Interleukin-36gamma Mediates the In Vitro Activation of CD8+ T Cells from Patients Living with Chronic Human Immunodeficiency Virus-1 Infection.

Interleukin-36 (IL-36) signaling plays an important role in promoting CD8+ T cell-mediated antitumor immune responses. The role of IL-36 signaling in CD8+ T cells that are involved in host immune responses during human immunodeficiency virus-1 (HIV-1) infection has not been characterized. Sixty-one patients living with chronic HIV-1 infection and 23 controls were enrolled in this study. The levels of IL-36 cytokine family members were measured by enzyme-linked immunosorbent assay. Purified CD8+ T cells were stimulated with recombinant IL-36gamma (1 or 10 ng/mL). The expression of inhibitory receptors, the secretion of cytotoxic molecules and interferon-gamma, and the mRNA levels of apoptosis-related ligands were assessed to evaluate the effect of IL-36gamma on CD8+ T cell function in vitro. There were no significant differences in IL-36alpha, IL-36beta, or IL-36 receptor antagonist levels between patients living with chronic HIV-1 infection and controls. Plasma IL-36gamma levels were reduced in patients living with chronic HIV-1 infection. Perforin, granzyme B, and granulysin secretion, as well as tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and Fas ligand (FasL) mRNA expression, but not programmed death-1 (PD-1) or cytotoxic T lymphocyte-associated protein-4 (CTLA-4) expression was downregulated in CD8+ T cells from patients living with chronic HIV-1 infection. The addition of both 1 and 10 ng/mL IL-36gamma enhanced perforin, granzyme B, granulysin, and interferon-gamma secretion by CD8+ T cells without affecting PD-1/CTLA-4 or TRAIL/FasL mRNA expression in CD8+ T cells from patients living with chronic HIV-1 infection. The addition of 1 ng/mL IL-36gamma also promoted perforin and granzyme B secretion by HIV-1-specific CD8+ T cells from patients living with chronic HIV-1 infection. The reduced IL-36gamma levels in patients living with chronic HIV-1 infection might be insufficient for the activation of CD8+ T cells, leading to CD8+ T cell exhaustion.

Rapid Initiation of Antiretroviral Therapy with Coformulated Bictegravir, Emtricitabine, Tenofovir Alafenamide Versus Efavirenz, Lamivudine and Tenofovir Disoproxil Fumarate in HIV-positive Men Who Have Sex with Men in China: Week 48 Results of the Multicenter, Randomized Clinical Trial.

BACKGROUND: Most international treatment guidelines recommend rapid initiation of antiretroviral therapy (ART) for people newly diagnosed with HIV-1 infection, but experiences with rapid ART initiation remain limited in China. We aimed to evaluate the efficacy and safety of efavirenz (400-mg) plus lamivudine and tenofovir disoproxil fumarate (EFV + 3TC + TDF) versus coformulated bictegravir, emtricitabine, tenofovir alafenamide (BIC/FTC/TAF) in rapid ART initiation among HIV-positive men who have sex with men (MSM). METHODS: This multicenter, open-label, randomized clinical trial enrolled MSM aged ≥18 years to start ART within 14 days of confirmed HIV diagnosis. The participants were randomly assigned in a 1:1 ratio to receive EFV(400-mg) + 3TC + TDF or BIC/FTC/TAF. The primary end point was viral suppression (<50 copies/ml) at 48 weeks per FDA Snapshot analysis. RESULTS: Between March 2021 and July 2022, 300 participants were enrolled; 154 were assigned to receive EFV + 3TC + TDF (EFV group) and 146 BIC/FTC/TAF (BIC group). At week 48, 118 (79.2%) and 140 (95.9%) participants in the EFV and BIC group, respectively, were retained in care with viral suppression; and 24 (16.1%) and 1 (0.7%) participant in the EFV and BIC group (p < 0.001), respectively, discontinued treatment due to adverse effects, death, or loss to follow-up. The median increase of CD4 count was 181 and 223 cells/µL (p = 0.020), respectively, for the EFV and BIC group, at week 48. The overall incidence of adverse effects was significantly higher for the EFV group (65.8% vs 37.7%, P < 0.001). CONCLUSION: BIC/FTC/TAF was more efficacious and safer than EFV(400-mg) + 3TC + TDF for rapid ART initiation among HIV-positive MSM in China.

