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

Immune 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.

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

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 <200 cells/µL, CD8 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.

Anxiety, depression, and sleep disturbances among people on long-term efavirenz-based treatment for HIV: a cross-sectional study in Beijing, China.

BACKGROUND: Efavirenz (EFV)-induced neuropsychiatric toxicity bothers people living with HIV (PLHIV). Neuropsychiatric adverse effects of EFV may differ by length of time on EFV-based antiretroviral treatment (ART). METHODS: A cross-sectional, single-center study was conducted at Beijing Ditan Hospital in China from June-August 2020 among ART-experienced PLHIV who were on long-term EFV-based ART. 424 eligible virological suppressed participants were enrolled and divided into four groups according to time on EFV-based ART: group A (0.5 ≤ ART < 2 year), B (2 ≤ ART < 4 year), C (4 ≤ ART < 6 year), and D (ART ≥ 6 year). The questionnaires about 12-item Short Form Health Survey (SF-12), Hospital Anxiety and Depression Scale (HADS) and Pittsburgh Sleep Quality Index (PSQI) were administered to assess neuropsychiatric adverse events of EFV among different groups. RESULTS: Overall mental component summary scores (MCS) of SF-12 in PLHIV was 50.2, which was lower than general population. Overall prevalence of anxiety, depression and sleep disturbances was 15.6%, 15.3% and 58%, respectively. Prevalence of anxiety, depression and sleep disturbances did not vary significantly between the time-on-ART groups. Anxiety, depression, sleep disturbances had no correlation with time on EFV-based ART or CD4+ T cells counts. CONCLUSIONS: In ART-experienced PLHIV in China, neuropsychiatric adverse events exist persistently and prevalence do not significantly change with prolonged time on EFV-based ART. The prevalence of sleep disturbances was high, suggesting that clinicians should pay more attention to long-standing psychiatric health to perform early and effective interventions.

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.

Assessment of Clinical Features in HIV-Infected Patients with Acute Coronary Syndromes Undergoing Percutaneous Coronary Intervention in China.

Objectives: We aimed to compare coronary risk factors, burden of coronary artery disease (CAD), and 1-year prognosis of people living with HIV (PLWH) and HIV-negative controls who underwent percutaneous coronary intervention (PCI) for acute coronary syndromes (ACSs). Background: Cardiovascular disease is drawing more and more attention in PLWH since effective antiretroviral therapy (ART) has been available. Clinical characteristics and outcomes of PLWH undergoing PCI for ACS in China remain unknown. Methods: We compared demographic characteristics, angiographic features, and 1-year outcomes of 48 PLWH versus 48 HIV-negative controls matched for age (±2 years), sex, diabetes mellitus, and year of PCI (±2 years) in Beijing Ditan Hospital, Capital Medical University from January 2008 to November 2020. Results: In PLWH (mean age: 53.6 ± 10.6 years, 95.8% male, and 79.2% on ART), high-density lipoprotein cholesterol was lower than in HIV-negative controls; however, the statin use was more common, the incidence of hypertension was lower, and low-density lipoprotein cholesterol, and the body mass index were significantly lower than in controls. Two groups had a similar extent of coronary atherosclerosis as measured by the presence of multivessel diseases and the median Gensini score; however, lesions of PLWH were longer and were more likely to locate at the proximal segment of the coronary artery. In addition, the risk of major adverse cardiac and cerebrovascular events at 1 year was similar in both groups. Conclusion: PLWH undergoing PCI displayed similar CAD burden and 1-year prognosis compared with HIV-negative patients. Early detection of cardiovascular risk factors and appropriate secondary prevention of CAD in PLWH might alleviate the risk of severe adverse cardiovascular events.

Decreased CD73+ Double-Negative T Cells and Elevated Level of Soluble CD73 Correlated With and Predicted Poor Immune Reconstitution in HIV-Infected Patients After Antiretroviral Therapy.

Although extensive use of antiretroviral therapy (ART) has made great progress in controlling HIV replication and improving CD4+ T cell recovery, the immune reconstitution remained insufficient in some patients, who were defined as poor immunological responders (PIRs). These PIRs were at a high risk of AIDS-related and non-AIDS complications, resulting in higher morbidity and mortality rate. Thus, it is a major challenge and urgently needed to distinguish PIRs early and improve their immune function in time. Immune activation is a key factor that leads to impaired immune reconstitution in people living with HIV (PLWH) who are receiving effective ART. Double negative T cells (DNT) were reported to associate with the control of immune activation during HIV infection. However, the precise mechanisms by which DNT cells exerted their suppressive capacity during HIV infection remained puzzled. CD73, both a soluble and a membrane-bound form, display immunosuppressive effects through producing adenosine (ADO). Thus, whether DNT cells expressed CD73 and mediated immune suppression through CD73-ADO pathway needs to be investigated. Here, we found a significant downregulation of CD73 expression on DNT cells in treatment-naïve PLWH (TNs) compared to healthy controls, accompanied with increased concentration of sCD73 in plasma. Both the frequency of CD73+ DNT cells and the level of plasma sCD73 recovered after ART treatment. However, PIRs showed decreased percentage of CD73+ DNT cells compared to immunological responders (IRs). The frequency of CD73+ DNT cells was positively correlated with CD4+ T cell count and CD4/CD8 ratio, and negatively correlated with immune activation in PLWH. The level of sCD73 also showed a negative correlation to CD4+ T cell count and CD4/CD8 ratio. More importantly, in the present cohort, a higher level of sCD73 at the time of initiating ART could predict poor immune reconstitution in PLWH after long-term ART. Our findings highlighted the importance of CD73+ DNT cells and sCD73 in the disease progression and immune reconstitution of PLWH, and provided evidences for sCD73 as a potential biomarker of predicting immune recovery.

