EDITORIAL published: 31 January 2020 doi: 10.3389/fimmu.2020.00070 Editorial: Immune Surveillance of the HIV Reservoir: Mechanisms, Therapeutic Targeting and New Avenues for HIV Cure Julia G. Prado 1,2* and John Frater 3,4* 1 IrsiCaixa AIDS Research Institute, Barcelona, Spain, 2 Germans Trias i Pujol Research Institute, Universitat Autonoma de Barcelona, Barcelona, Spain, 3 Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom, 4 NIHR Biomedical Research Centre, University of Oxford, Oxford, United Kingdom Keywords: HIV, reservoir, immunity, cure, CD8, BNAB, NK, immunotherapy Editorial on the Research Topic Immune Surveillance of the HIV Reservoir: Mechanisms, Therapeutic Targeting and New Avenues for HIV Cure Thirty-eight years after the first reports of HIV infection and the start of the AIDS pandemic (1), HIV is now a manageable condition. Where there is access to highly effective antiretroviral therapy (ART), the life expectancies of those living with HIV are no different to those without, and although there is some evidence for persisting non-AIDS morbidity in a few, the majority of individuals with suppressed viraemia on ART remain well (2). In addition, through PrEP, barrier methods and the knowledge that “Undetectable Equals Untransmissable” (U=U), HIV transmission can–with the right support and infrastructure–be prevented (3). Edited and reviewed by: However, despite these enormous leaps forward, there is no scalable cure for HIV. Two Francesca Chiodi, Karolinska Institutet (KI), Sweden confirmed cases of cure following CCR5-Delta 32 stem cell transplantations and evidence of extensive drug-free viral suppression in the “post-treatment controllers” of the VISCONTI cohort *Correspondence: provide tantalizing proof of principle that HIV can be cured or put into “virological remission” Julia G. Prado jgarciaprado@irsicaixa.es (4–6). Nevertheless, no strategy has yet been identified to replicate these cases on a large scale. John Frater In addition, it is widely hypothesized that any successful cure intervention is likely to require an john.frater@ndm.ox.ac.uk effective anti-HIV immune response as part of the armory. This collection of reviews, mini-reviews and original research presents a view on some of the cellular and humoral strategies that might Specialty section: prove valuable. This article was submitted to Among the different arms of antiviral immunity, the CD8+ T cell mediated immunity has Viral Immunology, always provided one of the strongest signals of HIV control (7). Early in the epidemic it became a section of the journal clear that cytotoxic T cells play a major role in virological control, even inducing “elite control” Frontiers in Immunology status with undetectable viremia in some infected individuals (8). Whether CD8+ T cells are also Received: 07 January 2020 important in preventing viral rebound from the reservoir of latently infected cells remains a moot Accepted: 13 January 2020 point. In their review Warren et al. explore how CD8+ T cells have proven efficacy at controlling Published: 31 January 2020 HIV viraemia, but become progressively exhausted and dysfunctional over time. ART can reverse Citation: much of this impairment (although not completely–with persistently elevated levels of immune Prado JG and Frater J (2020) Editorial: activation on treatment), but the authors argue that other interventions that may re-focus the Immune Surveillance of the HIV Reservoir: Mechanisms, Therapeutic immune response or induce stronger de novo responses may be needed as part of a strategy to allow Targeting and New Avenues for HIV virological remission in the absence of ART. This idea is expanded by Yang et al. who explore how Cure. Front. Immunol. 11:70. T cells can be engineered to be increasingly effective against the HIV reservoir, digging further into doi: 10.3389/fimmu.2020.00070 the potential of approaches such as CAR T cells, BiTEs, DARTs, and ImmTAVs, which are starting Frontiers in Immunology | www.frontiersin.org 1 January 2020 | Volume 11 | Article 70 Prado and Frater Immune Surveillance and HIV Cure to show promise within cancer therapeutics and in animal models exploring the role of Alecfacept. Although historically, CD8+ for HIV. In particular, their ability to non-specifically recruit T cells have been the focus of most attention, there is T cells–including those that are not exhausted–to antigen that increasing evidence from cohorts like VISCONTI that innate is expressed at very low levels could be of particular value in immunity and NK cells may be critical effectors in future cure tackling the HIV reservoir. However, this will need to be balanced strategies. Tomalka et al. present an in vitro data using an anti- with the increased potential for off-target effects including CD2 monoclonal antibody, alefacept, to induce natural killer cytotoxicity and potential autoimmune complications. (NK) cell-driven antibody-dependent cell-mediated cytotoxicity Clutton and Jones reinforce this message that potential (ADCC). Specifically targeting CD45RA- CD4+ memory T cells, promising interventions may come with unwanted effects, where they present evidence to show that killing can be induced and they explore how the act of inducing the “kick” as part of a that this can reduce HIV DNA levels in patient samples ex vivo. “kick and kill” strategy, may have negative connotations for Whilst very early steps toward clinical application, studies such as T cell function, thereby undermining the “kill” component. these provide proof-of-principle that alternative immunological They focus on histone deacetylase inhibitors (HDACi) and effectors–in this case NK cells–may have a potential role in protein kinase C agonists (PKCa), and explore whether–even if cure strategies. viral antigen presentation is enhanced–they can simultaneously This message underpins the current enthusiasm for the role impact T cell