Interferon-signaling pathways are upregulated in people with HIV with abnormal pulmonary diffusing capacity (DL CO ).

OBJECTIVE: People with HIV (PWH) are at greater risk of developing lung diseases even when they are antiretroviral therapy (ART)-adherent and virally suppressed. The most common pulmonary function abnormality in PWH is that of impaired diffusing capacity of the lungs for carbon monoxide (DL CO ), which is an independent risk factor for increased mortality in PWH. Earlier work has identified several plasma biomarkers of inflammation and immune activation to be associated with decreased DL CO . However, the underpinning molecular mechanisms of HIV-associated impaired DL CO are largely unknown. DESIGN: Cross-sectional pilot study with PWH with normal DL CO (values greater than or equal to the lower limit of normal, DL CO  ≥ LLN, N = 9) or abnormal DL CO (DL CO  < LLN, N = 9). METHODS: We compared the gene expression levels of over 900 inflammation and immune exhaustion genes in PBMCs from PWH with normal vs. abnormal DL CO using the NanoString technology. RESULTS: We found that 26 genes were differentially expressed in the impaired DL CO group. These genes belong to 4 categories: 1. Nine genes in inflammation and immune activation pathways, 2. seven upregulated genes that are direct targets of the interferon signaling pathway, 3. seven B-cell specific genes that are downregulated, and 4. three miscellaneous genes. These results were corroborated using the bioinformatics tools DAVID (Database for Annotation, Visualization and Integrated Discovery) and GSEA (Gene Sets Enrichment Analysis). CONCLUSION: The data provides preliminary evidence for the involvement of sustained interferon signaling as a molecular mechanism for impaired DL CO in PWH.

Case Report: Immune reconstitution inflammatory syndrome after hematopoietic stem cell transplantation for severe combined immunodeficiency.

We report a case of immune reconstitution inflammatory syndrome (IRIS) after hematopoietic stem cell transplantation (HSCT). The patient had sever bacillus Calmette-Guerin (BCG) vaccine-caused disseminated infection and had received allogeneic HSCT for X-linked severe combined immunodeficiency disease. After HSCT, complicated by treatment-responding veno-occlusive disease and acute graft-versus-host disease, at the time when immunosuppressants were withdrawn, the patient experienced recurrent fever accompanied by elevated inflammatory indicators. After receiving glucocorticoids and ibuprofen, the patient's condition improved, and a diagnosis with BCG-related IRIS was made.

The stage-specific impairment of granulopoiesis in people living with HIV/AIDS (PLWHA) with neutropenia.

Neutropenia and impaired functions were common manifestation in antiretroviral therapy (ART) in both naïve and experienced PLWHA. Granulopoiesis can be divided into two phases: lineage determination and committed granulopoiesis. However, stage-specific impairment of granulopoiesis in PLWHA with neutropenia remains unclear. A total of 48 ART-naïve and 49 ART-experienced PLWHA from 2016 to 2018 were recruited and divided into non-, mild-, and moderate-to-severe-neutropenia groups according to their neutrophil counts. The bone marrow aspirates and peripheral blood were collected and analyzed by multicolor flow cytometry for granulocyte subsets, hematopoietic stem/progenitor cells (HSPC), apoptosis, and emigration and retention of different subsets. Compared with healthy donors, the percentages of circulating segmented neutrophils were significantly decreased along with an increase of immature neutrophils in both groups. ART-naïve patients with moderate to severe neutropenia exhibited decreased proportion and accelerated apoptosis of relative mature segmented neutrophils. In contrast, ART-experienced patients with neutropenia displayed decreased proportion of granulocyte macrophage progenitors, indicating a defect at a stage of lineage determination. Meanwhile, ART-experienced patients with neutropenia also the expression of CXCR4 segmented neutrophils, suggesting an increased retention of segmented neutrophils inn the bone marrow. ART-naïve patients with neutropenia is caused by increased apoptosis of relatively differentiated neutrophils at committed granulopoiesis, whereas impaired lineage determination and enhanced retention of segmented neutrophils contribute to in ART-experienced patients.

