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

2017 ◽  
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.

scholarly journals Immune-driven recombination and loss of control after HIV superinfection

2008 ◽  
Vol 205 (8) ◽  
pp. 1789-1796 ◽  
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.

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

2009 ◽  
Vol 182 (4) ◽  
pp. 1829-1835 ◽  
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

scholarly journals Magnitude and Complexity of Rectal Mucosa HIV-1-Specific CD8+ T-Cell Responses during Chronic Infection Reflect Clinical Status

PLoS ONE ◽  
2008 ◽  
Vol 3 (10) ◽  
pp. e3577 ◽  
Author(s):  
J. William Critchfield ◽  
Delandy H. Young ◽  
Timothy L. Hayes ◽  
Jerome V. Braun ◽  
Juan C. Garcia ◽  
...  
Keyword(s):  
T Cell ◽  
Chronic Infection ◽  
Clinical Status ◽  
Rectal Mucosa ◽  
T Cell Responses ◽  
Cd8 T Cell ◽  
Cell Responses ◽  
Hiv 1

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

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.

scholarly journals Cellular immune selection with hepatitis C virus persistence in humans

2005 ◽  
Vol 201 (11) ◽  
pp. 1741-1752 ◽  
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.

scholarly journals Defining Kinetic Properties of HIV-Specific CD8+ T-cell Responses in Acute Infection

2019 ◽  
Author(s):  
Yiding Yang ◽  
Vitaly V. Ganusov
Keyword(s):  
T Cells ◽  
Viral Load ◽  
T Cell ◽  
Cd8 T Cells ◽  
Chronic Infection ◽  
T Cell Responses ◽  
Cd8 T Cell ◽  
T Cell Response ◽  
Cell Responses ◽  
Average Viral Load

Multiple lines of evidence indicate that CD8$^+$ T cells are important in the control of HIV-1 (HIV) replication. However, CD8$^+$ T cells induced by natural infection cannot eliminate the virus or reduce viral loads to acceptably low levels in most infected individuals. Understanding the basic quantitative features of CD8$^+$ T-cell responses induced during the course of HIV infection may therefore inform us about the limits that HIV vaccines, which aim to induce protective CD8$^+$ T-cell responses, must exceed. Using previously published experimental data from a cohort of HIV-infected individuals with sampling times from acute to chronic infection we defined the quantitative properties of CD8$^+$ T-cell responses to the whole HIV proteome. In contrast with a commonly held view, we found that the relative number of HIV-specific CD8$^+$ T-cell responses (response breadth) changed little over the course of infection (first 400 days post-infection), with moderate but statistically significant changes occurring only during the first 35 symptomatic days. This challenges the idea that a change in the T-cell response breadth over time is responsible for the slow speed of viral escape from CD8$^+$ T cells in the chronic infection. The breadth of HIV-specific CD8$^+$ T-cell responses was not correlated with the average viral load for our small cohort of patients. Metrics of relative immunodominance of HIV-specific CD8$^+$ T-cell responses such as Shannon entropy or the Evenness index were also not significantly correlated with the average viral load. Our mathematical-model-driven analysis suggested extremely slow expansion kinetics for the majority of HIV-specific CD8$^+$ T-cell responses and the presence of intra- and interclonal competition between multiple CD8$^+$ T-cell responses; such competition may limit the magnitude of CD8$^+$ T-cell responses, specific to different epitopes, and the overall number of T-cell responses induced by vaccination. Further understanding of mechanisms underlying interactions between the virus and virus-specific CD8$^+$ T-cell response will be instrumental in determining which T-cell-based vaccines will induce T-cell responses providing durable protection against HIV infection.

scholarly journals Transcription factor T-bet represses expression of the inhibitory receptor PD-1 and sustains virus-specific CD8+ T cell responses during chronic infection

2011 ◽  
Vol 12 (7) ◽  
pp. 663-671 ◽  
Author(s):  
Charlly Kao ◽  
Kenneth J Oestreich ◽  
Michael A Paley ◽  
Alison Crawford ◽  
Jill M Angelosanto ◽  
...  
Keyword(s):  
Transcription Factor ◽  
T Cell ◽  
Chronic Infection ◽  
T Cell Responses ◽  
Cd8 T Cell ◽  
Inhibitory Receptor ◽  
Cell Responses

scholarly journals 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 ◽  
2015 ◽  
Vol 29 (1) ◽  
pp. 23-33 ◽  
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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