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  1. Author Response

    Reviewer #2 (Public Review):

    This manuscript by Nkosi et al. presents SARS-Cov-2-specific CD4 and CD8 responses in people living with HIV in South Africa two to four weeks after having experienced COVID-19. The authors look at the magnitude of the SARS-CoV-2 T cell responses in the three groups, as well as the T cell response breadth and cross-reactivity to a SARS-CoV-2 variant. The authors show that HIV treatment naïve people had diminished SARS-CoV-2-specific T cell responses compared to healthy individuals and correlated with immune activation and HIV plasma viral load. This observation is not unexpected as we know very well that untreated HIV infection dampens immune responses in general. Importantly, people under suppressive ART mounted SARS-CoV-2-specific T cell responses comparable to healthy people emphasizing the importance of HIV control by ART. Overall, although the message is not new, has limited interest to the field, and does not assess B cell responses, the data presented are clear and bring additional knowledge on T cell responses against SARS-CoV-2 in people living with HIV.

    We thank the reviewer acknowledging the contribution of our to the field regarding SARS-CoV-2 in people living with HIV. We respectively disagree with the notion that our findings are not new because like other reviewers have pointed out, this study is the first to report significant reduction in cross-recognition of SARS-CoV-2 variants in individuals with unsuppressed HIV using a new and more robust assay for detecting low frequency responses. Importantly, we identify 4 spike mutations in Beta that abrogates T cell recognition by responses raised against wildtype.

    Reviewer #3 (Public Review):

    In this study, the authors investigated the impact of HIV infection on T cell immune responses to SARS-CoV-2 infection. To do this, in vitro stimulation with control and strain-specific peptides was used to activate T cells, and the secretion of IL2, IFNg, and TGFa was used as a proxy for T cell-mediated function. The authors also attempted to define peptide specificity to establish the breadth of the T cell responses and which mutations were responsible for any loss of cross-recognition. The results show that individuals with unsuppressed HIV infection defined by a viraemia above 1000 viral copies per ml, had poorer T cell polyfunctionality compared to those who were HIV negative or avireamic. Unsuppressed HIV-infected individuals also had lower cross-reactive responses to SARS-CoV-2 variants dominating the first and second COVID-19 waves in South Africa. Contrary, aviremic HIV-infected individuals had similar responses to those observed in healthy individuals. The conclusions of this paper are well supported by the data. Using a flow cytometric approach and bulking of T cells enabled phenotypic and peptide-specific analysis. It is however worth noting that HIV infection may have a direct impact on the survival of cells in long-term cultures and outcomes from those assays may be more reflective of invitro survival than the true in vivo situation. In addition, previous studies have shown notable levels of cross-reactive responses of SARS-CoV-2 and other human coronaviruses present prior to the pandemic, it is surprising that very low levels of cross-reactivity were observed across SARs-CoV-2 variants even in the healthy individuals.

    This paper addresses a critical issue within the African context where HIV is prevalent and may have a direct impact on the continent's success in controlling SARS-CoV-2 infections. The low cross-reactive responses more so in individuals with unsuppressed HIV reduce the benefits of the first-generation SARS-CoV-2 vaccine warranting additional considerations of emerging variants for future vaccine development. Unsuppressed HIV infection also places this population at increased risk of infection and more severe form of SARS-CoV-2 disease from future emerging variants. It is therefore important that uninterrupted ART is available to maintain viral suppression in HIV-infected individuals. Generation of second line SARS-Cov-2 vaccine designs will have to consider emerging variants and what are the true longer-term benefits of vaccination.

    We thank the reviewer for highlighting the importance of this study particularly in the context of African countries with high HIV burden. A detailed explanation for the discrepancy between this study and others in provided in response to reviewer 1. Regarding the comment on cell survival, our SEB positive controls shows similar cell survival between HIV negatives and viremics.

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  2. Evaluation Summary:

    The study shows that individuals with unsuppressed HIV infection had poorer T cell polyfunctionality and lower cross-reactive responses to SARS-CoV-2 variants compared to those who were HIV negative or aviremic. The conclusions of this paper are well supported by the data and will be of interest to clinicians, immunologists, and public health practitioners, particularly in Southern Africa.

    (This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 agreed to share their name with the authors.)

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  3. Reviewer #1 (Public Review):

    This manuscript definitively documents poorer virus-specific CD4 & CD8 responses to SARS-CoV-2 among people in South Africa with unsuppressed HIV viremia.

    The impact of these findings is significant. There is a long history of studying the synergistic impact of HIV on immune response, clinical severity, and transmission of other infections. With COVID-19, a leading hypothesis is that HIV-induced immunosuppression may facilitate prolonged infection with high SARS-CoV-2 viral loads and mutagenesis, which in turn may explain the emergence of new viral variants.

    While the results in the study are not unexpected, they required empirical proof as persons with uncontrolled HIV are somewhat surprisingly not at higher risk of severe manifestations of other respiratory viruses (at least in comparison to other immunocompromised hosts such as stem cell transplant recipients) and even the literature on COVID-19 severity in persons with HIV shows variable results.

    A strength of the study is that the authors interrogate T cell responses to SARS-CoV-2 in a detailed and rigorous fashion. They provide several results which allow a more nuanced appreciation of immune responses in persons with HIV including the observation that virally suppressed individuals mount relatively normal CoV2 specific CD4 and CD8 T cell responses and that immunodominance hierarchies and variant cross-reactivity are harmed in HIV viremic individuals.

