Elevated Foxp3+ double-negative T cells are associated with disease progression during HIV infection

Persistent immune activation, which occurs during the whole course of HIV infection, plays a pivotal role in CD4+ T cells depletion and AIDS progression. Furthermore, immune activation is a key factor that leads to impaired immune reconstitution after long-term effective antiretroviral therapy (ART), and is even responsible for the increased risk of developing non-AIDS co-morbidities. Therefore, it’s imperative to identify an effective intervention targeting HIV-associated immune activation to improve disease management. Double negative T cells (DNT) were reported to provide immunosuppression during HIV infection, but the related mechanisms remained puzzled. Foxp3 endows Tregs with potent suppressive function to maintain immune homeostasis. However, whether DNT cells expressed Foxp3 and the accurate function of these cells urgently needed to be investigated. Here, we found that Foxp3+ DNT cells accumulated in untreated people living with HIV (PLWH) with CD4+ T cell count less than 200 cells/µl. Moreover, the frequency of Foxp3+ DNT cells was negatively correlated with CD4+ T cell count and CD4/CD8 ratio, and positively correlated with immune activation and systemic inflammation in PLWH. Of note, Foxp3+ DNT cells might exert suppressive regulation by increased expression of CD39, CD25, or vigorous proliferation (high levels of GITR and ki67) in ART-naive PLWH. Our study underlined the importance of Foxp3+ DNT cells in the HIV disease progression, and suggest that Foxp3+ DNT may be a potential target for clinical intervention for the control of immune activation during HIV infection

Longitudinal analysis of immune reconstitution and metabolic changes in women living with HIV: A real-world observational study

Abstract. Background:. Women comprise more than half of people living with human immunodeficiency virus/acquired immune deficiency syndrome (HIV/AIDS) worldwide and incomplete immune recovery and metabolic abnormalities affect them deeply. Studies of HIV antiretroviral therapy (ART) have a low female representation in China. We aimed to investigate immune reconstitution and metabolic changes of female HIV-positive cohort in China longitudinally. Methods:. HIV-positive women who initiated ART from January 2005 to June 2021 and were followed up regularly at least once a year were included in this study. Immunological indicators (cluster of differentiation 4 [CD4] counts and CD8 counts), viral load (VL), and metabolic indicators were collected at follow-up. All data were collected from the China Disease Prevention and Control Information System (CDPCIS). VL was tested half a year, 1 year after receiving ART, and every other year subsequently according to local policy. CD4/CD8 ratio normalization was considered as the primary outcome and defined as a value ≥1. Incidence rate and probability of CD4/CD8 ratio normalization were estimated through per 100 person-years follow-up (PYFU) and Kaplan-Meier curve, respectively. Multivariate Cox regression was used to identify independent risk factors associated with CD4/CD8 ratio normalization. We further studied the rate of dyslipidemia, hyperuricemia, diabetes, liver injury, and renal injury after ART initiation with the chi-squared tests or Fisher's exact probability tests, and a generalized estimating equation model was used to analyze factors of dyslipidemia and hyperuricemia. Results:. A total of 494 female patients with HIV/AIDS started ART within 16 years from January 2005 to June 2021, out of which 301 women were enrolled with a median duration of ART for 4.1 years (interquartile range, 2.3-7.0 years). The overall incidence rate of CD4/CD8 ratio normalization was 8.9 (95% confidence interval [CI], 7.4-10.6) per 100 PYFU, and probabilities of CD4/CD8 normalization after initiating ART at 1 year, 2 years, 5 years, and 10 years follow-up were 11.7%, 23.2%, 44.0%, and 59.0%, respectively. Independent risk factors associated with CD4/CD8 normalization were baseline CD4 cell counts 1000 cells/μL, and more than 6 months from the start of combined ART (cART) to first virological suppression. Longitudinally, the rate of hypercholesterolemia (total cholesterol [TC]) and high triglyceride (TG) showed an increasing trend, while the rate of low high-density lipoprotein cholesterol (HDL) showed a decreasing trend. The rate of hyperuricemia presented a downtrend at follow-up. Although liver and renal injury and diabetes persisted during ART, the rate was not statistically significant. Older age and protease inhibitors were independent risk factors for increase of TC and TG, and ART duration was an independent factor for elevation of TC and recovery of HDL-C. Conclusions:. This study showed that women were more likely to normalize CD4/CD8 ratio in comparison with findings reported in the literature even though immune reconstruction was incomplete

CD70-induced differentiation of proinflammatory Th1/17/22/GM lymphocytes associated with disease progression and immune reconstitution during HIV infection

ABSTRACTImmune overactivation is a hallmark of chronic HIV infection, which is critical to HIV pathogenesis and disease progression. The imbalance of helper T cell (Th) differentiation and subsequent cytokine dysregulation are generally considered to be the major drivers of excessive activation and inflammatory disorders in HIV infection. However, the accurate factors driving HIV-associated Th changes remained to be established. CD70, which was a costimulatory molecule, was found to increase on CD4+ T cells during HIV infection. Overexpression of CD70 on CD4+ T cells was recently reported to associate with highly pathogenic proinflammatory Th1/Th17 polarization in multiple sclerosis. Thus, the role of CD70 in the imbalance of Th polarization and immune overactivation during HIV infection needs to be investigated. Here, we found that the elevated frequency of CD70 + CD4+ T cells was negatively correlated with CD4 count and positively associated with immune activation in treatment-naïve people living with HIV (PLWH). More importantly, CD70 expression defined a population of proinflammatory Th1/17/22/GM subsets in PLWH. Blocking CD70 decreased the mRNA expression of subset-specific markers during Th1/17/22/GM polarization. Furthermore, we demonstrated that CD70 influenced the differentiation of these Th cells through STAT pathway. Finally, it was revealed that patients with a high baseline level of CD70 on CD4+ T cells exhibited a greater risk of poor immune reconstitution after antiretroviral therapy (ART) than those with low CD70. In general, our data highlighted the role of CD70 in Th1/17/22/GM differentiation during HIV infection and provided evidence for CD70 as a potential biomarker for predicting immune recovery