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1.
Immunity ; 38(3): 425-36, 2013 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-23521884

RESUMO

The capacity of the immune system to adapt to rapidly evolving viruses is a primary feature of effective immunity, yet its molecular basis is unclear. Here, we investigated protective HIV-1-specific CD8+ T cell responses directed against the immunodominant p24 Gag-derived epitope KK10 (KRWIILGLNK263-272) presented by human leukocyte antigen (HLA)-B∗2705. We found that cross-reactive CD8+ T cell clonotypes were mobilized to counter the rapid emergence of HIV-1 variants that can directly affect T cell receptor (TCR) recognition. These newly recruited clonotypes expressed TCRs that engaged wild-type and mutant KK10 antigens with similar affinities and almost identical docking modes, thereby accounting for their antiviral efficacy in HLA-B∗2705+ individuals. A protective CD8+ T cell repertoire therefore encompasses the capacity to control TCR-accessible mutations, ultimately driving the development of more complex viral escape variants that disrupt antigen presentation.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Infecções por HIV/imunologia , HIV-1/imunologia , Antígeno HLA-B27/imunologia , Sequência de Aminoácidos , Apresentação de Antígeno/imunologia , Linfócitos T CD8-Positivos/metabolismo , Linfócitos T CD8-Positivos/virologia , Células Clonais/imunologia , Células Clonais/metabolismo , Células Clonais/virologia , Cristalografia por Raios X , Epitopos de Linfócito T/química , Epitopos de Linfócito T/imunologia , Epitopos de Linfócito T/metabolismo , Proteína do Núcleo p24 do HIV/genética , Proteína do Núcleo p24 do HIV/imunologia , Proteína do Núcleo p24 do HIV/metabolismo , Infecções por HIV/virologia , HIV-1/genética , HIV-1/metabolismo , Antígeno HLA-B27/química , Antígeno HLA-B27/metabolismo , Humanos , Epitopos Imunodominantes/química , Epitopos Imunodominantes/imunologia , Epitopos Imunodominantes/metabolismo , Modelos Moleculares , Dados de Sequência Molecular , Mutação , Ligação Proteica/imunologia , Estrutura Terciária de Proteína , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/imunologia , Receptores de Antígenos de Linfócitos T/metabolismo
2.
Blood ; 118(8): 2138-49, 2011 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-21734237

RESUMO

Mapping the precise determinants of T-cell efficacy against viruses in humans is a public health priority with crucial implications for vaccine design. To inform this effort, we performed a comprehensive analysis of the effective CD8(+) T-cell clonotypes that constitute responses specific for the HIV p24 Gag-derived KK10 epitope (KRWIILGLNK; residues 263-272) restricted by HLA-B*2705, which are known to confer superior control of viral replication in HIV-infected individuals. Particular KK10-specific CD8(+) T-cell clonotypes, characterized by TRBV4-3/TRBJ1-3 gene rearrangements, were found to be preferentially selected in vivo and shared between individuals. These "public" clonotypes exhibit high levels of TCR avidity and Ag sensitivity, which impart functional advantages and enable effective suppression of HIV replication. The early L(268)M mutation at position 6 of the KK10 epitope enables the virus to avoid recognition by these highly effective CD8(+) T-cell clonotypes. However, alternative clonotypes with variant reactivity provide flexibility within the overall KK10-specific response. These findings provide refined mechanistic insights into the workings of an effective CD8(+) T-cell response against HIV.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/virologia , HIV-1/imunologia , Sequência de Aminoácidos , Substituição de Aminoácidos , Estudos de Coortes , Epitopos/genética , Epitopos/imunologia , Rearranjo Gênico da Cadeia beta dos Receptores de Antígenos dos Linfócitos T , Proteína do Núcleo p24 do HIV/genética , Proteína do Núcleo p24 do HIV/imunologia , Infecções por HIV/genética , Infecções por HIV/imunologia , Infecções por HIV/virologia , HIV-1/genética , HIV-1/patogenicidade , HIV-1/fisiologia , Interações Hospedeiro-Patógeno/genética , Interações Hospedeiro-Patógeno/imunologia , Humanos , Técnicas In Vitro , Dados de Sequência Molecular , Replicação Viral/imunologia
3.
J Immunol ; 186(1): 359-71, 2011 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-21135165

