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      CD32 + and PD-1 + Lymph Node CD4 T Cells Support Persistent HIV-1 Transcription in Treated Aviremic Individuals

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          Abstract

          The existence of long-lived latently infected resting memory CD4 T cells represents a major obstacle to the eradication of HIV infection. Identifying cell markers defining latently infected cells containing replication-competent virus is important in order to determine the mechanisms of HIV persistence and to develop novel therapeutic strategies to cure HIV infection. We provide evidence that PD-1 and CD32 may have a complementary role in better defining CD4 T cell populations infected with HIV-1. Furthermore, CD4 T cells coexpressing CD32 and PD-1 identify a CD4 T cell population with high levels of persistent HIV-1 transcription.

          ABSTRACT

          A recent study conducted in blood has proposed CD32 as the marker identifying the “elusive” HIV reservoir. We have investigated the distribution of CD32 + CD4 T cells in blood and lymph nodes (LNs) of HIV-1-uninfected subjects and viremic untreated and long-term-treated HIV-1-infected individuals and their relationship with PD-1 + CD4 T cells. The frequency of CD32 + CD4 T cells was increased in viremic compared to treated individuals in LNs, and a large proportion (up to 50%) of CD32 + cells coexpressed PD-1 and were enriched within T follicular helper (Tfh) cells. We next investigated the role of LN CD32 + CD4 T cells in the HIV reservoir. Total HIV DNA was enriched in CD32 + and PD-1 + CD4 T cells compared to CD32 and PD-1 cells in both viremic and treated individuals, but there was no difference between CD32 + and PD-1 + cells. There was no enrichment of latently infected cells with inducible HIV-1 in CD32 + versus PD-1 + cells in antiretroviral therapy (ART)-treated individuals. HIV-1 transcription was then analyzed in LN memory CD4 T cell populations sorted on the basis of CD32 and PD-1 expression. CD32 + PD-1 + CD4 T cells were significantly enriched in cell-associated HIV RNA compared to CD32 PD-1 (averages of 5.2-fold in treated individuals and 86.6-fold in viremics), CD32 + PD-1 (2.2-fold in treated individuals and 4.3-fold in viremics), and CD32 PD-1 + (2.2-fold in ART-treated individuals and 4.6-fold in viremics) cell populations. Similar levels of HIV-1 transcription were found in CD32 + PD-1 and CD32 PD-1 + CD4 T cells. Interestingly, the proportion of CD32 + and PD-1 + CD4 T cells negatively correlated with CD4 T cell counts and length of therapy. Therefore, the expression of CD32 identifies, independently of PD-1, a CD4 T cell population with persistent HIV-1 transcription and coexpression of CD32 and PD-1, the CD4 T cell population with the highest levels of HIV-1 transcription in both viremic and treated individuals.

          IMPORTANCE The existence of long-lived latently infected resting memory CD4 T cells represents a major obstacle to the eradication of HIV infection. Identifying cell markers defining latently infected cells containing replication-competent virus is important in order to determine the mechanisms of HIV persistence and to develop novel therapeutic strategies to cure HIV infection. We provide evidence that PD-1 and CD32 may have a complementary role in better defining CD4 T cell populations infected with HIV-1. Furthermore, CD4 T cells coexpressing CD32 and PD-1 identify a CD4 T cell population with high levels of persistent HIV-1 transcription.

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          Most cited references 24

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          Identification of a reservoir for HIV-1 in patients on highly active antiretroviral therapy.

          The hypothesis that quiescent CD4+ T lymphocytes carrying proviral DNA provide a reservoir for human immunodeficiency virus-type 1 (HIV-1) in patients on highly active antiretroviral therapy (HAART) was examined. In a study of 22 patients successfully treated with HAART for up to 30 months, replication-competent virus was routinely recovered from resting CD4+ T lymphocytes. The frequency of resting CD4+ T cells harboring latent HIV-1 was low, 0.2 to 16.4 per 10(6) cells, and, in cross-sectional analysis, did not decrease with increasing time on therapy. The recovered viruses generally did not show mutations associated with resistance to the relevant antiretroviral drugs. This reservoir of nonevolving latent virus in resting CD4+ T cells should be considered in deciding whether to terminate treatment in patients who respond to HAART.
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            Quantification of latent tissue reservoirs and total body viral load in HIV-1 infection.

