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

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

Frontiers in Immunology ◽

10.3389/fimmu.2020.568217 ◽

2020 ◽

Vol 11 ◽

Author(s):

Emma C. Materne ◽

Daniele Lilleri ◽

Francesca Garofoli ◽

Giuseppina Lombardi ◽

Milena Furione ◽

...

Keyword(s):

T Cell ◽

Immune Escape ◽

Cell Epitope ◽

T Cell Responses ◽

Cd8 T Cell ◽

Viral Escape ◽

Maternal Loss ◽

Congenital Cytomegalovirus ◽

Epitope Recognition ◽

Cell Responses

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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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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Broad and persistent Gag-specific CD8+ T-cell responses are associated with viral control but rarely drive viral escape during primary HIV-1 infection

AIDS ◽

10.1097/qad.0000000000000508 ◽

2015 ◽

Vol 29 (1) ◽

pp. 23-33 ◽

Cited By ~ 29

Author(s):

Mopo Radebe ◽

Kamini Gounder ◽

Mammekwa Mokgoro ◽

Zaza M. Ndhlovu ◽

Zenele Mncube ◽

...

Keyword(s):

T Cell ◽

T Cell Responses ◽

Cd8 T Cell ◽

Viral Escape ◽

Viral Control ◽

Cell Responses ◽

Hiv 1

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Antisense-Derived HIV-1 Cryptic Epitopes Are Not Major Drivers of Viral Evolution during the Acute Phase of Infection

Journal of Virology ◽

10.1128/jvi.00711-18 ◽

2018 ◽

Vol 92 (19) ◽

Author(s):

Binghao J. Peng ◽

Jonathan M. Carlson ◽

Michael K. P. Liu ◽

Feng Gao ◽

Nilu Goonetilleke ◽

...

Keyword(s):

T Cell ◽

Acute Infection ◽

T Cell Responses ◽

Cd8 T Cell ◽

Viral Escape ◽

Cell Responses ◽

Acute Infections ◽

Cryptic Epitope ◽

Cryptic Epitopes ◽

Hiv 1

ABSTRACT While prior studies have demonstrated that CD8 T cell responses to cryptic epitopes (CE) are readily detectable during HIV-1 infection, their ability to drive escape mutations following acute infection is unknown. We predicted 66 CE in a Zambian acute infection cohort based on escape mutations occurring within or near the putatively predicted HLA-I-restricted epitopes. The CE were evaluated for CD8 T cell responses for patients with chronic and acute HIV infections. Of the 66 predicted CE, 10 were recognized in 8/32 and 4/11 patients with chronic and acute infections, respectively. The immunogenic CE were all derived from a single antisense reading frame within pol. However, when these CE were tested using longitudinal study samples, CE-specific T cell responses were detected but did not consistently select for viral escape mutations. Thus, while we demonstrated that CE are immunogenic in acute infection, the immune responses to CE are not major drivers of viral escape in the initial stages of HIV infection. The latter finding may be due to either the subdominant nature of CE-specific responses, the low antigen sensitivity, or the magnitude of CE responses during acute infections. IMPORTANCE Although prior studies demonstrated that cryptic epitopes of HIV-1 induce CD8 T cell responses, evidence that targeting these epitopes drives HIV escape mutations has been substantially limited, and no studies have addressed this question following acute infection. In this comprehensive study, we utilized longitudinal viral sequencing data obtained from three separate acute infection cohorts to predict potential cryptic epitopes based on HLA-I-associated viral escape. Our data show that cryptic epitopes are immunogenic during acute infection and that many of the responses they elicit are toward translation products of HIV-1 antisense reading frames. However, despite cryptic epitope targeting, our study did not find any evidence of early CD8-mediated immune escape. Nevertheless, improving cryptic epitope-specific CD8 T cell responses may still be beneficial in both preventative and therapeutic HIV-1 vaccines.

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CD8+ T Cell Responses during HCV Infection and HCC

Journal of Clinical Medicine ◽

10.3390/jcm10050991 ◽

2021 ◽

Vol 10 (5) ◽

pp. 991

Author(s):

Maike Hofmann ◽

Catrin Tauber ◽

Nina Hensel ◽

Robert Thimme

Keyword(s):

T Cells ◽

T Cell ◽

Cd8 T Cells ◽

Current Knowledge ◽

T Cell Responses ◽

Cd8 T Cell ◽

Hcv Infection ◽

Viral Escape ◽

Western World ◽

Cell Responses

Chronic hepatitis C virus (cHCV) infection is a major global health burden and the leading cause of hepatocellular carcinoma (HCC) in the Western world. The course and outcome of HCV infection is centrally influenced by CD8+ T cell responses. Indeed, strong virus-specific CD8+ T cell responses are associated with spontaneous viral clearance while failure of these responses, e.g., caused by viral escape and T cell exhaustion, is associated with the development of chronic infection. Recently, heterogeneity within the exhausted HCV-specific CD8+ T cells has been observed with implications for immunotherapeutic approaches also for other diseases. In HCC, the presence of tumor-infiltrating and peripheral CD8+ T cell responses correlates with a favorable prognosis. Thus, tumor-associated and tumor-specific CD8+ T cells are considered suitable targets for immunotherapeutic strategies. Here, we review the current knowledge of CD8+ T cell responses in chronic HCV infection and HCC and their respective failure with the potential consequences for T cell-associated immunotherapeutic approaches.

