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  1. Evaluation Summary:

    The authors investigate how HIV-1 infection affects the immune response in the context of SARS-CoV-2 infection by characterising the circulating B cell response. They conclude that people with HIV-1 infection, who become infected by SARS-CoV-2, produce B cell responses via an extra-follicular pathway to a greater degree than people who do not have HIV-1 infection. These findings imply that in HIV-1 infected individuals, long-term B cell and antibody responses against SARS-CoV-2 might not be as robust and durable compared to those in people without HIV-1 infection. The manuscript will be of interest to infectious disease specialists, virologists, and immunologists.

    (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 and Reviewer #2 agreed to share their name with the authors.)

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  2. Reviewer #1 (Public Review):

    The authors have examined different pathways of B cell differentiation in patients with SARS-CoV-2 infection who did or did not have HIV-1 infection. They conclude that B cell responses to SARS-CoV-2 infection occur via an extra-follicular (EF) pathway to a greater extent in people with HIV-1 infection compared with people who do not have HIV-1 infection.

    The data are important and generally robust but there are deficiencies related to presentation and interpretation of data, as indicated below:

    1. There are concerns about nomenclature of cell populations defined by tSNE plots (figure 2A). For example, the population defined as "CSM/marginal zone" does not express IgD or IgM, as would be expected for class-switched memory B cells but not marginal zone B cells. In addition, while tissue homing and GC homing CSM B cells express expected amounts of CXCR4 and CXCR5, both express high amounts of CXCR3, which would be unexpected for GC homing cells. Finally, in line 144, the authors should clarify what is meant by "class switched, IgMhi B cells (highlighted in blue)". The population highlighted in blue in figure 2A, referred to as "IgM++ GC homing B cells", has the immunophenotype IgDlow, IgMhigh, CD27-. Aren't these cells at one end of a naïve B cell spectrum ranging from IgD+/IgM- to IgD+/IgM+ to IgDlow /IgMhigh? There are also other populations that have unconventional names and/or appear to be intermediary populations.

    2. IgM switched memory B cells (lines 201-207) are referred to as IgM-only memory B cells by some investigators (for example, see - Bautista D et al. Front Immunol. 2020; 11:736). It would help the reader if this were indicated.

    3. The authors have defined DN2 B cells based on expression of the activation marker CD95 (Fas) (see Figure 4) but the original definition of DN2 B cells in patients with SLE was based on expression of CD11c and lack of expression of CXCR5 (see - Jenks SA et al. Immunity. 2020; 52:203). These cells also express T-bet and therefore, have many characteristics in common with CD11c+/T-bet+ memory B cells (also known as age-associated B cells or atypical memory B cells). It would be informative if data on CXCR5- DN B cells were in analysed in addition to, or instead of, CD95+ DN B cells.

    4. It might also be informative to discuss the extra-follicular (EF) response pathway in more detail. Recently published data from studies undertaken in mice indicate that CD11c+/T-bet+ MBCs interact with T follicular helper cells in lymphoid follicles but not in germinal centres (Song W et al. Immunity 2022; 55:290-307.e5), so it could be argued that the differentiation pathway is extra-GC rather than extra-follicular, at least in some situations. Also, in people with HIV-1 infection, HIV-1 gp140-specific B cells expressing T-bet are produced outside of GCs (Austin JW et al. Sci Transl Med. 2019; 11:eaax0904. Is the EF response pathway different to the extra-GC differentiation pathway? Where does it occur?

    5. Similarly, in lines 288-290, the authors should re-consider the statement that "Both DN2 and activated naïve B cells mature via an EF pathway, independent of T cell help and in response to pro-inflammatory cytokines IFNγ, TNFa, and IL-21; and TLR 7 and 9 stimulation". There are data indicating that differentiation of DN2 B cells is T-cell-dependent (Keller B et al. Sci. Immunol. 2021; 6:eabh0891).

    6. In lines 254-60 and figure 6, the investigators should consider the possibility that the CXCR3+ and DN2 SARS-CoV-2-specific MBCs that are increased in people with HIV infection are the same population of cells. CD11c+/T-bet+ MBCs (ie. DN2 B cells, age-associated B cells or atypical memory B cells) usually express high levels of CXCR3.

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  3. Reviewer #2 (Public Review):

    In this paper, detailed flow cytometry analysis of longitudinal samples with markers of B cell maturation, homing and regulatory features revealed a coordinated B cell response to COVID-19 that differed significantly between HIV-ve and PLWH. Memory B cells in PLWH displayed evidence of reduced germinal center activity, homing capacity and class-switching responses, with increased PD-L1 expression, and decreased Tfh frequency, accompanied with increased extrafollicular activity, with dynamic changes in activated double negative (DN2) and activated naïve B cells. This study proved the phenotypes of B cells in PLWH, however, the study lack of important functional assays.

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