Cytomegalovirus-Specific T Cell Epitope Recognition in Congenital Cytomegalovirus Mother-Infant Pairs

Background: Congenital cytomegalovirus (cCMV) infection is the most common infection acquired before birth and from which about 20% of infants develop permanent neurodevelopmental effects regardless of presence or absence of symptoms at birth. Viral escape from host immune control may be a mechanism of CMV transmission and infant disease severity. We sought to identify and compare CMV epitopes recognized by mother-infant pairs. We also hypothesized that if immune escape were occurring, then one pattern of longitudinal CD8 T cell responses restricted by shared HLA alleles would be maternal loss (by viral escape) and infant gain (by viral reversion to wildtype) of CMV epitope recognition.Methods: The study population consisted of 6 women with primary CMV infection during pregnancy and their infants with cCMV infection. CMV UL83 and UL123 peptides with known or predicted restriction by maternal MHC class I alleles were identified, and a subset was selected for testing based on several criteria. Maternal or infant cells were stimulated with CMV peptides in the IFN-γ ELISpot assay.Results: Overall, 14 of 25 (56%; 8 UL83 and 6 UL123) peptides recognized by mother-infant pairs were not previously reported as CD8 T cell epitopes. Of three pairs with longitudinal samples, one showed maternal loss and infant gain of responses to a CMV epitope restricted by a shared HLA allele.Conclusions: CD8 T cell responses to multiple novel CMV epitopes were identified, particularly in infants. Moreover, the hypothesized pattern of CMV immune escape was observed in one mother-infant pair. These findings emphasize that knowledge of paired CMV epitope recognition allows exploration of viral immune escape that may operate within the maternal-fetal system. Our work provides rationale for future studies of this potential mechanism of CMV transmission during pregnancy or clinical outcomes of infants with cCMV infection.

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CD8+T Cell Responses to a Viral Escape Mutant Epitope: Active Suppression via Altered SHP-1 Activity

The Journal of Immunology ◽

10.4049/jimmunol.0801798 ◽

2009 ◽

Vol 182 (4) ◽

pp. 1829-1835 ◽

Cited By ~ 8

Author(s):

Frederick J. Schnell ◽

Noah Alberts-Grill ◽

Brian D. Evavold

Keyword(s):

T Cell ◽

T Cell Responses ◽

Cd8 T Cell ◽

Viral Escape ◽

Escape Mutant ◽

Active Suppression ◽

Cell Responses

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Time intervals in sequence sampling, not data modifications, have a major impact on estimates of HIV escape rates

10.1101/221812 ◽

2017 ◽

Cited By ~ 1

Author(s):

Vitaly V. Ganusov

Keyword(s):

T Cell ◽

Chronic Infection ◽

T Cell Responses ◽

Cd8 T Cell ◽

Escape Rate ◽

Viral Escape ◽

Time Interval ◽

Acute Hiv Infection ◽

Cell Responses ◽

Data Modifications

AbstractThe ability of HIV to avoid recognition by humoral and cellular immunity (viral escape) is well documented but the strength of the immune response needed to cause such a viral escape remains poorly quantified. Several previous studies observed a more rapid escape of HIV from CD8 T cell responses in the acute phase of infection as compared to the chronic infection. With the help of simple mathematical models the rate of HIV escape was estimated and results were interpreted to suggest that CD8 T cell responses causing escape in acute HIV infection may be more efficient at killing virus-infected cells than responses that cause escape in chronic infection, or alternatively, early escapes occur in epitopes mutations in which there is minimal fitness cost to the virus. These conclusions, however, were challenged on several grounds, including linkage and interference of multiple escape mutations due to a low population size and because of potential issues associated with modifying the data to estimate escape rates. Here we use a parametric resampling method which does not require data modification to show that previous results on the decline of the viral escape rate with time since infection remain unchanged. However, using this method we also show that estimates of the escape rate are highly sensitive to the time interval between measurements with longer intervals biasing estimates of the escape rate downwards. Our results thus suggest that data modifications for early and late escapes were not the primary reason for the observed decline in the escape rate with time since infection. However, longer sampling periods for escapes in chronic infection strongly influence estimates of the escape rate. More frequent sampling of viral sequences in the chronic infection may improve our understanding of factors influencing the rate of HIV escape from CD8 T cell responses.

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Cross-Priming of T Cell Responses by Synthetic Microspheres Carrying a CD8+ T Cell Epitope Requires an Adjuvant Signal

The Journal of Immunology ◽

10.4049/jimmunol.174.6.3432 ◽

2005 ◽

Vol 174 (6) ◽

pp. 3432-3439 ◽

Cited By ~ 13

Author(s):

Florence Boisgérault ◽

Paloma Rueda ◽

Cheng Ming Sun ◽

Sandra Hervas-Stubbs ◽

Marie Rojas ◽

...

