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1.
AIDS ; 33(8): 1315-1325, 2019 07 01.
Article in English | MEDLINE | ID: mdl-30932955

ABSTRACT

DESIGN: This was an exploratory, single-arm clinical trial that tested the immune enhancement effects of 24-weeks of Toll-like receptor 9 (TLR9) agonist (MGN1703; Lefitolimod; 60 mg × 2 weekly) therapy. METHODS: We enrolled HIV-1-infected individuals on suppressive combination antiretroviral therapy. Safety was assessed throughout the study. The primary outcome was reduction in total CD4 T-cell viral DNA levels. Secondary outcomes included safety, detailed immunological and virological analyses, and time to viral rebound (viral load > 5000 copies/ml) after randomization into an analytical treatment interruption (ATI). RESULTS: A total of 12 individuals completed the treatment phase and nine completed the ATI. Adverse events were limited and consistent with previous reports for MGN1703. Although the dosing regimen led to potent T-cell activation and increased HIV-1-specific T-cell responses, there were no cohort-wide changes in persistent virus (total CD4 T cells viral DNA; P = 0.34). No difference in time to rebound was observed between the ATI arms (log rank P = 0.25). One of nine ATI participants, despite harboring a large replication-competent reservoir, controlled viremia for 150 days via both HIV-1-specific cellular and antibody-mediated immune responses. CONCLUSION: A period of 24 weeks of MGN1703 treatment was safe and improved innate as well as HIV-1-specific adaptive immunity in HIV-1+ individuals. These findings support the incorporation of TLR9 agonism into combination HIV-1 cure strategies. TRIAL NAME AND REGISTRATION: TLR9 Enhancement of antiviral immunity in chronic HIV-1 infection: a phase 1B/2A trial; ClinicalTrials.gov NCT02443935.


Subject(s)
CD4-Positive T-Lymphocytes/immunology , DNA/therapeutic use , HIV Infections/drug therapy , HIV Infections/immunology , HIV-1/isolation & purification , Immunologic Factors/therapeutic use , Toll-Like Receptor 9/agonists , Adult , Aged , Aged, 80 and over , CD4-Positive T-Lymphocytes/virology , DNA/adverse effects , Drug-Related Side Effects and Adverse Reactions/epidemiology , Female , Humans , Immunologic Factors/adverse effects , Male , Middle Aged , Treatment Outcome , Viral Load , Young Adult
2.
J Acquir Immune Defic Syndr ; 71(1): 8-16, 2016 Jan 01.
Article in English | MEDLINE | ID: mdl-26761268

ABSTRACT

BACKGROUND: Virus-specific CD8(+) T-cell responses are believed to play an important role in the control of HIV-1 infection; however, what constitutes an effective HIV-1 CD8(+) T-cell response remains a topic of debate. The ex vivo viral suppressive capacity was measured of CD8(+) T cells from 44 HIV-1-positive individuals. The phenotypic and cytokine profiles, and also the specificity of the CD8(+) T cells, were correlated with the suppression of HIV-1 replication. We also aimed to determine whether antiretroviral therapy (ART) had any positive effect on the HIV-1 suppressive CD8(+) T cells. METHOD: Ex vivo suppression assay was used to evaluate the ability of CD8(+) T cells to suppress HIV-1 replication in autologous CD4(+) T cells. The CD107a, interferon-γ, interleukin-2, tumor necrosis factor-α (TNF-α), and macrophage inflammatory protein-1ß (MIP-1ß) responses to HIV-1 were evaluated by intracellular staining. The phenotypic profile of CD8(+) T cells was determined by whole blood staining. RESULTS: The expression of CD57 on effector CD8(+) T cells correlated with the suppression of HIV-1 replication and to the duration of ART. CD107a and tumor necrosis factor-α expression levels were significantly higher in individuals with ex vivo suppressive activity compared with individuals without suppressive activity. CONCLUSIONS: Standard in vitro assays measuring one or several cytokines do not correlate with the functional viral suppressive capacity of CD8(+) T cells from HIV-1-positive individuals. The best correlation of viral suppression was found to be CD57 expression. CD57 expression correlated with the duration of ART, suggesting that ART restores the cytotoxic capacity of CD8(+) T lymphocytes.


Subject(s)
CD57 Antigens/metabolism , CD8-Positive T-Lymphocytes/immunology , HIV Infections/immunology , HIV Infections/virology , HIV-1/physiology , Virus Replication , Anti-Retroviral Agents/pharmacology , CD4-Positive T-Lymphocytes/virology , CD8-Positive T-Lymphocytes/drug effects , CD8-Positive T-Lymphocytes/metabolism , Cells, Cultured , Chemokine CCL4/metabolism , HIV-1/immunology , Humans , Interferon-gamma/metabolism , Interleukin-2/metabolism , Tumor Necrosis Factor-alpha/metabolism , Viral Load/immunology , Virus Replication/immunology
3.
J Acquir Immune Defic Syndr ; 68(2): 103-11, 2015 Feb 01.
Article in English | MEDLINE | ID: mdl-25394194

ABSTRACT

BACKGROUND: Natural killer (NK) cell phenotype and function have recently gained much attention as playing crucial roles in antibody-dependent cellular cytotoxicity (ADCC). We investigated NK cell function, as measured by ADCC, in HIV-1-positive individuals before and 6 months after highly active antiretroviral therapy (HAART) initiation. METHOD: The ability of antibodies and NK cells to mediate ADCC was investigated separately and in combination in an autologous model. The NK cell subset distribution and NK cell phenotype (ie, expression of maturation and activation markers within NK cell subsets) were analyzed. RESULTS: The ability of NK cells to mediate ADCC was significantly increased after only 6 months of HAART and was not explained by a normalization of NK cell subsets (CD56 CD16 and CD56 CD16 NK cells) but rather by normalization in the frequency of NK cells expressing CCR7 and CD27. For individuals with no increase in ADCC after 6 months of HAART, the frequency of NK cells expressing NKp46 was downregulated. The ability of antibodies to mediate ADCC alone and in combination in an autologous model was not improved. CONCLUSIONS: HAART improves the ability of NK cells to mediate ADCC after 6 months. This improvement does not correlate with general immune restoration, as measured by CD4 T-cell counts, but rather to a decrease in the frequency of NK cells expressing CCR7 and CD27.


Subject(s)
Anti-Retroviral Agents/therapeutic use , Antibody-Dependent Cell Cytotoxicity , HIV Antibodies/immunology , HIV Infections/drug therapy , HIV Infections/immunology , Killer Cells, Natural/immunology , Adult , Aged , Female , Humans , Immunophenotyping , Killer Cells, Natural/chemistry , Longitudinal Studies , Male , Middle Aged , Receptors, CCR7/analysis , Tumor Necrosis Factor Receptor Superfamily, Member 7/analysis , Young Adult
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