    An unavoidable weakness is the descriptive nature of the study. Some presented data does not appear internally consistent.

    Nevertheless, the analyses appear sufficient to justify the study's conclusions.

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  4. Reviewer #2 (Public Review):

    This manuscript by Nkosi et al. presents SARS-Cov-2-specific CD4 and CD8 responses in people living with HIV in South Africa two to four weeks after having experienced COVID-19. The authors look at the magnitude of the SARS-CoV-2 T cell responses in the three groups, as well as the T cell response breadth and cross-reactivity to a SARS-CoV-2 variant. The authors show that HIV treatment naïve people had diminished SARS-CoV-2-specific T cell responses compared to healthy individuals and correlated with immune activation and HIV plasma viral load. This observation is not unexpected as we know very well that untreated HIV infection dampens immune responses in general. Importantly, people under suppressive ART mounted SARS-CoV-2-specific T cell responses comparable to healthy people emphasizing the importance of HIV control by ART. Overall, although the message is not new, has limited interest to the field, and does not assess B cell responses, the data presented are clear and bring additional knowledge on T cell responses against SARS-CoV-2 in people living with HIV.

    Was this evaluation helpful?
  5. Reviewer #3 (Public Review):

    In this study, the authors investigated the impact of HIV infection on T cell immune responses to SARS-CoV-2 infection. To do this, in vitro stimulation with control and strain-specific peptides was used to activate T cells, and the secretion of IL2, IFNg, and TGFa was used as a proxy for T cell-mediated function. The authors also attempted to define peptide specificity to establish the breadth of the T cell responses and which mutations were responsible for any loss of cross-recognition. The results show that individuals with unsuppressed HIV infection defined by a viraemia above 1000 viral copies per ml, had poorer T cell polyfunctionality compared to those who were HIV negative or avireamic. Unsuppressed HIV-infected individuals also had lower cross-reactive responses to SARS-CoV-2 variants dominating the first and second COVID-19 waves in South Africa. Contrary, aviremic HIV-infected individuals had similar responses to those observed in healthy individuals. The conclusions of this paper are well supported by the data. Using a flow cytometric approach and bulking of T cells enabled phenotypic and peptide-specific analysis. It is however worth noting that HIV infection may have a direct impact on the survival of cells in long-term cultures and outcomes from those assays may be more reflective of invitro survival than the true in vivo situation. In addition, previous studies have shown notable levels of cross-reactive responses of SARS-CoV-2 and other human coronaviruses present prior to the pandemic, it is surprising that very low levels of cross-reactivity were observed across SARs-CoV-2 variants even in the healthy individuals.

    This paper addresses a critical issue within the African context where HIV is prevalent and may have a direct impact on the continent's success in controlling SARS-CoV-2 infections. The low cross-reactive responses more so in individuals with unsuppressed HIV reduce the benefits of the first-generation SARS-CoV-2 vaccine warranting additional considerations of emerging variants for future vaccine development. Unsuppressed HIV infection also places this population at increased risk of infection and more severe form of SARS-CoV-2 disease from future emerging variants. It is therefore important that uninterrupted ART is available to maintain viral suppression in HIV-infected individuals. Generation of second line SARS-Cov-2 vaccine designs will have to consider emerging variants and what are the true longer-term benefits of vaccination.

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  6. SciScore for 10.1101/2022.04.05.22273453: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    EthicsIRB: Ethical Declaration: The study protocol was approved by the University of KwaZulu-Natal Biomedical Research Ethics Committee (BREC) (approval BREC/00001275/2020).
    Sex as a biological variablenot detected.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.

    Table 2: Resources

    Antibodies
    SentencesResources
    The cells were stained with an antibody cocktail containing: Live/Dead fixable aqua dead cell stain, anti-CD3 PE-CF594 (BD)
    anti-CD3 PE-CF594
    suggested: None
    Thereafter, the cells were stained for 40 minutes at room temperature with an intracellular antibody cocktail containing: anti-IFN-γ BV 711 (
    anti-IFN-γ BV 711
    suggested: None
    Software and Algorithms
    SentencesResources
    Finally, the cells were washed and acquired on an LSR Fortessa and analysed on FlowJo v10.7.2.
    FlowJo
    suggested: (FlowJo, RRID:SCR_008520)
    Statistical analyses were performed using GraphPad Prism 8.0 (GraphPad Software, Inc.
    GraphPad
    suggested: (GraphPad Prism, RRID:SCR_002798)
    Statistical analyses: All statistical analyses were conducted with GraphPad Prism 9.3.1 (GraphPad Software, La Jolla, California, USA) and P values were considered significant if less than 0.05.
    GraphPad Prism
    suggested: (GraphPad Prism, RRID:SCR_002798)

    Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).


    Results from LimitationRecognizer: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.

    Results from TrialIdentifier: No clinical trial numbers were referenced.


    Results from Barzooka: We did not find any issues relating to the usage of bar graphs.


    Results from JetFighter: We did not find any issues relating to colormaps.


    Results from rtransparent:
    • Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
    • Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
    • No protocol registration statement was detected.

    Results from scite Reference Check: We found no unreliable references.


    About SciScore

    SciScore is an automated tool that is designed to assist expert reviewers by finding and presenting formulaic information scattered throughout a paper in a standard, easy to digest format. SciScore checks for the presence and correctness of RRIDs (research resource identifiers), and for rigor criteria such as sex and investigator blinding. For details on the theoretical underpinning of rigor criteria and the tools shown here, including references cited, please follow this link.

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