Cross-reactive microbial peptides can modulate HIV-specific CD8+ T cell responses

Pohlmeyer, Christopher W.; Laskey, Sarah B.; Beck, Sarah E.; Xu, Daniel; Capoferri, Adam A.; Garliss, Caroline C.; May, Megan; Livingston, Alison; Lichmira, Walt; Moore, Richard D.; Leffell, Mary S.; Butler, Nicholas J.; Thorne, Jennifer E.; Flynn, John A.; Siliciano, Robert F.; Blankson, Joel N.

doi:10.1371/journal.pone.0192098

Cited by 8 publications

(10 citation statements)

References 30 publications

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“…The frequency of Gag and Nef-specific CD8+ T cells in our subjects was not very high (combined median of 2,540 cells/million, Supplementary Table 1) which is consistent with the frequency of total HIV-specific CD8+ T cells found in a prior larger study (Pereyra et al, 2008). However, ES HIV-specific CD8+ T cells have been shown to proliferate in response to antigenic stimulation (Migueles et al, 2002(Migueles et al, , 2008Pohlmeyer et al, 2018) and it is likely some level of clonal expansion occurs over the 3 day period of co-culture in our assay. Furthermore, the percentage of infected cells that express antigen is very low initially and therefore the true ratio of effectors to antigen expressing CD4+ T cells at the start of the assay is very high and changes over time as both infection and expansion of HIV-specific CD8+ T proceeds.…”

Section: Resultssupporting

confidence: 88%

Combined Effects of HLA-B*57/5801 Elite Suppressor CD8+ T Cells and NK Cells on HIV-1 Replication

May

Pohlmeyer

Kwaa

et al. 2020

Front. Cell. Infect. Microbiol.

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Elite controllers or suppressors (ES) are HIV-1 infected individuals who maintain undetectable viral loads without anti-retroviral therapy. The HLA-B * 57 allele is overrepresented in ES suggesting a role for HIV-specific CD8+ T cells in immune control. Natural killer (NK) cells also play a role in controlling viral replication, and genetic studies demonstrate that specific combinations of killer cell immunoglobulin-like receptor (KIR) alleles and HLA subtypes including HLA-B * 57 correlate with delayed progression to AIDS. While prior studies have shown that both HIV-specific CD8+ T cells and NK cells can inhibit viral replication in vitro, the interaction between these two effector cells has not been studied. We performed in vitro suppression assays using CD8+ T cells and NK cells from HLA-B * 57 ES either alone or in combination with each other. We found no evidence of antagonism or synergy between the CD8+ T cells and NK cells, suggesting that they have independent mechanisms of inhibition in vitro. Our data has implications for combined immunotherapy with CD8+ T cells and NK cells in HIV cure strategies.

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Section: Resultssupporting

confidence: 88%

Combined Effects of HLA-B*57/5801 Elite Suppressor CD8+ T Cells and NK Cells on HIV-1 Replication

May

Pohlmeyer

Kwaa

et al. 2020

Front. Cell. Infect. Microbiol.

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“…However, preculturing of cells with S peptide pools resulted in a modest but significant (P = 0.03) increase in the frequency of T cells that responded to these peptides, suggesting that memory T cell responses existed in some HDs. Although it is also possible that these were de novo responses, the expansion assay we used did not involve the stimulation of T cells with isolated DCs, and in prior experiments, we were unable to generate de novo responses to peptides (22).…”

