Vol 15 (3) ◽  
pp. 153-164 ◽  
Author(s):  
P Ndumbi ◽  
J Gillis ◽  
J Raboud ◽  
C Cooper ◽  
RS Hogg ◽  
...  
Keyword(s):  
T Cell ◽  
Antiretroviral Therapy ◽  
Cell Phenotype ◽  
Hiv 1

scholarly journals Modulation of Human Immunodeficiency Virus Type 1-Induced Syncytium Formation by the Conformational State of LFA-1 Determined by a New Luciferase-Based Syncytium Quantitative Assay

1998 ◽  
Vol 72 (9) ◽  
pp. 7125-7136 ◽  
Author(s):  
Benoit Barbeau ◽  
Jean-François Fortin ◽  
Nicolas Genois ◽  
Michel J. Tremblay
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cell ◽  
Cell Line ◽  
Human Immunodeficiency Virus Type ◽  
Luciferase Activity ◽  
Syncytium Formation ◽  
High Affinity ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT The ICAM-1/LFA-1 interaction has been clearly demonstrated to play an active role in syncytium formation induced by human immunodeficiency virus type 1 (HIV-1). Since it is known that a high-affinity state of LFA-1 for ICAM-1 can be induced through conformational change, such a high-affinity state may also contribute to the process of syncytium formation. In this study, we have investigated the involvement of the conformational status of LFA-1 in HIV-1-dependent syncytium formation by using the anti-LFA-1 antibody NKI-L16, which is known to activate the high-affinity state. Initial visual observations by light microscopy indeed suggested that the addition of the NKI-L16 antibody led to bigger and more numerous syncytia when different cell lines were tested. To further analyze this NKI-L16-dependent increment of syncytium formation in a quantitative assay, a new luciferase-based assay was developed by using a T-cell line containing an HIV-1 long terminal repeat (LTR)-driven luciferase construct (1G5) in coincubation with an HIV-1-positive cell line (J1.1). Upon fusion, the viral Tat protein could diffuse to the 1G5 cells, leading to a transcriptional increase of the HIV-1 LTR-driven luciferase gene. Initial evaluation of this assay showed a good correlation between the level of syncytium formation determined by microscopic observation and the level of measured luciferase activity. In addition, this assay showed a greater induction of enzymatic activity correlating with syncytium formation in comparison to a similar incubation with the HeLa–CD4–LTR–β-gal indicator cell line. By using this test, NKI-L16 treatment of 1G5/J1.1 cells led to a three- to sevenfold increase in HIV-1 LTR-driven luciferase activity. The syncytium-dependent luciferase activity in NKI-L16-treated cells could be blocked by classical syncytium inhibitors such as soluble CD4, anti-CD4, and anti-gp120 antibodies. Inhibition could also be observed with specific blocking agents for the chemokine receptor CXCR4, as well as with soluble ICAM-1, anti-LFA-1, anti-ICAM-1, and anti-ICAM-2 blocking antibodies, indicating the requirement for the LFA-1/ICAM interaction. Treatment of peripheral blood mononuclear cells with NKI-L16 resulted in a higher level of syncytium formation in the presence of the cell line J1.1. Conversely, when PBMCs were infected with two different syncytium-inducing HIV-1 primary isolates, coincubation with NKI-L16-pretreated 1G5 cells led to higher levels of luciferase activity for both virus isolates. Our results therefore show for the first time a direct role for the LFA-1 high-affinity state in virus-mediated syncytium formation. Based on the demonstration that an increase in ICAM-1 binding is induced by T-cell activation, these data suggest an in vivo involvement of the high-affinity state of LFA-1 in HIV-1-induced syncytium formation. Moreover, syncytia might preferentially occur in lymph nodes, since this microenvironment harbors a high proportion of activated T cells.

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