Downregulation of TCF1 in HIV Infection Impairs T-cell Proliferative Capacity by Disrupting Mitochondrial Function.

Background: Despite the benefits of antiretroviral therapy (ART) for people with HIV, T-cell dysfunction cannot be fully restored. Metabolic dysregulation is associated with dysfunction of HIV-1-specific T-cells. Exploration of the factors regulating metabolic fitness can help reverse T-cell dysfunction and provide new insights into the underlying mechanism. Methods: In this study, HIV-infected individuals and HIV-negative control individuals (NCs) were enrolled. T-cell factor (TCF)1 expression in cells was determined by quantitative reverse-transcriptase polymerase chain reaction and flow cytometry. Relevant microarray data from the GEO database were analyzed to explore the underlying mechanism. The effects of TCF1 on T-cell function and metabolic function were assessed in vitro. Results: TCF7 mRNA expression in peripheral blood mononuclear cells was downregulated in rapid progressors compared with long-term non-progressors individuals and NCs. TCF1 expression on CD4+ and CD8+ T-cells was downregulated in treatment-naïve HIV-infected individuals compared with NCs. Interleukin (IL)2 production and proliferative capacity were impaired in TCF1 knockdown T-cells. Moreover, glycolytic capacity and mitochondrial respiratory function were decreased in TCF1 knockdown T-cells, and depolarized mitochondria were increased in TCF1 knockdown T-cells. Conclusion: Downregulation of TCF1 in HIV infection impairs T-cell proliferative capacity by disrupting mitochondrial function. These findings highlight the metabolic regulation as a pivotal mechanism of TCF1 in the regulation of T-cell dysfunction.

Decreased CD4+CD8low T cells in early HIV infection are associated with rapid disease progression.

BACKGROUND: HIV rapid progressors (RPs) present with a rapid decline of CD4+ T cells within a few years of infection. Determining the underlying mechanisms throughout this decline is important to identify prognostic biomarkers and intervention strategies. Determining the numbers of CD4+ and CD8+ T cells is essential for monitoring the immune status of HIV infected patients. There are additional kinds of cell subtypes in T cells, but their relationship to the rapid progression of HIV disease is not well defined. METHODS: Nineteen RPs and twenty-one chronic progressors (CPs) were enrolled in this study. Based on the intensity of CD4 and CD8 expression, different T cell subtypes were identified, including CD4+CD8+T cells, CD4-CD8- T cells, CD4+CD8low T cells and CD4-CD8low T cells. Alterations in these T cell subtypes in early HIV infection (within 120 days of infection) between RPs and CPs were measured, and the relationships between these subtypes and HIV disease progression were investigated. In addition, expression of IFN-γ in T cell subtypes after PMA stimulation was analyzed by flow cytometry. RESULTS: We found that during early HIV infection, CD4+CD8low T cells both significantly decreased in numbers and percentages in RPs compared to CPs. Furthermore, baseline CD4+CD8low T cells positively correlated not only with baseline CD4+T cells but also with CD4+T cells 12 months after infection. Moreover, survival analysis indicated that low levels of baseline CD4+CD8low T cells significantly accelerated the decline in CD4+ T cells as well as increased viral loads. CD4+CD8low T cells secreted significantly more IFN-γ after PMA stimulation compared to CD4+CD8-T cells and CD4-CD8+T cells, which may be beneficial for the prevention of disease progression. CONCLUSIONS: Our results identified that in early stage HIV-1 infection, a subtype of T cells, CD4+CD8low, are associated with subsequent disease progression.

Elevated Expression of miR-19b Enhances CD8+ T Cell Function by Targeting PTEN in HIV Infected Long Term Non-progressors With Sustained Viral Suppression.

Human immunodeficiency virus (HIV)-infected long-term non-progressors (LTNPs) are of particular importance because of their unique disease progression characteristics. Defined by the maintenance of normal CD4+T cells after more than 8 years of infection, these LTNPs are heterogeneous. Some LTNPs exhibit ongoing viral production, while others do not and are able to control viral production. The underlying basis for this heterogeneity has not been clearly elucidated. In this study, the miRNA expression profiles of LTNPs were assessed. The levels of microRNA-19b (miR-19b) were found to be significantly increased in peripheral blood mononuclear cells of LTNPs with lower rather than higher viral load. We made clear that miR-19b may regulate CD8+T cell functions in HIV infection, which has not been addressed before. Overexpression of miR-19b promoted CD8+T cell proliferation, as well as interferon-γ and granzyme B expression, while inhibiting CD8+T cells apoptosis induced by anti-CD3/CD28 stimulation. The target of miR-19b was found to be the "phosphatase and tensin homolog", which regulates CD8+T cells function during HIV infections. Furthermore, we found that miR-19b can directly inhibit viral production in in-vitro HIV infected T cells. These results highlight the importance of miR-19b to control viral levels, which facilitate an understanding of human immunodeficiency virus pathogenesis and provide potential targets for improved immune intervention.

