Naïve CD4+ T Cell Lymphopenia and Apoptosis in Chronic Hepatitis C Virus Infection Is Driven by the CD31+ Subset and Is Partially Normalized in Direct-Acting Antiviral Treated Persons

Abstract

BackgroundThe mechanisms underlying naïve CD4+ lymphopenia during chronic Hepatitis C Virus (HCV) infection are unclear. Whether direct-acting antiviral (DAA) therapy restores peripheral naïve CD4+ T cell numbers and function is unknown.MethodsWe enumerated frequencies and counts of peripheral naïve CD4+, CD4+CD31+ and CD4+CD31- T cells by flow cytometry in a cross sectional analysis comparing chronic HCV infected (n=34), DAA-treated(n=29), and age-range matched controls (n=25), as well as in a longitudinal cohort of HCV DAA treated persons (n=16). The cross-sectional cohort was stratified by cirrhosis state. Cell apoptosis/survival (AnnexinV+7AAD+/BCL-2 labeling) and cell cycle entry (Ki67 expression) of CD31+ and CD31- naïve CD4+ T cells was analyzed directly ex vivo and following 3 and 5 days of in vitro culture with media, interleukin (IL) -7 or CD3/CD28 activator.ResultsIn the cross-sectional cohort, naïve CD4+ proportions were lower in chronic HCV infected persons compared to controls and DAA-treated persons, an effect in part attributed to cirrhosis. Age was associated with naïve cell counts and proportions in HCV infected and treated persons as well. Naïve CD4+ cell proportions negatively correlated with plasma levels of soluble CD14 following therapy in DAA-treated persons. Naïve CD4+ cells from HCV infected persons exhibited greater direct ex vivo apoptosis and cell-cycling compared to cells from DAA-treated persons and controls, and this was localized to the CD4+CD31+ subset. On the other hand, no remarkable differences in expression of BCL-2 or IL-7 Receptor (CD127) at baseline or following in vitro media or IL7 containing culture were observed. In the longitudinal cohort, naïve CD4+CD31+/CD31- ratio tended to increase 24 weeks after DAA therapy initiation.ConclusionsActivation and apoptosis of peripheral naïve CD4+CD31+ T cells appear to contribute to naïve CD4+ lymphopenia in chronic HCV infection, and this defect is partially reversible with HCV DAA therapy. Age and cirrhosis -associated naïve CD4+ lymphopenia is present both before and after HCV DAA therapy. These findings have implications for restoration of host immune function after DAA therapy.

Transient elastography score is elevated during rheumatoid factor-positive chronic hepatitis C virus infection and rheumatoid factor decline is highly variable over the course of direct-acting antiviral therapy

“…Chronic HCV infection is associated with elevated plasma levels of systemic markers of immune activation such as sCD14, sCD163, IL-18, Mac-2BP, ATX, and IP-10, more so in patients with advanced liver disease [ 19 – 22 ]. The levels of some markers normalize following DAA therapy initiation (such as IP-10) while other markers often remain elevated (such as sCD14) [ 19 , 23 , 24 ]. Residual immune activation following DAA therapy has been attributed to presence of liver fibrosis and cirrhosis prior to DAA treatment [ 23 , 24 ].…”

“…The levels of some markers normalize following DAA therapy initiation (such as IP-10) while other markers often remain elevated (such as sCD14) [ 19 , 23 , 24 ]. Residual immune activation following DAA therapy has been attributed to presence of liver fibrosis and cirrhosis prior to DAA treatment [ 23 , 24 ]. In the current study, DAA treatment in the RF+ group (particularly within 4 weeks of therapy) was associated with a decline in levels of ATX (p = 0.05), IP-10 (p = 0.008), Mac-2BP (p = 0.003), sCD163 (p = 0.0003), and IL-18 (p = 0.03), and an increase in CRP levels (p = 0.05), while IL-6 and sCD163 levels remained unchanged ( S2 Fig ).…”

Aleukemic Acute Promyelocytic Leukemia: How Concomitant HIV, Hepatitis C, and Chronic Alcohol Use Disorder May Have Hidden an Underlying Malignancy

“…Leukemia has been found to occur in the absence of leukocytosis, with rare variants in which patients also have an absence of splenomegaly and some variants demonstrating aplastic anemia [ 16 ]. The etiology regarding leukopenia versus leukocytosis in APL remains poorly understood; however, patients can present with leukopenia prior to developing leukocytosis with this disease [ 17 ].…”

“…The etiology regarding leukopenia versus leukocytosis in APL remains poorly understood; however, patients can present with leukopenia prior to developing leukocytosis with this disease [ 17 ]. In a case series, many patients with aleukemic myelosis endorsed dyspnea, weakness, and palpitations [ 16 ]. Aleukemic leukemia cutis is a manifestation in which patients develop cutaneous manifestations of the disease, generally preceding the development of systemic leukemia [ 18 ].…”

Variable Normalization of Naïve CD4+ Lymphopenia and Markers of Monocyte and T Cell Activation over the Course of Direct-Acting Anti-Viral Treatment of Chronic Hepatitis C Virus Infection

“…More than half of all acute HCV infections become chronic [1]. The centers for disease control and prevention (CDC) estimated that there were 2.4 million cases of chronic HCV infection during 2013-2016 in the U.S., and a total of 137,713 new chronic hepatitis C cases were reported during 2018 [2,3]. Moreover, 10-20% of all chronic HCV infected individuals consequently develop liver cirrhosis due to persistent liver inflammation and fibrosis [4].…”