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      Incomplete immune reconstitution in HIV/AIDS patients on antiretroviral therapy: Challenges of immunological non‐responders

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          Abstract

          The morbidity and mortality of HIV type‐1 (HIV‐1)‐related diseases were dramatically diminished by the grounds of the introduction of potent antiretroviral therapy, which induces persistent suppression of HIV‐1 replication and gradual recovery of CD4 + T‐cell counts. However, ∼10–40% of HIV‐1‐infected individuals fail to achieve normalization of CD4 + T‐cell counts despite persistent virological suppression. These patients are referred to as “inadequate immunological responders,” “immunodiscordant responders,” or “immunological non‐responders (INRs)” who show severe immunological dysfunction. Indeed, INRs are at an increased risk of clinical progression to AIDS and non‐AIDS events and present higher rates of mortality than HIV‐1‐infected individuals with adequate immune reconstitution. To date, the underlying mechanism of incomplete immune reconstitution in HIV‐1‐infected patients has not been fully elucidated. In light of this limitation, it is of substantial practical significance to deeply understand the mechanism of immune reconstitution and design effective individualized treatment strategies. Therefore, in this review, we aim to highlight the mechanism and risk factors of incomplete immune reconstitution and strategies to intervene.

          Abstract

          Highlights the mechanism and risk factors of incomplete immune reconstitution and strategies to intervene.

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          Most cited references203

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          Dolutegravir plus abacavir-lamivudine for the treatment of HIV-1 infection.

          Dolutegravir (S/GSK1349572), a once-daily, unboosted integrase inhibitor, was recently approved in the United States for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in combination with other antiretroviral agents. Dolutegravir, in combination with abacavir-lamivudine, may provide a simplified regimen. We conducted a randomized, double-blind, phase 3 study involving adult participants who had not received previous therapy for HIV-1 infection and who had an HIV-1 RNA level of 1000 copies per milliliter or more. Participants were randomly assigned to dolutegravir at a dose of 50 mg plus abacavir-lamivudine once daily (DTG-ABC-3TC group) or combination therapy with efavirenz-tenofovir disoproxil fumarate (DF)-emtricitabine once daily (EFV-TDF-FTC group). The primary end point was the proportion of participants with an HIV-1 RNA level of less than 50 copies per milliliter at week 48. Secondary end points included the time to viral suppression, the change from baseline in CD4+ T-cell count, safety, and viral resistance. A total of 833 participants received at least one dose of study drug. At week 48, the proportion of participants with an HIV-1 RNA level of less than 50 copies per milliliter was significantly higher in the DTG-ABC-3TC group than in the EFV-TDF-FTC group (88% vs. 81%, P=0.003), thus meeting the criterion for superiority. The DTG-ABC-3TC group had a shorter median time to viral suppression than did the EFV-TDF-FTC group (28 vs. 84 days, P<0.001), as well as greater increases in CD4+ T-cell count (267 vs. 208 per cubic millimeter, P<0.001). The proportion of participants who discontinued therapy owing to adverse events was lower in the DTG-ABC-3TC group than in the EFV-TDF-FTC group (2% vs. 10%); rash and neuropsychiatric events (including abnormal dreams, anxiety, dizziness, and somnolence) were significantly more common in the EFV-TDF-FTC group, whereas insomnia was reported more frequently in the DTG-ABC-3TC group. No participants in the DTG-ABC-3TC group had detectable antiviral resistance; one tenofovir DF-associated mutation and four efavirenz-associated mutations were detected in participants with virologic failure in the EFV-TDF-FTC group. Dolutegravir plus abacavir-lamivudine had a better safety profile and was more effective through 48 weeks than the regimen with efavirenz-tenofovir DF-emtricitabine. (Funded by ViiV Healthcare; SINGLE ClinicalTrials.gov number, NCT01263015 .).
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            An altered intestinal mucosal microbiome in HIV-1 infection is associated with mucosal and systemic immune activation and endotoxemia