Keyword(s):

T Cell ◽

Cell Epitope ◽

T Cell Responses ◽

Cd8 T Cell ◽

T Cell Epitope ◽

Cell Responses

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CD147 regulates antitumor CD8+ T-cell responses to facilitate tumor-immune escape

Cellular and Molecular Immunology ◽

10.1038/s41423-020-00570-y ◽

2020 ◽

Author(s):

Yatong Chen ◽

Jing Xu ◽

Xiaodong Wu ◽

Hui Yao ◽

Zhou Yan ◽

...

Keyword(s):

T Cell ◽

Immune Escape ◽

T Cell Responses ◽

Cd8 T Cell ◽

Tumor Immune Escape ◽

Cell Responses

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Cellular immune selection with hepatitis C virus persistence in humans

Journal of Experimental Medicine ◽

10.1084/jem.20050121 ◽

2005 ◽

Vol 201 (11) ◽

pp. 1741-1752 ◽

Cited By ~ 210

Author(s):

Andrea L. Cox ◽

Timothy Mosbruger ◽

Qing Mao ◽

Zhi Liu ◽

Xiao-Hong Wang ◽

...

Keyword(s):

Hepatitis C Virus ◽

Hepatitis C ◽

T Cell ◽

T Cell Responses ◽

Cd8 T Cell ◽

Viral Escape ◽

Sequence Evolution ◽

T Cell Epitopes ◽

Cell Responses ◽

Cellular Immune

Hepatitis C virus (HCV) infection frequently persists despite substantial virus-specific cellular immune responses. To determine if immunologically driven sequence variation occurs with HCV persistence, we coordinately analyzed sequence evolution and CD8+ T cell responses to epitopes covering the entire HCV polyprotein in subjects who were followed prospectively from before infection to beyond the first year. There were no substitutions in T cell epitopes for a year after infection in a subject who cleared viremia. In contrast, in subjects with persistent viremia and detectable T cell responses, we observed substitutions in 69% of T cell epitopes, and every subject had a substitution in at least one epitope. In addition, amino acid substitutions occurred 13-fold more often within than outside T cell epitopes (P < 0.001, range 5–38). T lymphocyte recognition of 8 of 10 mutant peptides was markedly reduced compared with the initial sequence, indicating viral escape. Of 16 nonenvelope substitutions that occurred outside of known T cell epitopes, 8 represented conversion to consensus (P = 0.015). These findings reveal two distinct mechanisms of sequence evolution involved in HCV persistence: viral escape from CD8+ T cell responses and optimization of replicative capacity.

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Absence of viral escape within a frequently recognized HLA-A26-restricted CD8+ T-cell epitope targeting the functionally constrained hepatitis C virus NS5A/5B cleavage site

Journal of General Virology ◽

10.1099/vir.0.82826-0 ◽

2007 ◽

Vol 88 (7) ◽

pp. 1986-1991 ◽

Cited By ~ 14

Author(s):

Christoph Neumann-Haefelin ◽

Thomas Killinger ◽

Jörg Timm ◽

Scott Southwood ◽

Denise McKinney ◽

...

Keyword(s):

Hepatitis C Virus ◽

Hepatitis C ◽

T Cell ◽

Cleavage Site ◽

Cell Epitope ◽

T Cell Responses ◽

Hcv Infection ◽

Viral Fitness ◽

Viral Escape ◽

Cell Responses

CD8+ T-cell responses are central for the resolution of hepatitis C virus (HCV) infection, and viral escape from these CD8+ T-cell responses has been suggested to play a major role in HCV persistence. However, the factors determining the emergence of CD8 escape mutations are not well understood. Here, the first identification of four HLA-A26-restricted CD8+ T-cell epitopes is reported. Of note, two of these four epitopes are located in the NS3/4A and NS5A/5B cleavage sites. The latter epitope is targeted in all (three of three) patients with acute, resolving HCV infection and in a relatively high proportion (four of 14) of patients with chronic HCV infection. Importantly, the epitope corresponding to the NS5A/5B cleavage site is characterized by the complete absence of sequence variations, despite the presence of functional virus-specific CD8+ T cells in our cohort. These results support previous findings that showed defined functional constraints within this region. They also suggest that the absence of viral escape may be determined by viral fitness cost and highlight an attractive target for immunotherapies.

