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Currier, Jeffrey R.; Visawapoka, Unchalee; Tovanabutra, Sodsai; Mason, Carl J.; Birx, Deborah L.; McCutchan, Francine E.; Cox, Josephine H.

doi:10.1186/1471-2172-7-8

Cited by 32 publications

(16 citation statements)

References 46 publications

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“…In fact, as predicted in our computations, the HIV Nef 73–82 epitope was previously shown to bind strongly to HLA-A3 molecules [44]. The high immunogenetic property of the HIV Nef core region is reflected by the relative stability of the Nef sequence in this region [45]. This point is illustrated in Figure 4 in the form of sequence logos falling into the core region of Nef.…”

Section: Resultssupporting

confidence: 78%

Sequence- and Interactome-Based Prediction of Viral Protein Hotspots Targeting Host Proteins: A Case Study for HIV Nef

2011

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Virus proteins alter protein pathways of the host toward the synthesis of viral particles by breaking and making edges via binding to host proteins. In this study, we developed a computational approach to predict viral sequence hotspots for binding to host proteins based on sequences of viral and host proteins and literature-curated virus-host protein interactome data. We use a motif discovery algorithm repeatedly on collections of sequences of viral proteins and immediate binding partners of their host targets and choose only those motifs that are conserved on viral sequences and highly statistically enriched among binding partners of virus protein targeted host proteins. Our results match experimental data on binding sites of Nef to host proteins such as MAPK1, VAV1, LCK, HCK, HLA-A, CD4, FYN, and GNB2L1 with high statistical significance but is a poor predictor of Nef binding sites on highly flexible, hoop-like regions. Predicted hotspots recapture CD8 cell epitopes of HIV Nef highlighting their importance in modulating virus-host interactions. Host proteins potentially targeted or outcompeted by Nef appear crowding the T cell receptor, natural killer cell mediated cytotoxicity, and neurotrophin signaling pathways. Scanning of HIV Nef motifs on multiple alignments of hepatitis C protein NS5A produces results consistent with literature, indicating the potential value of the hotspot discovery in advancing our understanding of virus-host crosstalk.

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Section: Resultssupporting

confidence: 78%

Sequence- and Interactome-Based Prediction of Viral Protein Hotspots Targeting Host Proteins: A Case Study for HIV Nef

2011

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“…Many studies of HIV-1-specific T-cell immunity have used pools containing from 2 to over 100 HIV-1 synthetic peptides of 8 to 20 aa in length (3,7,9,14,17,24,25,31,32,34,37,49). These peptides have been added directly to the PBMC or purified T cells to gauge peptide-specific immune responses in persons with HIV-1 infection or in anti-HIV-1 drug treatment and vaccine trials.…”

Section: Discussionmentioning

confidence: 99%

“…There is little information, however, as to whether these professional APC can similarly enhance other T-cell functions that could be critical to control of HIV-1 infection, particularly their proliferative capacity and ability to produce multiple immune mediators. Moreover, many current approaches for measuring the magnitude and breadth of T-cell responses use pools of various numbers of synthetic peptides, usually 15 or 20 amino acids (aa) in length, which overlap by 10 to 11 aa (1,3,7,9,13,14,17,24,25,27,32,37,45,48,49), developed by Kern et al (26) and Maecker et al (31). Such studies have not accounted for a role of APC in processing that is required to reduce these peptides to their optimal, 8-to 10-mer length for presentation by MHC class I molecules to CD8 ϩ T cells (43), or to 13-to 17-mers for presentation by MHC class II to CD4 ϩ T cells (46).…”

mentioning

confidence: 99%

Multiple T-Cell Responses to Human Immunodeficiency Virus Type 1 Are Enhanced by Dendritic Cells