RESUMO

CD8(+) T cells play a significant role in the control of HIV replication, yet the associated qualitative and quantitative factors that determine the outcome of infection remain obscure. In this study, we examined Ag-specific CD8(+) TCR repertoires longitudinally in a cohort of HLA-B*2705(+) long-term nonprogressors with chronic HIV-1 infection using a combination of molecular clonotype analysis and polychromatic flow cytometry. In each case, CD8(+) T cell populations specific for the immunodominant p24 Gag epitope KRWIILGLNK (KK10; residues 263-272) and naturally occurring variants thereof, restricted by HLA-B*2705, were studied at multiple time points; in addition, comparative data were collected for CD8(+) T cell populations specific for the CMV pp65 epitope NLVPMVATV (NV9; residues 495-503), restricted by HLA-A*0201. Dominant KK10-specific clonotypes persisted for several years and exhibited greater stability than their contemporaneous NV9-specific counterparts. Furthermore, these dominant KK10-specific clonotypes exhibited cross-reactivity with antigenic variants and expressed significantly higher levels of CD127 (IL-7Rα) and Bcl-2. Of note, we also found evidence that promiscuous TCR α-chain pairing associated with alterations in fine specificity for KK10 variants could contribute to TCR ß-chain prevalence. Taken together, these data suggest that an antiapoptotic phenotype and the ability to cross-recognize variant epitopes contribute to clonotype longevity and selection within the peripheral memory T cell pool in the presence of persistent infection with a genetically unstable virus.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/virologia , Epitopos de Linfócito T/imunologia , HIV-1/imunologia , Epitopos Imunodominantes/imunologia , Produtos do Gene gag do Vírus da Imunodeficiência Humana/imunologia , Sequência de Aminoácidos , Apresentação de Antígeno/imunologia , Variação Antigênica/imunologia , Apoptose/imunologia , Linfócitos T CD8-Positivos/patologia , Separação Celular , Sobrevivência Celular/imunologia , Células Clonais , Epitopos de Linfócito T/metabolismo , Citometria de Fluxo , Infecções por HIV/imunologia , Infecções por HIV/patologia , Infecções por HIV/virologia , Humanos , Evasão da Resposta Imune/imunologia , Dados de Sequência Molecular , Fenótipo , Prevalência
4.
J Immunol ; 186(1): 479-88, 2011 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-21115730

RESUMO

The CTL response in HLA-B*27(+) HIV-infected individuals is characterized by an immunodominant response to a conserved epitope in gag p24 (aa 263-272, KRWIILGLNK; KK10). Mutations resulting in substitution of the arginine (R264) at position 2 of this epitope have been identified as escape mutations. Nineteen HLA-B*27(+) long-term nonprogressors were identified from an Australian cohort with an average follow-up of 16 y following infection. Viral and host genetic factors impacting on disease progression were determined at multiple time points. Twelve of 19 had wild-type sequences at codon 264 at all time points; 7 of 19 carried CTL escape variants. Median viral load and CD4(+) T cell counts were not significantly different between these groups at enrollment. Viral load, as judged by levels at their last visit (1,700 and 21,000 RNA copies/ml, respectively; p = 0.01) or by time-weighted area under the curve was higher in the escape group (p = 0.02). Escape mutants at other HLA-B*27-restricted epitopes were uncommon. Moreover, host polymorphisms, such as CCR5Δ32, CCR2-64I, and SDF1-3'A, or breadth of TCR repertoire responding to KK10 did not segregate to wild-type or escape groups. Host and viral factors were examined for a relationship to viral load. The only factor to affect viral load was the presence of the R264 escape mutations at the immunodominant epitope. CTL escape at R264 in the KK10 epitope is a major determinant of subsequent viral load in these HLA-B*27(+) individuals.


Assuntos
Proteína do Núcleo p24 do HIV/imunologia , Infecções por HIV/imunologia , Infecções por HIV/virologia , HIV-1/imunologia , Antígenos HLA-B/biossíntese , Evasão da Resposta Imune/imunologia , Epitopos Imunodominantes/imunologia , Carga Viral/imunologia , Adulto , Substituição de Aminoácidos/genética , Substituição de Aminoácidos/imunologia , Arginina/genética , Códon/imunologia , Sequência Conservada/genética , Sequência Conservada/imunologia , Progressão da Doença , Proteína do Núcleo p24 do HIV/genética , Infecções por HIV/patologia , HIV-1/genética , HIV-1/patogenicidade , Antígenos HLA-B/genética , Antígenos HLA-B/imunologia , Humanos , Evasão da Resposta Imune/genética , Epitopos Imunodominantes/genética , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Linfócitos T Citotóxicos/imunologia , Linfócitos T Citotóxicos/patologia , Linfócitos T Citotóxicos/virologia , Carga Viral/genética
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