Dataset Information

Translation of HLA-HIV associations to the cellular level: HIV adapts to inflate CD8 T cell responses against Nef and HLA-adapted variant epitopes.

ABSTRACT: Strong statistical associations between polymorphisms in HIV-1 population sequences and carriage of HLA class I alleles have been widely used to identify possible sites of CD8 T cell immune selection in vivo. However, there have been few attempts to prospectively and systematically test these genetic hypotheses arising from population-based studies at a cellular, functional level. We assayed CD8 T cell epitope-specific IFN-? responses in 290 individuals from the same cohort, which gave rise to 874 HLA-HIV associations in genetic analyses, taking into account autologous viral sequences and individual HLA genotypes. We found immunological evidence for 58% of 374 associations tested as sites of primary immune selection and identified up to 50 novel HIV-1 epitopes using this reverse-genomics approach. Many HLA-adapted epitopes elicited equivalent or higher-magnitude IFN-? responses than did the nonadapted epitopes, particularly in Nef. At a population level, inclusion of all of the immunoreactive variant CD8 T cell epitopes in Gag, Pol, Nef, and Env suggested that HIV adaptation leads to an inflation of Nef-directed immune responses relative to other proteins. We concluded that HLA-HIV associations mark viral epitopes subject to CD8 T cell selection. These results can be used to guide functional studies of specific epitopes and escape mutations, as well as to test, train, and evaluate analytical models of viral escape and fitness. The inflation of Nef and HLA-adapted variant responses may have negative effects on natural and vaccine immunity against HIV and, therefore, has implications for diversity coverage approaches in HIV vaccine design.

SUBMITTER: Almeida CA

PROVIDER: S-EPMC3183574 | biostudies-literature | 2011 Sep

REPOSITORIES: biostudies-literature

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Translation of HLA-HIV associations to the cellular level: HIV adapts to inflate CD8 T cell responses against Nef and HLA-adapted variant epitopes.

Almeida Coral-Ann M CA Bronke Corine C Roberts Steven G SG McKinnon Elizabeth E Keane Niamh M NM Chopra Abha A Kadie Carl C Carlson Jonathan J Haas David W DW Riddler Sharon A SA Haubrich Richard R Heckerman David D Mallal Simon S John Mina M

Journal of immunology (Baltimore, Md. : 1950) 20110805 5

Strong statistical associations between polymorphisms in HIV-1 population sequences and carriage of HLA class I alleles have been widely used to identify possible sites of CD8 T cell immune selection in vivo. However, there have been few attempts to prospectively and systematically test these genetic hypotheses arising from population-based studies at a cellular, functional level. We assayed CD8 T cell epitope-specific IFN-γ responses in 290 individuals from the same cohort, which gave rise to 8 ...[more]

PMID: 21821798

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Project description:HIV frequently escapes CD8 T cell responses, leading to the accumulation of viral adaptations. We recently demonstrated that during chronic HIV infection, adapted epitopes can promote maturation of dendritic cells (DCs) through direct CD8 T cell interactions and lead to enhanced HIV trans-infection of CD4 T cells. Here, we sought to determine the role of such adaptations following HIV MRKAd5 vaccination. We observed that vaccine-induced adapted epitope-specific CD8 T cells promoted higher levels of DC maturation than nonadapted ones and that these matured DCs significantly enhanced HIV trans-infection. These matured DCs were associated with higher levels of interleukin 5 (IL-5) and IL-13 and a lower level of CXCL5, which have been shown to impact DC maturation, as well as a lower level of CXCL16. Finally, we observed that vaccine recipients with high HLA-I-associated adaptation became HIV infected more quickly. Our results offer another possible mechanism for enhanced infection among MRKAd5 vaccinees. IMPORTANCE Despite the well-established contribution of CD8 T cells in HIV control, prior CD8 T cell-based HIV vaccines have failed to demonstrate any efficacy in preventing viral infection. One such vaccine, known as the MRKAd5 vaccine, showed a potential increased risk of viral infection among vaccine recipients. However, the underlying mechanism(s) remains unclear. In this study, we observed that vaccine recipients with high adaptation to their HLA-I alleles were associated with an increased HIV infection risk in comparison to the others. Similar to what we observed in HIV infection in the prior study, adapted epitope-specific CD8 T cells obtained from vaccine recipients exhibit a greater capacity in facilitating viral infection by promoting dendritic cell maturation. Our findings provide a possible explanation for the enhanced viral acquisition risk among MRKAd5 vaccine recipients and highlight the importance of optimizing vaccine design with consideration of HLA-I-associated HIV adaptation.