Huang

Zheng

Borowski

et al. 2009

Clin Vaccine Immunol

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Human immunodeficiency virus type 1 (HIV-1)-specific T-cell reactivity has been related to protection from disease progression. Optimal T-cell reactivity to HIV-1 presumably requires antigen processing and presentation by professional antigen-presenting cells, particularly dendritic cells (DC). Here we examined whether multiple HIV-1-specific T-cell functions are enhanced by stimulation with HIV-1 peptide-loaded DC derived from HIV-1-infected subjects on antiretroviral therapy. We first found that mature DC increased the number of gamma interferon (IFN-␥)-producing T cells detected by enzyme-linked immunospot assay to overlapping 15-mer peptides of HIV-1 Gag and Nef, compared to stimulation with peptide-loaded, immature DC or to peptides without DC. IFN-␥ production was lower in response to large pools of the Gag and Nef peptides, regardless of presentation by DC. We further observed that HIV-1 peptide-loaded, mature DC stimulated greater CD8؉ and CD4 ؉ T-cell proliferation than did the peptides without DC and that T-cell proliferation was lower in response to larger pools of the peptides. The lower T-cell IFN-␥ and proliferation responses to the larger peptide pools were related to lower T-cell viability. Finally, the number of polyfunctional CD8؉ and CD4 ؉ T cells stimulated by HIV-1 peptide-loaded, mature DC, defined as positive by intracellular staining for more than one immune mediator (IFN-␥, interleukin 2, tumor necrosis factor alpha, macrophage inhibitory protein 1␤, or CD107a), was greater than that stimulated by the peptides alone. These results indicate that DC can enhance multiple types of HIV-1-specific T-cell functions.

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“…These libraries need to pass previously a quality control to ensure they do not induce unspecific results [7]. In addition, these peptide-based approaches have other drawbacks, the extent to which the sequence of a reference strain as well as the length and degree of peptide overlap influence the detection of T cell responses is not well characterized [23], [25].…”

Section: Discussionmentioning

confidence: 99%

Use of RT-Defective HIV Virions: New Tool to Evaluate Specific Response in Chronic Asymptomatic HIV-Infected Individuals

et al. 2013

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BackgroundGeneration of new reagents that can be used to screen or monitor HIV-1-specific responses constituted an interesting field in the development of HIV vaccines to improve their efficacy.MethodsWe have evaluated the specific T cell response against different types of NL4-3 virions (including NL4-3 aldrithiol-2 treated, NL4-3/ΔRT and R5 envelopes: NL4-3/ΔRT/ΔEnv[AC10] and NL4-3/ΔRT/ΔEnv[Bal]) and against pools of overlapping peptides (15 mer) encompassing the HIV-1 Gag and Nef regions. Cryopreserved PBMC from a subset of 69 chronic asymptomatic HIV positive individuals have been employed using different techniques including IFN-γ ELISPOT assay, surface activation markers and intracellular cytokine staining (ICS) by flow cytometry.ResultsThe differential response obtained against NL4-3 aldrithiol-2 treated and NL4-3/ΔRT virions (25% vs 55%, respectively) allow us to divide the population in three groups: “full-responders” (positive response against both viral particles), “partial-responders” (positive response only against NL4-3/ΔRT virions) and “non-responders” (negative responses). There was no difference between X4 and R5 envelopes. The magnitude of the total responses was higher against NL4-3/ΔRT and was positively correlated with gender and inverse correlated with viral load. On the contrary CD4+ T cell count was not associated with this response. In any case responses to the viruses tended to be lower in magnitude than those detected by the overlapping peptides tested. Finally we have found an increased frequency of HLA-B27 allele (23% vs 9%) and a significant reduction in some activation markers (CD69 and CD38) on T cells surface in responders vs non-responders individuals.ConclusionsIn summary these virions could be considered as alternative and useful reagents for screening HIV-1-specific T cell responses in HIV exposed uninfected people, HIV infected patients and to assess immunogenicity of new prototypes both in vitro and in vaccine trials, by a feasible, simply, effective and low cost assay.

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Untitled

Cited by 32 publications

References 46 publications

Sequence- and Interactome-Based Prediction of Viral Protein Hotspots Targeting Host Proteins: A Case Study for HIV Nef

Sequence- and Interactome-Based Prediction of Viral Protein Hotspots Targeting Host Proteins: A Case Study for HIV Nef

Multiple T-Cell Responses to Human Immunodeficiency Virus Type 1 Are Enhanced by Dendritic Cells

Use of RT-Defective HIV Virions: New Tool to Evaluate Specific Response in Chronic Asymptomatic HIV-Infected Individuals

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