HIV-1 low-level viremia affects T cell activation rather than T cell development in school-age children, adolescents, and young adults during antiretroviral therapy.

OBJECTIVES: Given the improvements in antiretroviral therapy (ART) in recent years, more pediatric HIV patients receiving ART are reaching adolescence and adulthood. This study investigated the influence of poor virological response (low-level viremia (LLV) and virological failure (VF)) on the immune system of these patients. METHODS: HIV-infected, ART-experienced pediatric patients (n=206) were enrolled in this cross-sectional study. The patients were subdivided into school-age children/early adolescents, middle adolescents, and late adolescents/young adults according to their age, and further classified into virological suppression (VS), LLV, and VF groups according to plasma viral load (pVL) measurement. Thymic output, T cells subsets, and immune activation were analyzed by flow cytometry. RESULTS: Compared with VS patients, VF patients displayed decreased CD4+ T cell counts, while LLV and VS patients had comparable CD4+ T cell counts regardless of age. Compared with VS patients, LLV and VF patients had higher percentages of CD8+HLA-DR+ and CD8+CD38high T cells, and the immune activation was positively correlated with pVL in VF and LLV patients. Thymic output levels (CD31+) and regulatory T cell subpopulations in LLV and VF patients were comparable to those in VS patients. LLV patients showed comparable percentages of T cell subsets (TN, TCM, TEMRA, and TEM) as VS patients in all age groups. CONCLUSIONS: LLV causes excessive immune activation although it does not impair T cell recovery or naïve-to-memory T cell conversion in pediatric patients living with HIV. Therefore, T cell immune activation should be monitored at the management of LLV during ART.

Two types of poor immunological responder showing distinct responses to long-term HAART.

OBJECTIVES: Most previous studies on poor immunological responders (PIRs) have been performed on one cohort at one time-point following highly active antiretroviral therapy (HAART). The aim of this study was to investigate whether there are different subtypes of PIR and whether a certain population might achieve better immune reconstitution following longer HAART. METHODS: This study was designed as an ambispective cohort study, including a 4-5-year retrospective study and a 2-year prospective follow-up investigation. Thymic output, activated T cell and regulatory T cell (Treg) subset frequencies, expression levels of interferon-stimulated genes, and plasma concentrations of neopterin were determined at 4-5 years and 6-7 years following HAART initiation. RESULTS: PIRs were subdivided into two populations after 4-5 years of HAART, according to the kinetics of T cell recovery. Type II PIRs exhibited a significantly lower percentage of naïve CD4+ T cells and CD31+ naïve CD4+ T cells compared with type I PIRs. After an additional 2 years of HAART treatment, type I PIRs showed a better outcome than type II PIRs. Furthermore, it was found that 2 years of additional HAART could persistently improve thymic output. CONCLUSIONS: The two PIR subgroups are different in terms of immune characteristics and the response to prolonged HAART.

Efficacy and tolerability of chemotherapy in Chinese patients with AIDS-related Burkitt lymphoma and diffuse large B-cell lymphoma: An observational study.

We evaluated the efficacy and tolerability of chemotherapy in HIV-infected patients with diffuse large B-cell lymphoma (DLBCL) receiving CHOP ± R (n = 17) or Burkitt lymphoma (BL) receiving CODOX-M/IVAC ± R (n = 15). The study was conducted in Beijing Ditan Hospital from January 2009 to August 2015. The following grade 4 adverse effects were observed in BL and DLBCL patients, respectively: neutropenia (80% versus 47.1%), anaemia (46.7% versus 5.9%), thrombocytopenia (53.3% versus 11.8%), bacterial pneumonia (33.3% versus 5.9%), and sepsis (20% versus 5.9%) (p < 0.05). In the BL group, 10 (66.7%) patients died from treatment-related or tumour-related causes, 5 (33.3%) achieved complete response, 1 achieved partial response (6.7%), and 7 developed progressive disease. The 1-year overall survival and progression-free survival rates were 33.3%. Of the DLBCL patients, 3 (17.6%) died from treatment-related causes, 14 (82.4%) achieved complete response, and 3 had progressive disease. The 1-year overall survival and progression-free survival rates were 82.4%. The strongest risk factor for death was relapse between chemotherapy cycles (adjusted hazard ratio = 47.3; 95%CI, 4.2-528.6, p = 0.002). Initiating antiretroviral therapy before chemotherapy failed to improve overall survival. DLBCL patients demonstrated good responses and survival outcomes, while BL patients could not tolerate chemotherapy due to more severe toxicity, and showed poor responses and survival outcomes.