The Incidence and Prevalence of Thromboangiitis Obliterans in Taiwan: A Nationwide, Population-based Analysis of Data Collected from 2002 to 2011.

OBJECTIVE: To estimate the incidence and prevalence of thromboangiitis obliterans in Taiwan in the period spanning from 2002 to 2011. METHODS: We identified all incident and prevalent cases with a diagnosis of thromboangiitis obliterans (International Classification of Diseases, Ninth Revision code 443.1) in the period spanning from 2002 to 2011 using Taiwan's National Health Insurance Research Database. We calculated the age- and sex-specific incidence and prevalence rates of thromboangiitis obliterans during the study period. RESULTS: From 2002 to 2011, 158 patients were diagnosed with thromboangiitis obliterans; of these, 76% were men. Most (63%) of the patients were <50 years old when they were first diagnosed. After reaching 20 years of age, the incidence rate increased with age and peaked among those aged ≥60 years. The average incidence rate of thromboangiitis obliterans during the 2002-2011 period was 0.068 per 105 years. The incidence of thromboangiitis obliterans decreased with time, from 0.10 per 105 years in 2002 to 0.04 per 105 years in 2011. The prevalence increased from 0.26 × 10-5 in 2002 to 0.65 × 10-5 in 2011. CONCLUSION: This is the first epidemiologic study of thromboangiitis obliterans using claims data from a general population in Taiwan. This nationwide, population-based study found that the incidence and prevalence of thromboangiitis obliterans in Taiwan in the 2002-2011 period were lower than those in other countries before 2000. This study also revealed a trend of decreasing incidence with simultaneous increasing prevalence of thromboangiitis obliterans in Taiwan from 2002 to 2011.

The Incidence and Prevalence of Thromboangiitis Obliterans in Taiwan: A Nationwide, Population-based Analysis of Data Collected from 2002 to 2011

OBJECTIVE: To estimate the incidence and prevalence of thromboangiitis obliterans in Taiwan in the period spanning from 2002 to 2011. METHODS: We identified all incident and prevalent cases with a diagnosis of thromboangiitis obliterans (International Classification of Diseases, Ninth Revision code 443.1) in the period spanning from 2002 to 2011 using Taiwan’s National Health Insurance Research Database. We calculated the age- and sex-specific incidence and prevalence rates of thromboangiitis obliterans during the study period. RESULTS: From 2002 to 2011, 158 patients were diagnosed with thromboangiitis obliterans; of these, 76% were men. Most (63%) of the patients were <50 years old when they were first diagnosed. After reaching 20 years of age, the incidence rate increased with age and peaked among those aged ≥60 years. The average incidence rate of thromboangiitis obliterans during the 2002–2011 period was 0.068 per 105 years. The incidence of thromboangiitis obliterans decreased with time, from 0.10 per 105 years in 2002 to 0.04 per 105 years in 2011. The prevalence increased from 0.26 × 10−5 in 2002 to 0.65 × 10−5 in 2011. CONCLUSION: This is the first epidemiologic study of thromboangiitis obliterans using claims data from a general population in Taiwan. This nationwide, population-based study found that the incidence and prevalence of thromboangiitis obliterans in Taiwan in the 2002–2011 period were lower than those in other countries before 2000. This study also revealed a trend of decreasing incidence with simultaneous increasing prevalence of thromboangiitis obliterans in Taiwan from 2002 to 2011.

[Phanerogenetic retrocochlear low frequency hearing loss].

OBJECTIVE: To study the pathogenisis of retrocochlear low frequency hearing loss. METHODS: Clinical and audiologic findings [auditory brainstem response (ABR), evoked otoacoustic emission (EOAE), et al] of 29 cases with retrocochlear low frequency hearing loss were studied. RESULTS: The head injury, acoustic neuroma, peripheral neurophathy, hereditary hear loss, multiple sclerosis and brainstem disease can cause retrocochlear low frequency hearing loss. The typical clinical manifestations of retrocochlear low frequency hearing loss were normal EOAE which cannot be suppressed by contralateral white noise, but with abnormal ABR as well as with no acoustic reflex and -SP/AP > 0.44. CONCLUSIONS: The results suggest that phanerogenetic retrocochlear low frequency hearing loss should be a syndrome rather than a disease called "auditory neuropathy". The main lesions of the disease are brainstem, cochlear nuclei and auditory nerve.