viability, proliferative potential, degranulation, of broadly neutralizing antibodies (bNAbs) following exciting and killing. studies in macaques and humans showing evidence of virological This is explored further by Ruiz et al., where they developed suppression and some suggestion of a post-therapy “vaccinal a novel “Kick and kill assay” to determine the effectiveness effect” which may confer longer-term protection (11–13). This of CTL following LRA treatments, and show that although topical area is reviewed by Carrillo et al.. They provide a there is evidence of killing there may be multiple inhibitory detailed and comprehensive review of the technologies that have factors to be overcome. They find evidence for increased allowed the frameshift toward effective bNAbs, and how these killing of reactivated cells (proportional to the degree of new agents show antiviral activity initially in animal models reactivation), but with significant inter-individual variation, and now in human clinical trials. The potential for bNAbs partly explained by CD8+ T cellular dysfunction associated with both on their own and in conjunction with other interventions the co-expression of inhibitory receptors including PD-1, Tim-3, could have an enormous impact on both future treatment and and LAG-3. prevention strategies. However, these negative effects of immune checkpoint Overall, the aim of this collection was to provide an overview markers may be turned on their heads according to Boyer and of how the immune system remains a key player in future Palmer, where they describe how although molecules such as HIV therapeutics. Our current best treatment strategies are PD-1 are markers of dysfunction on CD8+ T cells, they have highly effective and have revolutionized the course of HIV an additional role on CD4+ T cells as markers of enrichment infection. However, there is always room for improvement, and of HIV-latent infection. As such, they argue that monoclonal these papers explore how new agents and approaches might antibodies targeted against these molecules (e.g., nivolumab vs. eventually lead to long-acting sustained responses, ideally in the PD-1 and ipilimumab vs. CTLA-4) might effectively reverse absence of side-effects. These long-lasting immune responses latency, as well as improving CTL functionality, as they do in will lead the continuous immune surveillance of infected cancer therapeutics. However, the clear message that toxicities cells in the body, allowing the control or elimination of the and side-effects of Immune Checkpoint (IC) molecules may HIV reservoir. undermine any positive effects is not lost on the authors, and it It is an exciting time to consider how the leaps forward is clear that future HIV treatment strategies need to be safe as in treatments for cancer and autoimmune conditions, can also well as effective. help people living with HIV. It is important not to become In the context of finding a biomarker for the HIV reservoir, complacent and to always strive for better. We wish to convey whereas IC molecules show evidence for enrichment, it has been our appreciation to all the authors who have participated in this suggested that the FC gamma receptor CD32 may be a more Research Topic and the reviewers for their insightful comments. specific marker (9). Due to the importance and implications of this finding, many investigators turned to CD32, including AUTHOR CONTRIBUTIONS Martin et al.. Although they were able to find evidence of CD32 expression in analysis of cells that contained HIV DNA, there All authors listed have made a substantial, direct and intellectual was no correlation with total or integrated HIV DNA levels (or contribution to the work, and approved it for publication. time to rebound on stopping ART), consistent with subsequent findings that CD32 may in fact be a marker of T cell—B cell ACKNOWLEDGMENTS doublets that have survived flow cytometry gating (10), but this remains a contentious area. We wish to convey our appreciation to all the authors who have Also considered as a biomarker for the reservoir is CD2, participated in this Research Topic and the reviewers for their and this is explored by Tomalka et al. who present a study insightful comments. Frontiers in Immunology | www.frontiersin.org 2 January 2020 | Volume 11 | Article 70 Prado and Frater Immune Surveillance and HIV Cure REFERENCES 9. Descours B, Petitjean G, López-Zaragoza J-L, Bruel T, Raffel R, Psomas C, et al. CD32a is a marker of a CD4 T-cell HIV reservoir harbouring replication- 1. Centers for Disease Control (CDC). Pneumocystis pneumonia–Los Angeles. competent proviruses. Nature. (2017) 543:564–7. doi: 10.1038/nature21710 MMWR Morb Mortal Wkly Rep. (1981) 30:250–2. 10. Thornhill JP, Pace M, Martin GE, Hoare J, Peake S, Herrera C, et al. 2. UNAIDS 2019 Report; AIDS Data. Available online at: https://www.unaids. 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PLoS Pathog. (2013) 9:e1003211. potential conflict of interest. doi: 10.1371/journal.ppat.1003211 7. Kiepiela P, Leslie AJ, Honeyborne I, Ramduth D, Thobakgale C, Chetty Copyright © 2020 Prado and Frater. This is an open-access article distributed S, et al. Dominant influence of HLA-B In mediating the potential co- under the terms of the Creative Commons Attribution License (CC BY). The use, evolution of HIV and HLA. Nature. (2004) 432:769–74. doi: 10.1038/nature distribution or reproduction in other forums is permitted, provided the original 03113 author(s) and the copyright owner(s) are credited and that the original publication 8. Goulder PJ, Walker BD. HIV and HLA class I: an evolving relationship. in this journal is cited, in accordance with accepted academic practice. No use, Immunity. (2012) 37:426–40. doi: 10.1016/j.immuni.2012.09.005 distribution or reproduction is permitted which does not comply with these terms. 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