Project description:BACKGROUND: All four dengue virus (DV) serotypes (D1V, D2V, D3V and D4V) can cause a series of disorders, ranging from mild dengue fever (DF) to severe dengue hemorrhagic fever and dengue shock syndrome (DHF/DSS). Previous studies have revealed that DV serotype-specific CD8(+) T cells are involved in controlling DV infection. Serotype cross-reactive CD8(+) T-cells may contribute to the immunopathogenesis of DHF/DSS. The aim of the study was to identify HLA-A*0201-binding peptides from four DV serotypes. We then examined their immunogenicity in vivo and cross-reactivity within heterologous peptides. METHODS: D1V-derived candidate CD8(+) T-cell epitopes were synthesized and evaluated for their affinity to the HLA-A*0201 molecule. Variant peptides representing heterologous D2V, D3V, D4V serotypes were synthesized. The immunogenicity of the high-affinity peptides were evaluated in HLA-A*0201 transgenic mice. RESULTS: Of the seven D1V-derived candidate epitopes [D1V-NS4a(56-64)(MLLALIAVL), D1V-C(46-54)(LVMAFMAFL), D1V-NS4b(562-570)(LLATSIFKL), D1V-NS2a(169-177)(AMVLSIVSL), D1V-NS4a(140-148)(GLLFMILTV), D1V-NS2a(144-152)(QLWAALLSL) and D1V-NS4b(183-191)(LLMRTTWAL)], three peptides [D1V-NS4a(140-148), D1V-NS2a(144-152) and D1V-NS4b(183-191)] had a high affinity for HLA-A*0201 molecules. Moreover, their variant peptides for D2V, D3V and D4V [D2V-NS4a(140-148)(AILTVVAAT), D3V-NS4a(140-148)(GILTLAAIV), D4V-NS4a(140-148)(TILTIIGLI), D2V-NS2a(144-152)(QLAVTIMAI), D3V-NS2a(144-152)(QLWTALVSL), D4V-NS2a(143-151)(QVGTLALSL), D2V-NS4b(182-190)(LMMRTTWAL), D3V-NS4b(182-190) (LLMRTSWAL) and D4V-NS4b(179-187)(LLMRTTWAF)] also had a high affinity for HLA-A*0201 molecules. Furthermore, CD8+ T cells directed to these twelve peptides were induced in HLA-A*0201 transgenic mice following immunization with these peptides. Additionally, cross-reactivity within four peptides (D1V-NS4b(183-191), D2V-NS4b(182-190), D3V-NS4b(182-190) and D4V-NS4b(179-187)) was observed. CONCLUSIONS: Two novel serotype-specific HLA-A*0201-restricted CD8(+) T-cell epitopes (NS4a(140-148) and NS2a(144-152)) and one cross-reactive HLA-A*0201-restricted CD8(+) T-cell epitopes which is similar to a previously identified epitope were identified in D1V-D4V. Combining prediction algorithms and HLA transgenic mice is an effective strategy to identify HLA-restricted epitopes. Serotype-specific epitopes would be used to determine the protective role of serotype-specific CD8(+) T cells, while cross-reactive epitopes may provide assistance in exploring the role of serotype cross-reactive CD8(+) T cells in the immunopathogenesis of DHF/DSS.

Project description:Human immunodeficiency virus type 1 (HIV-1) has evolved elaborate ways to evade immune cell recognition, including downregulation of classical HLA class I (HLA-I) from the surfaces of infected cells. Recent evidence identified HLA-E, a nonclassical HLA-I, as an important part of the antiviral immune response to HIV-1. Changes in HLA-E surface levels and peptide presentation can prompt both CD8+ T-cell and natural killer (NK) cell responses to viral infections. Previous studies reported unchanged or increased HLA-E levels on HIV-1-infected cells. Here, we examined HLA-E surface levels following infection of CD4+ T cells with primary HIV-1 strains and observed that a subset downregulated HLA-E. Two primary strains of HIV-1 that induced the strongest reduction in surface HLA-E expression were chosen for further testing. Expression of single Nef or Vpu proteins in a T-cell line, as well as tail swap experiments exchanging the cytoplasmic tail of HLA-A2 with that of HLA-E, demonstrated that Nef modulated HLA-E surface levels and targeted the cytoplasmic tail of HLA-E. Furthermore, infection of primary CD4+ T cells with HIV-1 mutants showed that a lack of functional Nef (and Vpu to some extent) impaired HLA-E downmodulation. Taken together, the results of this study demonstrate for the first time that HIV-1 can downregulate HLA-E surface levels on infected primary CD4+ T cells, potentially rendering them less vulnerable to CD8+ T-cell recognition but at increased risk of NKG2A+ NK cell killing.IMPORTANCE For almost two decades, it was thought that HIV-1 selectively downregulated the highly expressed HLA-I molecules HLA-A and HLA-B from the cell surface in order to evade cytotoxic-T-cell recognition, while leaving HLA-C and HLA-E molecules unaltered. It was stipulated that HIV-1 infection thereby maintained inhibition of NK cells via inhibitory receptors that bind HLA-C and HLA-E. This concept was recently revised when a study showed that primary HIV-1 strains reduce HLA-C surface levels, whereas the cell line-adapted HIV-1 strain NL4-3 lacks this ability. Here, we demonstrate that infection with distinct primary HIV-1 strains results in significant downregulation of surface HLA-E levels. Given the increasing evidence for HLA-E as an important modulator of CD8+ T-cell and NKG2A+ NK cell functions, this finding has substantial implications for future immunomodulatory approaches aimed at harnessing cytotoxic cellular immunity against HIV.

Dataset Information

Translation of HLA-HIV associations to the cellular level: HIV adapts to inflate CD8 T cell responses against Nef and HLA-adapted variant epitopes.

Publications

Translation of HLA-HIV associations to the cellular level: HIV adapts to inflate CD8 T cell responses against Nef and HLA-adapted variant epitopes.

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