            HIV-1 infection disrupts the intestinal immune system, leading to microbial translocation and systemic immune activation. We investigated the impact of HIV-1 infection on the intestinal microbiome and its association with mucosal T cell and dendritic cell (DC) frequency and activation, as well as with levels of systemic T cell activation, inflammation and microbial translocation. Bacterial 16S ribosomal DNA sequencing was performed on colon biopsies and fecal samples from subjects with chronic, untreated HIV-1 infection and uninfected control subjects. Colon biopsies of HIV-1 infected subjects had increased abundances of Proteobacteria and decreased abundances of Firmicutes compared to uninfected donors. Furthermore at the genus level, a significant increase in Prevotella and decrease in Bacteroides was observed in HIV-1 infected subjects, indicating a disruption in the Bacteroidetes bacterial community structure. This HIV-1-associated increase in Prevotella abundance was associated with increased numbers of activated colonic T cells and myeloid DCs. Principal coordinates analysis demonstrated an HIV-1-related change in the microbiome that was associated with increased mucosal cellular immune activation, microbial translocation and blood T cell activation. These observations suggest that an important relationship exists between altered mucosal bacterial communities and intestinal inflammation during chronic HIV-1 infection.
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              Alterations in the gut microbiota associated with HIV-1 infection.

              Understanding gut microbiota alterations associated with HIV infection and factors that drive these alterations may help explain gut-linked diseases prevalent with HIV. 16S rRNA sequencing of feces from HIV-infected individuals revealed that HIV infection is associated with highly characteristic gut community changes, and antiretroviral therapy does not consistently restore the microbiota to an HIV-negative state. Despite the chronic gut inflammation characteristic of HIV infection, the associated microbiota showed limited similarity with other inflammatory states and instead showed increased, rather than decreased, diversity. Meta-analysis revealed that the microbiota of HIV-infected individuals in the U.S. was most similar to a Prevotella-rich community composition typically observed in healthy individuals in agrarian cultures of Malawi and Venezuela and related to that of U.S. individuals with carbohydrate-rich, protein- and fat-poor diets. By evaluating innate and adaptive immune responses to lysates from bacteria that differ with HIV, we explore the functional drivers of these compositional differences. Copyright © 2013 Elsevier Inc. All rights reserved.
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                Author and article information

                Contributors
                zt_doc@ccmu.edu.cn
                Journal
                J Leukoc Biol
                J. Leukoc. Biol
                10.1002/(ISSN)1938-3673
                JLB
                Journal of Leukocyte Biology
                John Wiley and Sons Inc. (Hoboken )
                0741-5400
                1938-3673
                22 January 2020
                April 2020
                : 107
                : 4 , Targeted Science — Special Focus Issue ( doiID: 10.1002/jlb.v107.4 )
                : 597-612
                Affiliations
                [ 1 ] Center for Infectious Diseases Beijing Youan Hospital Capital Medical University Beijing China
                [ 2 ] Beijing Key Laboratory for HIV/AIDS Research Beijing China
                Author notes
                [*] [* ] Correspondence

                Dr. Tong Zhang. Center for Infectious Diseases, Beijing Youan Hospital, Capital Medical University, Beijing 100069, China.

                Email: zt_doc@ 123456ccmu.edu.cn

                Article
                JLB10539
                10.1002/JLB.4MR1019-189R
                7187275
                31965635
                3be7a66b-60b6-4b70-b3e2-c4d2a2860739
                © 2020 The Authors. Journal of Leukocyte Biology published by Wiley Periodicals, Inc. on behalf of Society for Leukocyte Biology

                This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.

                History
                : 01 August 2019
                : 25 October 2019
                : 13 November 2019
                Page count
                Figures: 2, Tables: 1, Pages: 16, Words: 14171
                Funding
                Funded by: National Natural Science Foundation of China , open-funder-registry 10.13039/501100001809;
                Award ID: 81772165
                Award ID: 81974303
                Funded by: National 13th Five‐Year Grand Program on Key Infectious Disease Control
                Award ID: 2017ZX10202102‐005‐003
                Award ID: 2017ZX10202101‐004‐001
                Funded by: NSFC‐NIH Biomedical
                Award ID: 81761128001
                Funded by: Beijing Municipal of Science and Technology Major Project
                Award ID: D161100000416003
                Funded by: Beijing Key Laboratory for HIV/AIDS Research
                Award ID: BZ0089
                Categories
                Review
                Chinese Society for Immune Cell Biology Annual Meeting
                Guest Editor: Zhongjun Dong
                Reviews
                Custom metadata
                2.0
                April 2020
                Converter:WILEY_ML3GV2_TO_JATSPMC version:5.8.1 mode:remove_FC converted:28.04.2020

                Hematology
                antiretroviral therapy,cd4+ t cells,hiv‐1 infection,immunological non‐responders,immune reconstitution

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