Dendritic cells focus CTL responses toward highly conserved and topologically important HIV-1 epitopes

García-Bates, Tatiana M.; Palma, Mauri Sérgio Alves; Anderko, Renee R.; Hsu, Denise C.; Ananworanich, Jintanat; Korber, Bette T.; Gaiha, Gaurav D.; Phanuphak, Nittaya; Thomas, Rasmi; Tovanabutra, Sodsai; Walker, Bruce D.; Mellors, John W.; Piazza, Paolo; Kroon, Eugène; Riddler, Sharon A.; Michael, Nelson L.; Rinaldo, Charles R.; Mailliard, Robbie B.; groups, Rv study

doi:10.1016/j.ebiom.2020.103175

Cited by 10 publications

(6 citation statements)

References 61 publications

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“…We excised individual HIV genes from proviral sequences using Gene Cutter 106 . We then identified polymorphisms within these genes that are known to be associated with one or more host HLA alleles expressed, as defined using a published list of HLA-associated polymorphisms across the HIV subtype B proteome 99 . For the escape mutation analysis, each HLA-associated viral site was categorized into one of three groups: (1) ‘non-adapted’ viral sites showed the specific HIV-1 residue predicted to be susceptible to the restricting HLA, (2) ‘adapted’ sites showed the specific HIV-1 residue predicted to confer escape from the restricting HLA, and (3) ‘possibly adapted’ sites showed any residue other than the ‘non-adapted’ form, supporting it as a possible escape variant 100 .…”

Section: Methodsmentioning

confidence: 99%

Viral and host mediators of non-suppressible HIV-1 viremia

Mohammadi,

Etemad,

Zhang

et al. 2023

Nat Med

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Non-suppressible HIV-1 viremia (NSV) is defined as persistent low-level viremia on antiretroviral therapy (ART) without evidence of ART non-adherence or significant drug resistance. Unraveling the mechanisms behind NSV would broaden our understanding of HIV-1 persistence. Here we analyzed plasma virus sequences in eight ART-treated individuals with NSV (88% male) and show that they are composed of large clones without evidence of viral evolution over time in those with longitudinal samples. We defined proviruses that match plasma HIV-1 RNA sequences as ‘producer proviruses’, and those that did not as ‘non-producer proviruses’. Non-suppressible viremia arose from expanded clones of producer proviruses that were significantly larger than the genome-intact proviral reservoir of ART-suppressed individuals. Integration sites of producer proviruses were enriched in proximity to the activating H3K36me3 epigenetic mark. CD4+ T cells from participants with NSV demonstrated upregulation of anti-apoptotic genes and downregulation of pro-apoptotic and type I/II interferon-related pathways. Furthermore, participants with NSV showed significantly lower HIV-specific CD8+ T cell responses compared with untreated viremic controllers with similar viral loads. We identified potential critical host and viral mediators of NSV that may represent targets to disrupt HIV-1 persistence.

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Section: Methodsmentioning

confidence: 99%

Viral and host mediators of non-suppressible HIV-1 viremia

Mohammadi,

Etemad,

Zhang

et al. 2023

Nat Med

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“…Vaccine studies involving highly networked epitope immunogens remain in development, although an ex vivo DC-based priming model demonstrated a relative enhancement of CD8 + T cell response induction in comparison to both full-length Gag and conserved antigens [87]. Additionally, while highly networked epitopes are derived from the optimal A-list [49], they have quite limited overlap with other epitope-based immunogens [88], indicating that they will target distinct regions of the viral proteome.…”

Section: Implications For Hiv T Cell Vaccine Developmentmentioning

confidence: 99%

Features of functional and dysfunctional CD8+ T cells to guide HIV vaccine development

Bhattacharyya

Crain

Goldberg

et al. 2023

Current Opinion in HIV and AIDS

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Purpose of review CD8+ T cell responses are a key component of the host immune response to human immunodeficiency virus (HIV) but vary significantly across individuals with distinct clinical outcomes. These differences help inform the qualitative features of HIV-specific CD8+ T cells that we should aim to induce by vaccination. Recent findings We review previous and more recent findings on the features of dysfunctional and functional CD8+ T cell responses that develop in individuals with uncontrolled and controlled HIV infection, with particular emphasis on proliferation, cytotoxic effector function, epitope specificity, and responses in lymph nodes. We also discuss the implications of these findings for both prophylactic and therapeutic T cell vaccine development within the context of T cell vaccine trials. Summary The induction of HIV specific CD8+ T cell responses is an important goal of ongoing vaccine efforts. Emerging data on the key features of CD8+ T cell responses that distinguish individuals who spontaneously control from those with progressive disease continues to provide key guidance.

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“…Responses greater than 10 spots per well and 3-fold above negative controls were scored as positive. 87,88…”

Section: Assessment Of Hiv-specific Cd8 + T Cell Reactivitymentioning

confidence: 99%

Viral and Host Mediators of Non-Suppressible HIV-1 Viremia

Mohammadi

Etemad

Zhang

et al. 2023

Preprint

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Non-suppressible HIV-1 viremia (NSV) can occur in persons with HIV despite adherence to combination antiretroviral therapy (ART) and in the absence of significant drug resistance. Here, we show that plasma NSV sequences are comprised primarily of large clones without evidence of viral evolution over time. We defined proviruses that contribute to plasma viremia as producer, and those that did not as non-producer. Compared to ART-suppressed individuals, NSV participants had a significantly larger producer reservoir. Producer proviruses were enriched in chromosome 19 and in proximity to the activating H3K36me3 epigenetic mark. CD4+ cells from NSV participants demonstrated upregulation of anti-apoptotic genes and downregulation of pro-apoptotic and type I/II interferon-related pathways. Furthermore, NSV participants showed no elevation in HIV-specific CD8+ cell responses and producer proviruses were enriched for HLA escape mutations. We identified critical host and viral mediators of NSV that represent potential targets to disrupt HIV persistence and promote viral silencing.

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Dendritic cells focus CTL responses toward highly conserved and topologically important HIV-1 epitopes

Cited by 10 publications

References 61 publications

Viral and host mediators of non-suppressible HIV-1 viremia

Viral and host mediators of non-suppressible HIV-1 viremia

Features of functional and dysfunctional CD8+ T cells to guide HIV vaccine development

Viral and Host Mediators of Non-Suppressible HIV-1 Viremia

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