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Fluidity of HIV-1-Specific T-Cell Responses during Acute and Early Subtype C HIV-1 Infection and Associations with Early Disease Progression

Journal of Virology ◽

10.1128/jvi.01472-10 ◽

2010 ◽

Vol 84 (22) ◽

pp. 12018-12029 ◽

Cited By ~ 21

Author(s):

Mandla Mlotshwa ◽

Catherine Riou ◽

Denis Chopera ◽

Debra de Assis Rosa ◽

Roman Ntale ◽

...

Keyword(s):

T Cell ◽

Disease Progression ◽

Cell Epitope ◽

T Cell Responses ◽

Temporal Patterns ◽

Viral Escape ◽

Subtype C ◽

Cell Responses ◽

Ifn Γ ◽

Hiv 1

ABSTRACT Deciphering immune events during early stages of human immunodeficiency virus type 1 (HIV-1) infection is critical for understanding the course of disease. We characterized the hierarchy of HIV-1-specific T-cell gamma interferon (IFN-γ) enzyme-linked immunospot (ELISPOT) assay responses during acute subtype C infection in 53 individuals and associated temporal patterns of responses with disease progression in the first 12 months. There was a diverse pattern of T-cell recognition across the proteome, with the recognition of Nef being immunodominant as early as 3 weeks postinfection. Over the first 6 months, we found that there was a 23% chance of an increased response to Nef for every week postinfection (P = 0.0024), followed by a nonsignificant increase to Pol (4.6%) and Gag (3.2%). Responses to Env and regulatory proteins appeared to remain stable. Three temporal patterns of HIV-specific T-cell responses could be distinguished: persistent, lost, or new. The proportion of persistent T-cell responses was significantly lower (P = 0.0037) in individuals defined as rapid progressors than in those progressing slowly and who controlled viremia. Almost 90% of lost T-cell responses were coincidental with autologous viral epitope escape. Regression analysis between the time to fixed viral escape and lost T-cell responses (r = 0.61; P = 0.019) showed a mean delay of 14 weeks after viral escape. Collectively, T-cell epitope recognition is not a static event, and temporal patterns of IFN-γ-based responses exist. This is due partly to viral sequence variation but also to the recognition of invariant viral epitopes that leads to waves of persistent T-cell immunity, which appears to associate with slower disease progression in the first year of infection.

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Degenerate CD8 Epitopes Mapping to Structurally Constrained Regions of the Spike Protein: A T Cell-Based Way-Out From the SARS-CoV-2 Variants Storm

Frontiers in Immunology ◽

10.3389/fimmu.2021.730051 ◽

2021 ◽

Vol 12 ◽

Author(s):

Carolina Boni ◽

Davide Cavazzini ◽

Angelo Bolchi ◽

Marzia Rossi ◽

Andrea Vecchi ◽

...

Keyword(s):

T Cell ◽

Cell Epitope ◽

Cd8 T Cell ◽

T Cell Response ◽

Viral Escape ◽

Cell Mediated Immunity ◽

Structural Constraints ◽

T Cell Epitopes ◽

Cell Responses ◽

Hla Class I Molecules

There is an urgent need for new generation anti-SARS-Cov-2 vaccines in order to increase the efficacy of immunization and its broadness of protection against viral variants that are continuously arising and spreading. The effect of variants on protective immunity afforded by vaccination has been mostly analyzed with regard to B cell responses. This analysis revealed variable levels of cross-neutralization capacity for presently available SARS-Cov-2 vaccines. Despite the dampened immune responses documented for some SARS-Cov-2 mutations, available vaccines appear to maintain an overall satisfactory protective activity against most variants of concern (VoC). This may be attributed, at least in part, to cell-mediated immunity. Indeed, the widely multi-specific nature of CD8 T cell responses should allow to avoid VoC-mediated viral escape, because mutational inactivation of a given CD8 T cell epitope is expected to be compensated by the persistent responses directed against unchanged co-existing CD8 epitopes. This is particularly relevant because some immunodominant CD8 T cell epitopes are located within highly conserved SARS-Cov-2 regions that cannot mutate without impairing SARS-Cov-2 functionality. Importantly, some of these conserved epitopes are degenerate, meaning that they are able to associate with different HLA class I molecules and to be simultaneously presented to CD8 T cell populations of different HLA restriction. Based on these concepts, vaccination strategies aimed at potentiating the stimulatory effect on SARS-Cov-2-specific CD8 T cells should greatly enhance the efficacy of immunization against SARS-Cov-2 variants. Our review recollects, discusses and puts into a translational perspective all available experimental data supporting these “hot” concepts, with special emphasis on the structural constraints that limit SARS-CoV-2 S-protein evolution and on potentially invariant and degenerate CD8 epitopes that lend themselves as excellent candidates for the rational development of next-generation, CD8 T-cell response-reinforced, COVID-19 vaccines.

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