High Levels of CD244 Rather Than CD160 Associate With CD8+ T-Cell Aging.

Aging leads to functional dysregulation of the immune system, especially T cell defects. Previous studies have shown that the accumulation of co-inhibitory molecules plays an essential role in both T cell exhaustion and aging. In the present study, we showed that CD244 and CD160 were both up-regulated on CD8+ T cells of elderly individuals. CD244+CD160- CD8+ T cells displayed the increased activity of ß-GAL, higher production of cytokines, and severe metabolic disorders, which were characteristics of immune aging. Notably, the functional dysregulation associated with aging was reversed by blocking CD244 instead of CD160. Meanwhile, CD244+CD160+ CD8+ T cells exhibited features of exhaustion, including lower levels of cytokine, impaired proliferation, and intrinsic transcriptional regulation, compared to CD244+CD160- population. Collectively, our findings demonstrated that CD244 rather than CD160 acts as a prominent regulator involved in T cell aging, providing a solid therapeutic target to improve disorders and comorbidities correlated to immune system aging.

Efficacy and safety of Efavirenz 400 mg-based regimens switching from 600 mg-based regimens in people living with HIV with virological suppression in China: a randomized, open-label, non-inferiority study.

BACKGROUND: Efavirenz (EFV) 400 mg has been recommended to replace EFV 600 mg. There are only 200 mg and 600 mg dosage forms of EFV in China. Whether switching from one-tablet EFV 600 mg to two-tablet EFV 200 mg would weaken adherence or further affect efficacy or safety is unknown. METHODS: Virologically suppressed people living with HIV with a regimen composed of one-tablet tenofovir (TDF), one-tablet lamivudine (3TC), and one-tablet EFV (600 mg) were randomized to continue original regimen or switch to two-tablet EFV (200 mg). Self-reported adherence questionnaires, 12-Item Short-Form Health Survey (SF-12), Hospital Anxiety and Depression Scale (HADS), and Pittsburgh Sleep Quality Index (PSQI) were used. Primary end point was the difference in proportions of participants with plasma HIV-RNA ≥ 50 copies/mL at week 48 with noninferiority margin of 4%. RESULTS: A total of 209 participants were randomized to the EFV 400 mg group and 211 to the EFV 600 mg. Primary end point result was -3.3% (95% CI -8.1-1.6). Further decrease of GGT (-3.1 vs. -0.3 U/L) and TC (-0.26 vs. 0.12 U/L) was observed in EFV 400 mg participants through 48 weeks. No significant changes in adherence, quality of life, and neuropsychologic condition were reported. CONCLUSIONS: EFV 400 mg was noninferior to EFV 600 mg and showed mild improvement of safety profile. Adherence was not weakened in patients taking EFV 400 mg. For patients taking EFV 600 mg with neuropsychologic symptoms, it would be better to switch to other drugs instead of EFV 400 mg.

Risk factors associated with pulmonary arterial hypertension among HIV-infected adults: A meta-analysis and systematic review.

Pulmonary arterial hypertension (PAH) occurs more frequently in patients with HIV infection than in general population. The predictive value of HIV-related factors and traditional cardiovascular factors with PAH is inconsistent across studies. The objective is to determine the roles of HIV-related risk factors and traditional cardiovascular risk factors in the development of PAH in adults with HIV. We searched Pubmed/Medline, Embase, Web of Science, and Google Scholar to identify studies published between January 1, 2000 and February 23, 2021 on risk factors associated with PAH among people living with HIV (PLWH). Ten studies were included for final analysis. PLWH with PAH had higher mean age (weighted mean difference [WMD] = 2.27, 95% confidence interval [CI] 0.31 ~ 4.24), and lower mean CD4 cell count (WMD = -95.8, 95% CI -153.41 ~ -38.2). Meanwhile, they were more likely to have detectable viral load (odds ratio [OR] = 1.36, 95% CI 1.16 ~ 1.60), to accompany arterial hypertension (OR = 2.02, 95% CI 1.51 ~ 2.71) and less likely to receive antiretroviral therapy (ART) (OR = 0.84, 95% CI 0.72 ~ 0.99). Besides, more intravenous drug users were observed in HIV-infected adults with PAH (OR = 2.25, 95% CI 1.51 ~ 3.33). HIV infection itself and ART impact PAH in two opposite ways. Traditional cardiovascular factors such as arterial hypertension, and older age are also important to the development of PAH. Screening HIV-related factors and traditional cardiovascular factors may help to target and manage patients at risk.