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Immune-driven recombination and loss of control after HIV superinfection

Journal of Experimental Medicine ◽

10.1084/jem.20080281 ◽

2008 ◽

Vol 205 (8) ◽

pp. 1789-1796 ◽

Cited By ~ 75

Author(s):

Hendrik Streeck ◽

Bin Li ◽

Art F.Y. Poon ◽

Arne Schneidewind ◽

Adrianne D. Gladden ◽

...

Keyword(s):

T Cell ◽

De Novo ◽

Subsequent Development ◽

T Cell Responses ◽

Cd8 T Cell ◽

Viral Escape ◽

Immune Selection ◽

Viral Control ◽

Acute Hiv Infection ◽

Cell Responses

After acute HIV infection, CD8+ T cells are able to control viral replication to a set point. This control is often lost after superinfection, although the mechanism behind this remains unclear. In this study, we illustrate in an HLA-B27+ subject that loss of viral control after HIV superinfection coincides with rapid recombination events within two narrow regions of Gag and Env. Screening for CD8+ T cell responses revealed that each of these recombination sites (∼50 aa) encompassed distinct regions containing two immunodominant CD8 epitopes (B27-KK10 in Gag and Cw1-CL9 in Env). Viral escape and the subsequent development of variant-specific de novo CD8+ T cell responses against both epitopes were illustrative of the significant immune selection pressures exerted by both responses. Comprehensive analysis of the kinetics of CD8 responses and viral evolution indicated that the recombination events quickly facilitated viral escape from both dominant WT- and variant-specific responses. These data suggest that the ability of a superinfecting strain of HIV to overcome preexisting immune control may be related to its ability to rapidly recombine in critical regions under immune selection pressure. These data also support a role for cellular immune pressures in driving the selection of new recombinant forms of HIV.

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3 POPULATIONAL ANALYSIS REVEALS A LINK BETWEEN COMPLEX VIRAL ESCAPE FROM CD8+ T-CELL RESPONSES AND PROTECTION IN HCV INFECTION

Journal of Hepatology ◽

10.1016/s0168-8278(11)60005-6 ◽

2011 ◽

Vol 54 ◽

pp. S2

Author(s):

T. Kuntzen ◽

C. Neumann-Haefelin ◽

N. Lennon ◽

A.H. Talal ◽

J. Carlson ◽

...

Keyword(s):

T Cell ◽

T Cell Responses ◽

Cd8 T Cell ◽

Hcv Infection ◽

Viral Escape ◽

Cell Responses

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Utility of Human Immunodeficiency Virus Type 1 Envelope as a T-Cell Immunogen

Journal of Virology ◽

10.1128/jvi.01408-07 ◽

2007 ◽

Vol 81 (23) ◽

pp. 13125-13134 ◽

Cited By ~ 27

Author(s):

Viv Peut ◽

Stephen J. Kent

Keyword(s):

Human Immunodeficiency Virus ◽

T Cells ◽

T Cell ◽

T Lymphocytes ◽

Immune Responses ◽

T Cell Responses ◽

Cd8 T Cell ◽

Viral Escape ◽

Cell Responses ◽

Immunodeficiency Virus

ABSTRACT Human immunodeficiency virus (HIV)-specific CD8 T lymphocytes are important for the control of viremia, but the relative utility of responses to the various HIV proteins is controversial. Immune responses that force escape mutations that exact a significant fitness cost from the mutating virus would help slow progression to AIDS. The HIV envelope (Env) protein is subject to both humoral and cellular immune responses, suggesting that multiple rounds of mutation are needed to facilitate viral escape. The Gag protein, however, has recently been shown to elicit a more effective CD8 T-cell immune response in humans. We studied 30 pigtail macaques for their CD8 T-lymphocyte responses to HIV-1 Env and simian immunodeficiency virus (SIV) Gag following prime/boost vaccination and intrarectal challenge with simian-human immunodeficiency virus SHIVmn229. Eight CD8 Env-specific T-cell epitopes were identified and mapped in 10 animals. Animals that generated Env-specific CD8 T-cell responses had equivalent viral loads and only a modest advantage in retention of peripheral CD4 T lymphocytes compared to those animals without responses to Env. This contrasts with animals that generated CD8 T-cell responses to SIV Gag in the same trial, demonstrating superior control of viral load and a larger advantage in retention of peripheral CD4 T cells than Gag nonresponders. Mutational escape was common in Env but, in contrast to mutations in Gag, did not result in the rapid emergence of dominant escape motifs, suggesting modest selective pressure from Env-specific T cells. These results suggest that Env may have limited utility as a CD8 T-cell immunogen.

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