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Background: Around 10% of people with HIV (PWH) exhibit a low-level viremia (LLV) under antiretroviral therapy (ART). However, its origin and clinical significance are largely unknown, particularly at viremias between 50 and 200 copies/mL and under modern ART based on integrase strand transfer inhibitors (INSTIs). Our aim was to characterize their poor immune response against HIV in comparison to individuals with suppressed viremia (SV) and non-HIV controls (NHC). Methods: Transversal observational study in 81 matched participants: 27 PWH with LLV, 27 PWH with SV, and 27 NHC. Activation (CD25, HLA-DR, and CD38) and senescence [CD57, PD1, and HAVCR2 (TIM3)] were characterized in peripheral T-cell subsets by spectral flow cytometry. 45 soluble biomarkers of systemic inflammation were evaluated by immunoassays. Differences in cell frequencies and plasma biomarkers among groups were evaluated by a generalized additive model for location, scale, and shape (GAMLSS) and generalized linear model (GLM) respectively, adjusted by age, sex at birth, and ART regimen. Results: The median age was 53 years and 77.8% were male. Compared to NHC, PWH showed a lower CD4+/CD8+ ratio and increased activation, senescence, and inflammation, highlighting IL-13 in LLV. In addition, LLV showed a downtrend in the frequency of CD8+ naive and effector memory (EM) type 1 compared to SV, along with higher activation and senescence in CD4+ and CD8+ EM and terminally differentiated effector memory RA+ (TEMRA) subpopulations. No significant differences in systemic inflammation were observed between PWH groups. Conclusion: LLV between 50 and 200 copies/mL leads to reduced cytotoxic activity and T-cell dysfunction that could affect cytokine production, being unable to control and eliminate infected cells. The increase in senescence markers suggests a progressive loss of immunological memory and a reduction in the proliferative capacity of immune cells. This accelerated immune aging could lead to an increased risk of developing future comorbidities. These findings strongly advocate for heightened surveillance of these PWH to promptly identify potential future complications. [ABSTRACT FROM AUTHOR]

Coinfection with hepatitis C virus (HCV) and human immunodeficiency virus (HIV) increases immune activation, inflammation, and oxidative stress that could lead to premature senescence. Different HCV infections, either acute or chronic infection, could lead to distinct premature cellular senescence in people living with HIV (PLWHIV). Observational study in 116 PLWHIV under antiretroviral treatment with different HCV status: (i) n = 45 chronically infected with HCV (CHC); (ii) n = 36 individuals who spontaneously clarify HCV (SC); (iii) n = 35 HIV controls. Oxidative stress biomarkers were analyzed at lipid, DNA, protein, and nitrates levels, as well as antioxidant capacity and glutathione reductase enzyme. Replicative senescence was evaluated by relative telomere length (RTL) measurement. Additionally, 26 markers of Senescence‐Associated Secretory Phenotype (SASP) were analyzed by multiplex immunoassays (Luminex xMAP technology). Differences were evaluated by generalized linear model (GLMs) adjusted by most significant covariates. The SC group had a senescence signature similar to the HIV control group and slightly lower SASP levels. However, significant differences were observed with respect to the CHC group, where an increase in the nitrate concentration [adjusted arithmetic mean ratio, aAMR = 1.73 (1.27–2.35), p < 0.001, q = 0.009] and the secretion of 13 SASP‐associated factors [granulocyte macrophage colony‐stimulating factor (GM‐CSF), interferon‐β, interleukin (IL)‐1β, IL‐2, IL‐8, IL‐13, tumor necrosis factor (TNF)‐α, IL‐1α, IL‐1RA, IL‐7, IL‐15, C‐X‐C motif chemokine ligand 10 (IP‐10), stem cell factor (SCF); q < 0.1)] was detected. The CHC group also showed higher values of IL‐1α, IP‐10, and placental growth factor 1 (PIGF‐1) than HIV controls. The SC group showed a slightly lower senescence profile than the HIV group, which could indicate a more efficient control of viral‐induced senescence due to their immune strengths. Chronic HCV infection in PLWHIV led to an increase in nitrate and elevated SASP biomarkers favoring the establishment of viral persistence. [ABSTRACT FROM AUTHOR]