Distinct Mitochondrial Disturbance in CD4+T and CD8+T Cells From HIV-Infected Patients.

BACKGROUND: Mitochondrial dysfunction has frequently been found in HIV-infected patients regardless of whether they received antiretroviral therapy (ART). Accumulating evidence suggests that HIV-infected patients exhibit marked changes in mitochondrial membrane potential (MMP), reactive oxygen species (ROS) accumulation, adenosine triphosphate generation, mitochondrial mass (MM), mitochondrial DNA, etc. However, mitochondrial toxicity in CD4T and CD8T cells caused by different levels of HIV progression and ART is poorly understood. METHODS: Blood samples were obtained from 97 ART-naïve HIV-infected patients with different CD4T cell counts, 97 nucleoside-reverse transcriptase inhibitors-exposed HIV-infected patients, and 25 HIV-negative subjects. MMP, ROS, and MM in CD4T and CD8T cells were assessed by flow cytometry. RESULTS: In healthy subjects, the levels of MMP and MM in CD4T cells were higher than those in CD8T cells. HIV infection led to an increase in MM in CD4T and CD8T cells, but mainly influenced MMP in CD8T cells and ROS accumulation in CD4T cells. MM in CD4T and CD8T cells gradually increased after the loss of CD4T cells. Although the dynamic changes in MMP in CD4T cells were different from those in CD8T cells during highly active ART, MM in both CD4T and CD8T cells was significantly decreased after 2 years of therapy, but increased again after 3 years. CONCLUSIONS: HIV infection and antiretroviral therapy both led to mitochondrial disturbances in CD4T cells and CD8T cells; however, the abnormal changes in mitochondrial parameters in CD4+T cells were different from those in CD8T cells caused by HIV infection and antiretroviral therapy.

Anemia in combined antiretroviral treatment-naive HIV-infected patients in China: A retrospective study of prevalence, risk factors, and mortality.

Anemia is one of the most important complications of HIV infection. In China, the prevalence, risk factors, and association between anemia and prognosis in HIV-infected patients are poorly elucidated. We analyzed data from 3452 HIV-infected patients not yet on combined antiretroviral therapy (cART) attending Beijing Ditan Hospital from June, 2003 to December, 2015. The overall prevalence of anemia was 9.8% (7.6% mild, 1.9% moderate, and 0.2% severe anemia). Female sex (odds ratio [OR] = 3.71, 95% confidence interval [CI]: 1.46-6.51, p = 0.003), age 40-59 years (OR = 2.54, 95% CI: 1.59-4.05, p < 0.001), body mass index < 18.5 kg/m2 (OR = 2.23, 95% CI: 1.31-3.79, p = 0.003), baseline HIV RNA CI: 1.32-5.99, p = 0.007) were risk factors for anemia. Age 40-59 years (adjusted hazard ratio [AHR] = 5.76, 95% CI: 1.62-20.55, p = 0.007), and anemia ‒ mild (AHR = 7.46, 95% CI: 1.48-37.50, p = 0.015), moderate (AHR = 9.89, CI: 1.35-72.38, p = 0.024), and severe (AHR = 28.29, 95% CI: 2.75-290.54, p = 0.005) anemia ‒ were associated with an increased hazard of death. In this cohort, mild anemia was most common. Anemia was associated with female sex, older age, lower body mass index, lower baseline CD4 count, and higher viral load. Moreover, anemia was associated with an increased risk of death. These findings should promote awareness among physicians to make a timely diagnosis of HIV and to help physicians prioritize prevention and intervention strategies for anemia in HIV-infected patients.