Enhanced Detection of Human Immunodeficiency Virus Type 1-Specific T-Cell Responses to Highly Variable Regions by Using Peptides Based on Autologous Virus Sequences

Altfeld, Marcus; Addo, Marylyn M.; Shankarappa, Raj; Lee, Paul K.; Allen, Todd M.; Yu, Xu G.; Rathod, Almas; Harlow, Jason; O’Sullivan, Kristin; Johnston, Mary N.; Goulder, Philip; Mullins, James I.; Rosenberg, Eric S.; Berthou, Christian; Korber, Bette T.; Walker, Bruce D.

doi:10.1128/jvi.77.13.7330-7340.2003

Cited by 136 publications

(107 citation statements)

References 53 publications

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“…First, mapping with clade B consensus sequence-based reagents may lead to a proportion of T cell responses (particularly in more variable regions of the virus) being missed due to lack of T cell recognition of the consensus sequence peptide (23,24), an issue that we confirmed in analyses performed on a small subset of patients. Secondly, by mapping T cell responses at ϳ2-3 mo FOSx, we may have missed initially immunodominant responses that declined in frequency below the limit of detection by the time mapping was performed.…”

Section: Discussionsupporting

confidence: 57%

Kinetics of Expansion of Epitope-Specific T Cell Responses during Primary HIV-1 Infection

Turnbull

Wong

Wang

et al. 2009

The Journal of Immunology

131

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Multiple lines of evidence support a role for CD8؉ T cells in control of acute/early HIV replication; however, features of the primary HIV-specific CD8؉ T cell response that may impact on the efficiency of containment of early viral replication remain poorly defined. In this study, we performed a novel, comprehensive analysis of the kinetics of expansion of components of the HIV-specific CD8؉ T cell response in 21 acutely infected individuals. Epitope-specific T cell responses expanded asynchronously during primary infection in all subjects. The most rapidly expanded responses peaked as early as 5 days following symptomatic presentation and were typically of very limited epitope breadth. Responses of additional specificities expanded and contracted in subsequent waves, resulting in successive shifts in the epitope immunodominance hierarchy over time. Sequence variation and escape were temporally associated with the decline in magnitude of only a subset of T cell responses, suggesting that other factors such as Ag load and T cell exhaustion may play a role in driving the contraction of HIV-specific T cell responses. These observations document the preferential expansion of CD8 ؉ T cells recognizing a subset of epitopes during the viral burst in acute HIV-1 infection and suggest that the nature of the initial, very rapidly expanded T cell response may influence the efficiency with which viral replication is contained in acute/early HIV infection.

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Section: Discussionsupporting

confidence: 57%

Kinetics of Expansion of Epitope-Specific T Cell Responses during Primary HIV-1 Infection

Turnbull

Wong

Wang

et al. 2009

The Journal of Immunology

131

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“…It is widely known that the use of peptides based on HIV-1 reference strains in order to screen CTL responses fails to detect the true breadth and magnitude of the response (4). The data presented here indicate that the use of two peptide sets based on the more prevalent subtypes circulating in our region increased the rate of detected responses.…”

Section: Discussionsupporting

confidence: 54%

Magnitude, Breadth, and Functional Profile of T-Cell Responses during Human Immunodeficiency Virus Primary Infection with B and BF Viral Variants