Section: Discussionmentioning

confidence: 99%

Healthy donor T cell responses to common cold coronaviruses and SARS-CoV-2

Woldemeskel

Kwaa

Garliss

et al. 2020

Journal of Clinical Investigation

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BACKGROUND. T cell responses to the common cold coronaviruses have not been well characterized. Preexisting T cell immunity to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been reported, and a recent study suggested that this immunity was due to cross-recognition of the novel coronavirus by T cells specific for the common cold coronaviruses. METHODS. We used the enzyme-linked immunospot (ELISPOT) assay to characterize the T cell responses against peptide pools derived from the spike protein of 3 common cold coronaviruses (HCoV-229E, HCoV-NL63, and HCoV-OC43) and SARS-CoV-2 in 21 healthy donors (HDs) who were seronegative for SARS-CoV-2 and had no known exposure to the virus. An in vitro expansion culture assay was also used to analyze memory T cell responses. RESULTS. We found responses to the spike protein of the 3 common cold coronaviruses in many of the donors. We then focused on HCoV-NL63 and detected broad T cell responses to the spike protein and identified 22 targeted peptides. Interestingly, only 1 study participant had a significant response to SARS-CoV-2 spike or nucleocapsid protein in the ELISPOT assay. In vitro expansion studies suggested that T cells specific for the HCoV-NL63 spike protein in this individual could also recognize SARS-CoV-2 spike protein peptide pools. CONCLUSION. HDs have circulating T cells specific for the spike proteins of HCoV-NL63, HCoV-229E, and HCoV-OC43. T cell responses to SARS-CoV-2 spike and nucleocapsid proteins were present in only 1 participant and were potentially the result of cross-recognition by T cells specific for the common cold coronaviruses. Further studies are needed to determine whether this cross-recognition influences coronavirus disease 2019 (COVID-19) outcomes.

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“…Autologous HIV-1 gag and nef was sequenced from provirus and plasma obtained in 2004,2005,2007, and 2010 and from replication-competent virus cultured in 2006 and 2018 (3,(21)(22)(23)(24) as outlined in Table 1. The patient initially had wild type sequence in the HLA-B * 57 restricted Gag epitopes TW10 and IW9 in proviral clones and in replication-competent virus (3, 22), but he consistently had variants in both epitopes in plasma clones starting in 2004, the earliest time point studied (22).…”

Section: Clinical Characteristics and Viral Evolutionmentioning

confidence: 99%

“…This assay has yet to be utilized to evaluate HIV-1-specific responses. This could be particularly useful given the potential for cross-reactivity of HIV-specific T-cell receptors (16)(17)(18)(19)(20)(21).…”

Section: Introductionmentioning

confidence: 99%

A T Cell Receptor Sequencing-Based Assay Identifies Cross-Reactive Recall CD8+ T Cell Clonotypes Against Autologous HIV-1 Epitope Variants

et al. 2020

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HIV-1 positive elite controllers or suppressors control viral replication without antiretroviral therapy, likely via CTL-mediated elimination of infected cells, and therefore represent a model of an HIV-1 functional cure. Efforts to cure HIV-1 accordingly rely on the existence or generation of antigen-specific cytotoxic T lymphocytes (CTL) to eradicate infected cells upon reversal of latency. Detecting and quantifying these HIV-1-specific CTL responses will be crucial for developing vaccine and T cell-based immunotherapies. A recently developed assay, called MANAFEST, uses T cell receptor (TCR) Vβ sequencing of peptide-stimulated cultures followed by a bioinformatic pipeline to identify neoantigen-specific T cells in cancer patients. This assay is more sensitive than conventional immune assays and therefore has the possibility to identify HIV-1 antigenic targets that have not been previously explored for vaccine or T cell immunotherapeutic strategies. Here we show that a modified version of the MANAFEST assay, called ViraFEST, can identify memory CD8 + T cell responses against autologous HIV-1 Gag and Nef epitope variants in an elite suppressor. Nine TCR Vβ clonotypes were identified and 6 of these were cross-reactive for autologous variants or known escape variants. Our findings are a proof of principle that the ViraFEST assay can be used to detect and monitor these responses for downstream use in immunotherapeutic treatment approaches.

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Cross-reactive microbial peptides can modulate HIV-specific CD8+ T cell responses

Cited by 8 publications

References 30 publications

Combined Effects of HLA-B*57/5801 Elite Suppressor CD8+ T Cells and NK Cells on HIV-1 Replication

Combined Effects of HLA-B*57/5801 Elite Suppressor CD8+ T Cells and NK Cells on HIV-1 Replication

Healthy donor T cell responses to common cold coronaviruses and SARS-CoV-2

A T Cell Receptor Sequencing-Based Assay Identifies Cross-Reactive Recall CD8+ T Cell Clonotypes Against Autologous HIV-1 Epitope Variants

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