A novel prediction model to evaluate the probability of CD4+/CD8+ cell ratio restoration in HIV-infected individuals.

BACKGROUND: Our study aimed to develop a clinical prediction model to evaluate the possibility of CD4+/CD8+ ratio restoration in HIV-positive individuals. METHODS: About 1980, HIV/AIDS patients initiated with antiretroviral treatment from 1 January 2013, to 30 December 2016, at Beijing Ditan Hospital and achieved persistent virological suppression during the 4 years follow-up were included in this study. Multivariate Cox proportional regression analysis was used to identify the independent risk factors and establish a predictive model. The model's performance was assessed using the area under the receiver operating characteristic and calibration plots. RESULTS: Overall, after 4 years of treatment, a total of 455 individuals (22.98%) restored their CD4+/CD8+ ratio (≥1). The area under the receiver operating characteristic was 0.782 and 0.743 in the deriving and validation cohort, respectively. The ultimate model included five indexes: age at AIDS diagnosis, albumin, and syphilis status, and baseline CD4+ and CD8+ values. A nomogram further visualized the model, and the calibration plots indicated high agreement of predicted and observed outcomes. CONCLUSION: Our prediction model might be practical and easily applied to recognize HIV/AIDS individuals most likely to benefit from modern antiretroviral therapy.

COVID-19 Vaccination in People Living with HIV (PLWH) in China: A Cross Sectional Study of Vaccine Hesitancy, Safety, and Immunogenicity.

The administration of COVID-19 vaccines is the primary strategy used to prevent further infections by COVID-19, especially in people living with HIV (PLWH), who are at increased risk for severe symptoms and mortality. However, the vaccine hesitancy, safety, and immunogenicity of COVID-19 vaccines among PLWH have not been fully characterized. We estimated vaccine hesitancy and status of COVID-19 vaccination in Chinese PLWH, explored the safety and impact on antiviral therapy (ART) efficacy and compared the immunogenicity of an inactivated vaccine between PLWH and healthy controls (HC). In total, 27.5% (104/378) of PLWH hesitated to take the vaccine. The barriers included concerns about safety and efficacy, and physician counselling might help patients overcome this vaccine hesitancy. A COVID-19 vaccination did not cause severe side effects and had no negative impact on CD4+ T cell counts and HIV RNA viral load. Comparable spike receptor binding domain IgG titer were elicited in PLWH and HC after a second dose of the CoronaVac vaccine, but antibody responses were lower in poor immunological responders (CD4+ T cell counts < 350 cells/µL) compared with immunological responders (CD4+ T cell counts ≥ 350 cells/µL). These data showed that PLWH have comparable safety and immune response following inactivated COVID-19 vaccination compared with HC, but the poor immunological response in PLWH is associated with impaired humoral response.

Manifestations and Related Risk Factors of Thrombocyte Abnormalities in HIV-Positive Patients Before and After the Initiation of ART.

BACKGROUND: At present, the thrombocyte abnormality is not well described before and after the initiation of antiretroviral therapy (ART). The purpose of this research is to investigate the dynamic changes and related risk factors of thrombocytopenia and thrombocytosis in HIV-infected individuals. METHODS: We performed a real-world observational study among 6637 HIV patients who started ART from January, 2013 to August, 2020 at the Beijing Ditan Hospital. Hazard indicators linked with thrombocytopenia and thrombocytosis were analyzed by logistic/Cox regression. RESULTS: The prevalence of thrombocytopenia and thrombocytosis was 2.65% and 5.85% among ART-naïve patients, respectively. Correlated risk factors: (thrombocytopenia) older age, coinfection with HBV, leucopenia, anemia, and CD4 count <350 cells/uL; (thrombocytosis) WBC level ≥4.0 x 109/L, anemia, NLR ≥2.0, and CD4 count ≥350 cells/uL. As for the recovery rate, it was 86.6/54.2, 83.4/46.3, 66.0/35.1, and 65.3/ 33.9 per 100 PYFU in thrombocytopenia/thrombocytosis at different treatment period (12m, 24m, 36m, and 48m). While the new-onset incidence of thrombocytopenia/thrombocytosis at different ART period (12m, 24m, 36m, 48m, 60m, 72m, and 84m) was 0.25/7.2, 0.19/6.31, 0.16/4.74, 0.16/4.55, 0.16/4.48, 0.15/4.41, and 0.15/4.39. And the driving forces of thrombocytosis were antiretroviral treatment, female, overweight, and WBC level ≥ 4.0 x 109/L. CONCLUSION: In the medical practice, while paying attention to thrombocytopenia, clinicians should be highly vigilant about the thrombocytosis of HIV/AIDS patients, and related treatment strategies need to be further studied.