Turk

Gherardi

Laufer

et al. 2008

J Virol

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Human immunodeficiency virus type 1 (HIV-1)-specific cytotoxic T lymphocytes (CTLs) arising during the acute phase of infection are associated with containment of viral replication and resolution of acute-phase symptoms (5,13,14,44). Detailed characterization of these cell populations and viral immunodominant epitopes will provide key data for developing and enhancing immunization strategies. In this sense, one major challenge is HIV variability, characterized by substantial inter-and intraclade sequence diversity. To date, most reports aimed at studying CTL responses are focused on HIV clade Band C-infected patients. In Argentina, epidemiological studies revealed that early predominance of B subtype has been overshadowed by the emergence of BF recombinants (16,23,32,33,53). These reports indicate that near 50% of the HIVinfected people living in Argentina are infected either with the circulating recombinant form CRF12_BF or other BF recombinant forms related to CRF12_BF. Moreover, in other South American countries, such as Brazil and Uruguay, high prevalence of F subtype and BF recombinant variants are also found (16,32,34). These findings provide an adequate scenario to fill the gap concerning fine mapping of CTL responses in nonclade B-and C-infected patients.Cross-clade CTL responses were studied by different groups using different approaches. The first publications used vaccinia virus-based constructs or peptide pools as stimulating factors (2,19,20,27). Not until recently was fine mapping of these responses achieved by using individual peptides based on different subtypes (22,28). The latter allows for a more detailed and comprehensive understanding of cross-clade reactive populations.Here, cross-clade and clade-specific T-cell responses in Band BF-infected patients from Argentina are reported. These assays were performed shortly after seroconversion in order to avoid the confounders associated with viral diversification, selection of escape mutants, and superinfection. Overlapping peptides spanning the Nef protein were chosen as antigens because of the following: (i) Nef is halfway along the spectrum of variability found in HIV proteins; (ii) during primary HIV infection, Nef-specific CTLs represent between 46% and 94% of the total magnitude of the HIV T-cell response (43); (iii) Nef has, together with Gag, the highest epitope density (1,39). This study also contributes to minimizing the problem of breadth underestimation during CTL screening and provides insights into discrepancies of CD8 T-cell effector function.

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“…Finally, because relatively conserved regions of the viral genome were chosen for this study, the observed benefits of using toggled peptides when compared with consensus sequence based test sets reflect conservative increases, which may be even more significant when applying this approach to more variable proteins in HV and other variable pathogens (33). However, while designing toggled peptides for highly variable targets is feasible, it will, as illustrated in Fig.…”

Section: Discussionmentioning

confidence: 99%

“…Just as assessing the T cell immune response by IFN-␥ expression alone gives only a limited view of T cell function (32), using only one peptide to probe T cell specificity fails to adequately detect T cell responses. Although autologous peptides are frequently considered the most appropriate test set, peptide test sets reflecting the individuals' autologous viral sequences are prohibitively expensive (33), and given the changing nature of the immune response and viral sequence over time in a given individual, may only allow a limited view of the true extent of the immune response. Thus, toggled peptides may even outperform autologous peptides because they predominantly probe immune responses generated by the incoming virus, but also cover possible escape variants that may have induced de novo responses later in infection (34).…”

Section: Discussionmentioning

confidence: 99%

Increased Sequence Diversity Coverage Improves Detection of HIV-Specific T Cell Responses

Frahm

Kaufmann

Yusim

et al. 2007

The Journal of Immunology

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The accurate identification of HIV-specific T cell responses is important for determining the relationship between immune response, viral control, and disease progression. HIV-specific immune responses are usually measured using peptide sets based on consensus sequences, which frequently miss responses to regions where test set and infecting virus differ. In this study, we report the design of a peptide test set with significantly increased coverage of HIV sequence diversity by including alternative amino acids at variable positions during the peptide synthesis step. In an IFN-γ ELISpot assay, these “toggled” peptides detected HIV-specific CD4+ and CD8+ T cell responses of significantly higher breadth and magnitude than matched consensus peptides. The observed increases were explained by a closer match of the toggled peptides to the autologous viral sequence. Toggled peptides therefore afford a cost-effective and significantly more complete view of the host immune response to HIV and are directly applicable to other variable pathogens.

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Enhanced Detection of Human Immunodeficiency Virus Type 1-Specific T-Cell Responses to Highly Variable Regions by Using Peptides Based on Autologous Virus Sequences

Cited by 136 publications

References 53 publications

Kinetics of Expansion of Epitope-Specific T Cell Responses during Primary HIV-1 Infection

Kinetics of Expansion of Epitope-Specific T Cell Responses during Primary HIV-1 Infection

Magnitude, Breadth, and Functional Profile of T-Cell Responses during Human Immunodeficiency Virus Primary Infection with B and BF Viral Variants

Increased Sequence Diversity Coverage Improves Detection of HIV-Specific T Cell Responses

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