Relative Dominance of Gag p24-Specific Cytotoxic T Lymphocytes Is Associated with Human Immunodeficiency Virus Control

Zuñiga, Rosario; Lucchetti, Aldo; Galván, P; Sanchez, Shyla; Sánchez, Carmen Nibot; Hernández, Ana González; Sánchez, Hugo; Frahm, Nicole; Linde, Caitlyn; Hewitt, Hannah S.; Hildebrand, William H.; Altfeld, Marcus; Allen, Todd M.; Walker, Bruce D.; Korber, Bette T.; Leitner, Thomas; Sánchez, Jorge; Berthou, Christian

doi:10.1128/jvi.80.6.3122-3125.2006

Cited by 271 publications

(242 citation statements)

References 23 publications

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“…Because Gag-specific immunity may be particularly effective for the control of HIV-1 infection (8,22,36), the highly conserved TV9, which overlaps with the HLA-B57-restricted p24 peptide recognized by long-term nonprogressors (9, 40 -42), may be a potentially useful vaccine target for HLA-A2 carriers. The fact that it is subdominant in patients may be particularly advantageous in a therapeutic vaccine setting because the responding repertoire would not have been exhausted by the infection.…”

Section: Discussionmentioning

confidence: 99%

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Availability of a Diversely Avid CD8+ T Cell Repertoire Specific for the Subdominant HLA-A2-Restricted HIV-1 Gag p2419–27 Epitope

Schaubert

Price

Frahm

et al. 2007

The Journal of Immunology

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HLA-A2-restricted CTL responses to immunodominant HIV-1 epitopes do not appear to be very effective in the control of viral replication in vivo. In this study, we studied human CD8+ T cell responses to the subdominant HLA-A2-restricted epitope TV9 (Gag p2419–27, TLNAWVKVV) to explore the possibility of increasing its immune recognition. We confirmed in a cohort of 313 patients, infected by clade B or clade C viruses, that TV9 is rarely recognized. Of interest, the functional sensitivity of the TV9 response can be relatively high. The potential T cell repertoires for TV9 and the characteristics of constituent clonotypes were assessed by ex vivo priming of circulating CD8+ T cells from healthy seronegative donors. TV9-specific CTLs capable of suppressing viral replication in vitro were readily generated, suggesting that the cognate T cell repertoire is not limiting. However, these cultures contained multiple discrete populations with a range of binding avidities for the TV9 tetramer and correspondingly distinct functional dependencies on the CD8 coreceptor. The lack of dominant clonotypes was not affected by the stage of maturation of the priming dendritic cells. Cultures primed by dendritic cells transduced to present endogenous TV9 were also incapable of clonal maturation. Thus, a diffuse TCR repertoire appeared to be an intrinsic characteristic of TV9-specific responses. These data indicate that subdominance is not a function of poor immunogenicity, cognate TCR repertoire availability, or the potential avidity properties thereof, but rather suggest that useful responses to this epitope are suppressed by competing CD8+ T cell populations during HIV-1 infection.

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Section: Discussionmentioning

confidence: 99%

“…In particular, the extreme conservation and intolerance of escape variations in Gag p24 indicate that it may be a critical target for vaccine design (35,36). There is only one well-defined HLA-A2-restricted epitope in p24, abbreviated as TV9 (TLNAWVKVV, Gag p24 19 -27 ).…”

mentioning

confidence: 99%

Availability of a Diversely Avid CD8+ T Cell Repertoire Specific for the Subdominant HLA-A2-Restricted HIV-1 Gag p2419–27 Epitope

Schaubert

Price

Frahm

et al. 2007

The Journal of Immunology

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“…Although the importance of CD8 T cells in controlling HIV replication is widely accepted, earlier reports have failed to show either a positive or negative correlation between viral load and the breadth or magnitude of CTL responses. Now it is known that Gag-specific responses are associated with low viremia (29,38,61), which can be explained by the capacity of Gag-specific CTLs to kill very recently infected cells, even before the viral genome integrates into the host genome (55). Also, it was shown that the functional profile of HIV-specific CD8 T cells in progressors is limited compared to that of nonprogressors, who consistently maintain highly functional CD8 T cells (12).…”

Section: Discussionmentioning

confidence: 99%

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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“…Loss or dysregulation of CD8+ T cells was found to be associated with disease progression. It is also found that CTL response towards the p24 subunit of the Gag protein was the dominant form of immunity in HIV controllers (Zuniga et al, 2006). CTL from LTNPs are shown to have poly-functional responses compared to HIV+ rapid progressors.…”

Section: Cd8+ Tellsmentioning

confidence: 91%

Innate, Adaptive and Intrinsic Immunity in Human Immunodeficiency Virus Infection

Perera

Saksena

2012

American Journal of Infectious Diseases

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The first line of defence of the innate immune system functions by recognizing highly conserved sets of molecular structures specific to the microbes, termed pathogen-associated molecular patterns, or PAMPs via the germ line-encoded receptors Pattern-Recognition Receptors (PRRs). In addition to the innate immune system, the vertebrates have also evolved a second line of defence termed adaptive immune system, which uses a diverse set of somatically rearranged receptors T-Cell Receptors (TCRs) and B Cell Receptors (BCRs), which have the inherent ability to effectively recognise diverse antigens. The innate and adaptive immune systems are functionally tied in with the intrinsic immunity, which comprises of endogenous antiviral factors. Thus, this effective response to diverse microbial infections, including HIV, requires a coordinated interaction at several functional levels between innate, adaptive and intrinsic immune systems. This review provides a snapshot of roles played by the innate, adaptive and the intrinsic immune systems during HIV-infection, along with discussing recent developments highlighting the genomic basis of these responses and their regulation by micro-RNA (miRNAs).

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Relative Dominance of Gag p24-Specific Cytotoxic T Lymphocytes Is Associated with Human Immunodeficiency Virus Control

Cited by 271 publications

References 23 publications

Availability of a Diversely Avid CD8+ T Cell Repertoire Specific for the Subdominant HLA-A2-Restricted HIV-1 Gag p2419–27 Epitope

Availability of a Diversely Avid CD8+ T Cell Repertoire Specific for the Subdominant HLA-A2-Restricted HIV-1 Gag p2419–27 Epitope

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

Innate, Adaptive and Intrinsic Immunity in Human Immunodeficiency Virus Infection

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