CD8+ lymphocytes respond to different HIV epitopes in seronegative and infected subjects

Kaul, Rupert; Dong, Tao; Plummer, Francis A.; Kimani, Joshua; Rostron, Timothy; Kiama, Peter; Njagi, Ephantus; Irungu, Elizabeth; Farah, Bashir; Oyugi, Julius; Chakraborty, Rana; MacDonald, Kelly S.; Bwayo, Job J.; McMichael, Andrew; Rowland‐Jones, Sarah

doi:10.1172/jci12433

Cited by 196 publications

(139 citation statements)

References 29 publications

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“…The emergence over time in an infected person of virus-escape mutants that elude CTL recognition suggests that strong CTL responses are a major influence on the survival of HIV populations within the host (8,9). Finally, the demonstration of HIV-specific CTL in highly exposed but apparently uninfected individuals is consistent with a potential role for CTL in protection against HIV infection (4,51).…”

Section: Discussionmentioning

confidence: 93%

“…Current knowledge about the nature of protective immunity in HIV infection is incomplete, but accumulating evidence suggests that CTLs play an important role in the control of viral replication during HIV infection (4,51). In primary infection, HIV-1 specific CTL can appear only a few days after clinical presentation and several weeks before neutralizing Abs (52).…”

Section: Discussionmentioning

confidence: 99%

“…Spleens were harvested on day 9 and set up in a 5-day primary culture with irradiated BALB/c splenocytes as feeder cells and 1 M of either the immunodominant Gag or LLO epitope. Effector cells were used in a standard 4-h 51 Cr release assay with P815 cells pulsed with either peptide at 1 M. Results are plotted as percentage of specific lysis ϭ [(experimental-spontaneous)/(total-spontaneous)] ϫ 100.…”

Section: Cr Release Assaymentioning

confidence: 99%

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The Induction of HIV Gag-Specific CD8+ T Cells in the Spleen and Gut-Associated Lymphoid Tissue by Parenteral or Mucosal Immunization with RecombinantListeria monocytogenesHIV Gag

Peters

Peng

Douven

et al. 2003

The Journal of Immunology

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The induction of mucosal immunity is crucial in controlling viral replication during HIV infection. In this study we compare the ability of a recombinant Listeria monocytogenes that expresses and secretes the HIV Ag Gag to induce CD8+ T cells against this Ag in the spleen, mesenteric lymph nodes, and Peyer’s patches and the ability to provide effector Gag-specific CD8+ T cells to the lamina propria after i.v., oral, or rectal administration of the vaccine. The levels of Ag-specific CD8+-activated T cells were measured ex vivo using intracellular cytokine staining for IFN-γ and H-2Kd Gag peptide tetramer staining. We found that all routes of immunization induced Gag-specific CD8+ T cells in the spleen. After secondary infection, we observed substantial increases in splenic levels of CD8+ T cells, and levels of Gag-specific cells were similar to those against listeriolysin O, the immunodominant Ag of L. monocytogenes. Both primary and secondary oral immunization resulted in abundant Gag-specific CD8+-activated T cells in the lamina propria that constituted ∼35% of the CD8 compartment. However, significant levels of Gag and listeriolysin O-specific CD8+ T cells were observed in mucosal lymphoid tissue only after two immunizations, perhaps because they had already entered the lamina propria compartment after a single immunization. In the context of HIV, a mucosally administered vaccine seems best calculated to prompt an immune response that is capable of preventing infection. The data presented in this report demonstrate that mucosally administered Listeria can prompt such a response and that booster doses can maintain this response.

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Section: Discussionmentioning

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Section: Cr Release Assaymentioning

confidence: 99%

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The Induction of HIV Gag-Specific CD8+ T Cells in the Spleen and Gut-Associated Lymphoid Tissue by Parenteral or Mucosal Immunization with RecombinantListeria monocytogenesHIV Gag

Peters

Peng

Douven

et al. 2003

The Journal of Immunology

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“…However, there have only been sporadic reports of TV9-specific CD8 ϩ T cell responses during infection. TV9 reactivity was detected, but was not the dominant HLA-A2-restricted response, in HLA-A2 ϩ -exposed seronegative sex workers (43,44). Persistently high numbers of TV9-specific IFN-␥-producing cells were reported for one patient (45).…”

mentioning

confidence: 89%

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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“…There are also some individuals who remain seronegative despite high risk and/or multiple exposures to HIV-1. These exposed seronegatives (ES) include infants born to HIV-1 infected mothers [5][6][7], commercial sex workers in epidemic areas [8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25], hemophiliacs who received HIV contaminated factor VIII preparations [26,27], and sexual partners of known HIV-1 infected persons [28][29][30][31][32][33]. Understanding the mechanisms that account for slower disease progression in LTNP and the protection against HIV-1 infection observed with ES is important for the development of more potent therapeutic regimens and a vaccine.…”

Section: Introductionmentioning

confidence: 99%

Global human genetics of HIV-1 infection and China

et al. 2005

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CD8+ lymphocytes respond to different HIV epitopes in seronegative and infected subjects

Cited by 196 publications

References 29 publications

The Induction of HIV Gag-Specific CD8+ T Cells in the Spleen and Gut-Associated Lymphoid Tissue by Parenteral or Mucosal Immunization with RecombinantListeria monocytogenesHIV Gag

The Induction of HIV Gag-Specific CD8+ T Cells in the Spleen and Gut-Associated Lymphoid Tissue by Parenteral or Mucosal Immunization with RecombinantListeria monocytogenesHIV Gag

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

Global human genetics of HIV-1 infection and China

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