Evaluation of the IP-10 mRNA release assay for diagnosis of TB in HIV-infected individuals.

HIV-infected individuals are susceptible to Mycobacterium tuberculosis (M.tb) infection and are at high risk of developing active tuberculosis (TB). Interferon-gamma release assays (IGRAs) are auxiliary tools in the diagnosis of TB. However, the performance of IGRAs in HIV-infected individuals is suboptimal, which limits clinical application. Interferon-inducible protein 10 (IP-10) is an alternative biomarker for identifying M.tb infection due to its high expression after stimulation with M.tb antigens. However, whether IP-10 mRNA constitutes a target for the diagnosis of TB in HIV-infected individuals is unknown. Thus, we prospectively enrolled HIV-infected patients with suspected active TB from five hospitals between May 2021 and May 2022, and performed the IGRA test (QFT-GIT) alongside the IP-10 mRNA release assay on peripheral blood. Of the 216 participants, 152 TB patients and 48 non-TB patients with a conclusive diagnosis were included in the final analysis. The number of indeterminate results of IP-10 mRNA release assay (13/200, 6.5%) was significantly lower than that of the QFT-GIT test (42/200, 21.0%) (P = 0.000026). IP-10 mRNA release assay had a sensitivity of 65.3% (95%CI 55.9% - 73.8%) and a specificity of 74.2% (95%CI 55.4% - 88.1%), respectively; while the QFT-GIT test had a sensitivity of 43.2% (95%CI 34.1% - 52.7%) and a specificity of 87.1% (95%CI 70.2% - 96.4%), respectively. The sensitivity of the IP-10 mRNA release assay was significantly higher than that of QFT-GIT test (P = 0.00062), while no significant difference was detected between the specificities of these two tests (P = 0.198). The IP-10 mRNA release assay showed a lower dependence on CD4+ T cells than that of QFT-GIT test. This was evidenced by the fact that the QFT-GIT test had a higher number of indeterminate results and a lower sensitivity when the CD4+ T cells counts were decreased (P < 0.05), while no significant difference in the number of indeterminate results and sensitivity were observed for the IP-10 mRNA release assay among HIV-infected individuals with varied CD4+T cells counts (P > 0.05). Therefore, our study suggested that M.tb specific IP-10 mRNA is a better biomarker for diagnosis of TB in HIV-infected individuals.

MicroRNA-27a restrains the immune response to mycobacterium tuberculosis infection by targeting IRAK4, a promoter of the NF-κB pathway.

This study aimed to explore the influence of microRNA-27a on immune response to mycobacterium tuberculosis (Mtb) and the molecular mechanism. MiRNA-27a was screened one of the downregulated miRNAs in Mtb infected macrophages. The concentrations of IFN-γ, IL-ß, IL-6, and TNF-α in THP-1 macrophages after infection with Mtb and simultaneous transfection with miR-27a mimics or inhibitor were determined by ELISA. Colony-forming unit (CFU) assay was used to determine the survival situation of THP-1 infected with Mtb after transfection with miR-27a mimics or inhibitor. We used luciferase reporter assay and western blotting to study the relationship between miR-27a and IRAK4. MiR-27a was found differential expressed in Mtb infected macrophages, and the expressions of miR-27a in Mtb-infected THP-1 were remarkably downregulated with the increase of time and dose. Compared with the control, the levels of IFN-γ, IL-ß, IL-6, and TNF-α were enhanced after macrophages infected with Mtb, while further transfection of miR-27a mimics abolished the increase. IRAK4 was found the target gene of miR-27a and transfection of miR-27a mimics decreased the relative level of IRAK4. The concentration of IFN-γ, IL-ß, IL-6, and TNF-α in Mtb infected macrophages were reduced significantly after transfection of miR-27a mimics, while simultaneous transfection of pcDNA-IRAK4 abolished the decrease, which is the upstream molecular of NF-κB. In conclusion, miR-27a plays a key role in immune response to Mtb infection and intervening on miR-27a may be an effective way to treat TB.