Identification of HIV-reservoir cells with reduced susceptibility to antibody-dependent immune response
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Curated by eLife
Evaluation Summary:
Persistence of the viral reservoir is hampering HIV cure and thus understanding how these cells persist is important. This study describes a possible way that HIV-infected cells in the reservoir may escape antibody killing. The reservoir cells tend to have less availability of a receptor that binds HIV antibodies that would ordinarily help in killing. These cells are not only less susceptible to antibody killing but also seem to be susceptible to proliferation, which helps maintain the reservoir.
(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 #2 agreed to share their name with the authors.)
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Abstract
Human immunodeficiency virus (HIV) establishes a persistent infection in heterogeneous cell reservoirs, which can be maintained by different mechanisms including cellular proliferation, and represent the main obstacle to curing the infection. The expression of the Fcγ receptor CD32 has been identified as a marker of the active cell reservoirs in people on antiretroviral therapy (ART), but if its expression has any role in conferring advantage for viral persistence is unknown. Here, we report that HIV-infected cells expressing CD32 have reduced susceptibility to natural killer (NK) antibody-dependent cell cytotoxicity (ADCC) by a mechanism compatible with the suboptimal binding of HIV-specific antibodies. Infected CD32 cells have increased proliferative capacity in the presence of immune complexes, and are more resistant to strategies directed to potentiate NK function. Remarkably, reactivation of the latent reservoir from antiretroviral-treated people living with HIV increases the pool of infected CD32 cells, which are largely resistant to the ADCC immune mechanism. Thus, we report the existence of reservoir cells that evade part of the NK immune response through the expression of CD32.
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Evaluation Summary:
Persistence of the viral reservoir is hampering HIV cure and thus understanding how these cells persist is important. This study describes a possible way that HIV-infected cells in the reservoir may escape antibody killing. The reservoir cells tend to have less availability of a receptor that binds HIV antibodies that would ordinarily help in killing. These cells are not only less susceptible to antibody killing but also seem to be susceptible to proliferation, which helps maintain the reservoir.
(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 #2 agreed to share their name with the authors.)
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Reviewer #1 (Public Review):
Persistence of the viral reservoir is hampering HIV cure. This study describes a possible way that HIV-infected cells in the reservoir may escape antibody killing. The reservoir cells tend to have less availability of a receptor that binds HIV antibodies that would ordinarily help in killing. These cells are not only less susceptible to antibody killing but also seem to be susceptible to proliferation, which helps maintain the reservoir. While there are likely many aspects of HIV reservoir persistence, these studies provide evidence for one aspect.
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Reviewer #2 (Public Review):
The goal of this work was to explain previous observations as to why CD4 T cells expressing CD32, a Fc gamma receptor, are enriched in HIV in both untreated and treated HIV infection. The authors suggest that i) CD32 promotes resistance to NK mediated ADCC but not cytotoxicity ii) CD32lo cells have elevated HLA-E expression which is an inhibitory NK receptor and iii) that CD32lo cells exhibit stronger proliferation in response to gp120-Ab immune complexes. Overall, the authors' conclusions are supported by data presented.
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Reviewer #3 (Public Review):
This study by Astorga-Gamaza et al. investigates the role that the receptor CD32 may play in active CD32dim HIV cell reservoirs. Using primary CD4 T cells from ART-treated and virologically suppressed individuals and autologous NK cells isolated from each donor, they show that CD32dim CD4 T cells were the most resistant to ADCC, both using coated and ex vivo infected cell elimination assays, and by killing of reactivated infected cells in the reservoir. They go on to demonstrate that infected cells expressing HLA-E, and particularly HLA-E+ CD4dim cells, were more resistant to ADCC. They hypothesize this may be due to antibodies or pentraxins binding to CD32 on these cells and consequently protecting these cells from HIV-specific ADCC-mediating antibodies. Using gp120 coated cell, they observe a decrease in …
Reviewer #3 (Public Review):
This study by Astorga-Gamaza et al. investigates the role that the receptor CD32 may play in active CD32dim HIV cell reservoirs. Using primary CD4 T cells from ART-treated and virologically suppressed individuals and autologous NK cells isolated from each donor, they show that CD32dim CD4 T cells were the most resistant to ADCC, both using coated and ex vivo infected cell elimination assays, and by killing of reactivated infected cells in the reservoir. They go on to demonstrate that infected cells expressing HLA-E, and particularly HLA-E+ CD4dim cells, were more resistant to ADCC. They hypothesize this may be due to antibodies or pentraxins binding to CD32 on these cells and consequently protecting these cells from HIV-specific ADCC-mediating antibodies. Using gp120 coated cell, they observe a decrease in A32 binding to CD32 dim cells compared to CD32- cells. This is further supported by an increase in CD32dim - NK cell doublets which the authors hypothesize may be due to inefficient elimination of infected CD32dim cells due to suboptimal antibody-induced immune synapses.
This study provides important data on a potentially difficult-to-target reservoir population that needs to be considered in cure strategies. While there is debate about the role of CD32 as a marker of latent infection, there is reasonable evidence that CD32+(dim) CD4 cells contribute to the reservoir and will consequently need to be targeted in cure strategies and the authors have shown this population may be difficult to target by ADCC. The authors have given the context of CD32dim cells in the total CD4 population well. In addition, the experiments have been designed and conducted in a careful and rigorous manner. Overall, the experiments support the conclusions the authors reach.
While the autologous CD4 and NK cell system used by the authors is interesting, it is unclear how useful it is in the context of assessing the impact of CD4dim cells in an ex vivo infection model. This is because, as the authors state, there is a substantial range of NK cell function in ART suppressed individuals. This difference is particularly observed in Figure 1C, where the resistance of gp120 coated CD32dim cells to ADCC mediated by NK cells from ART-treated individuals relative to other CD4 T cell populations is substantially lower compared to other groups. Since this study focuses on the target cell population, there is some concern the differences in effector cell function from individual to individual could be a confounder.
It is also interesting to note that in some cases the differences from individual to individual in some cases is stark, leading to statistical differences between cell populations being seemingly driven by bimodal populations (e.g. proliferation in Figure 5A and B) or a subset of individuals (e.g. killing in 1H, CD4-NK conjugation in Figure 4D). Specifically in the case of 1H, it would be useful to understand more clearly NK cell function in the two apparent groups to understand if differences observed are due to NK cell differences that somehow impact targeting of CD32dim cells.
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