            The capacity of HIV-1 to establish latent infection of CD4+ T cells may allow viral persistence despite immune responses and antiretroviral therapy. Measurements of infectious virus and viral RNA in plasma and of infectious virus, viral DNA and viral messenger RNA species in infected cells all suggest that HIV-1 replication continues throughout the course of infection. Uncertainty remains over what fraction of CD4+ T cells are infected and whether there are latent reservoirs for the virus. We show here that during the asymptomatic phase of infection there is an extremely low total body load of latently infected resting CD4+ T cells with replication-competent integrated provirus (<10(7) cells). The most prevalent form of HIV-1 DNA in resting and activated CD4+ T cells is a full-length, linear, unintegrated form that is not replication competent. The infection progresses even though at any given time in the lymphoid tissues integrated HIV-1 DNA is present in only a minute fraction of the susceptible populations, including resting and activated CD4+ T cells and macrophages.
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              Follicular B Helper T Cells Express Cxc Chemokine Receptor 5, Localize to B Cell Follicles, and Support Immunoglobulin Production

              Chemokines and their receptors have been identified as major regulators controlling the functional organization of secondary lymphoid organs. Here we show that expression of CXC chemokine receptor 5 (CXCR5), a chemokine receptor required for B cell homing to B cell follicles, defines a novel subpopulation of B helper T cells localizing to follicles. In peripheral blood these cells coexpress CD45RO and the T cell homing CC chemokine receptor 7 (CCR7). In secondary lymphoid organs, CD4+CXCR5+ cells lose expression of CCR7, which allows them to localize to B cell follicles and germinal centers where they express high levels of CD40 ligand (CD40L), a costimulatory molecule required for B cell activation and inducible costimulator (ICOS), a recently identified costimulatory molecule of the CD28 family. Thus, when compared with CD4+CD45RO+CXCR5− cells, CD4+CD45RO+CXCR5+ tonsillar T cells efficiently support the production of immunoglobulin (Ig)A and IgG. In contrast, analysis of the memory response revealed that long-lasting memory cells are found within the CD4+CD45RO+CXCR5− population, suggesting that CXCR5+CD4 cells represent recently activated effector cells. Based on the characteristic localization within secondary lymphoid organs, we suggest to term these cells “follicular B helper T cells” (TFH).
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                Author and article information

                Contributors
                Role: Editor
                Journal
                J Virol
                J. Virol
                jvi
                jvi
                JVI
                Journal of Virology
                American Society for Microbiology (1752 N St., N.W., Washington, DC )
                0022-538X
                1098-5514
                5 July 2018
                26 September 2018
                15 October 2018
                26 September 2018
                : 92
                : 20
                Affiliations
                [a ]Service of Immunology and Allergy, Lausanne University Hospital, University of Lausanne, Lausanne, Switzerland
                [b ]Service of Vascular Surgery, Lausanne University Hospital, University of Lausanne, Lausanne, Switzerland
                [c ]Service of Infectious Diseases, Lausanne University Hospital, University of Lausanne, Lausanne, Switzerland
                [d ]Vaccine Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA
                [e ]Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA
                [f ]Swiss Vaccine Research Institute, Lausanne University Hospital, University of Lausanne, Lausanne, Switzerland
                [g ]Infectious Disease Division, Luigi Sacco University Hospital, Milan, Italy
                Emory University
                Author notes
                Address correspondence to Giuseppe Pantaleo, Giuseppe.Pantaleo@ 123456chuv.ch .

                Citation Noto A, Procopio FA, Banga R, Suffiotti M, Corpataux J-M, Cavassini M, Riva A, Fenwick C, Gottardo R, Perreau M, Pantaleo G. 2018. CD32 + and PD-1 + lymph node CD4 T cells support persistent HIV-1 transcription in treated aviremic individuals. J Virol 92:e00901-18. https://doi.org/10.1128/JVI.00901-18.

                Article
                00901-18
                10.1128/JVI.00901-18
                6158413
                29976671
                Copyright © 2018 Noto et al.

                This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.

                Page count
                Figures: 7, Tables: 2, Equations: 0, References: 34, Pages: 14, Words: 8196
                Product
                Funding
                Funded by: Swiss National Fund;
                Award Recipient :
                Categories
                Pathogenesis and Immunity
                Custom metadata
                October 2018

                Microbiology & Virology

                cd32, lymph node, pd-1, tfh cells, human immunodeficiency virus

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