Persistent chronic immune activation in HIV/HBV coinfected patients after antiretroviral therapy

2021 ◽  
Author(s):  
Yaozu He ◽  
Weiping Cai ◽  
Jingliang Chen ◽  
Fengyu Hu ◽  
Feng Li ◽  
...  
Keyword(s):  
Antiretroviral Therapy ◽  
Immune Activation ◽  
Chronic Immune Activation

scholarly journals HIV-1 Nef-induced secretion of the proinflammatory protease TACE into extracellularvesicles is mediated by Raf-1, and can be suppressed by clinical protein kinase inhibitors

2021 ◽  
Author(s):  
Zhe Zhao ◽  
Riku Fagerlund ◽  
Andreas S. Baur ◽  
Kalle Saksela
Keyword(s):  
Antiretroviral Therapy ◽  
Extracellular Vesicles ◽  
Protein Secretion ◽  
Immune Activation ◽  
Kinase Inhibitors ◽  
Mapk Pathway ◽  
Protein Kinase Inhibitors ◽  
Chronic Immune Activation ◽  
Cd4 Lymphocyte ◽  
Hiv 1

Chronic immune activation is an important driver of HIV-1 pathogenesis, and has been associated with the presence of tumor necrosis factor-α converting enzyme (TACE) in extracellular vesicles (EV) circulating in infected individuals. We have recently shown that activation of the Src-family tyrosine kinase Hck by HIV-1 Nef can trigger the packaging of TACE into EVs via an unconventional protein secretion pathway. Using a panel of HIV-1 Nef mutants and natural HIV-2 and SIV Nef alleles we now show that the capacity to promote TACE secretion depends on the superior ability of HIV-1-like Nef alleles to induce Hck kinase activity, whereas other Nef effector functions are dispensable. Strikingly, among the numerous Src-family downstream effectors, serine/threonine kinase Raf-1 was found to be necessary and alone sufficient to trigger secretion of TACE into EVs. These data reveal the involvement of Raf-1 in regulation of unconventional protein secretion, and highlight the importance of Raf-1 as a cellular effector of Nef, thereby suggesting a novel rationale for testing pharmacological inhibitors of the Raf-MAPK pathway to treat HIV-associated immune activation. IMPORTANCE Chronic immune activation contributes to the immunopathogenesis of HIV-1 infection, and is associated with poor recovery of the immune system despite potent antiretroviral therapy, which is observed in 10-40% drug-treated patients depending on the definition of immune reconstitution. We have previously shown that the HIV pathogenicity factor Nef can promote loading of the proinflammatory protease TACE into extracellular vesicles (EV), and the levels of such TACE-containing EVs circulating in the blood correlate with low CD4 lymphocyte counts in HIV patients receiving antiretroviral therapy. Here we show that Nef promotes uploading of TACE into EVs by triggering unconventional secretion via activation of the Hck/Raf/MAPK kinase cascade. We find that several pharmaceutical inhibitors of these kinases that are currently in clinical use for other diseases can potently suppress this pathogenic deregulation, and could thus provide a novel strategy for treating HIV-associated immune activation.

scholarly journals Short Intracellular HIV-1 Transcripts as Biomarkers of Residual Immune Activation in Patients on Antiretroviral Therapy

2016 ◽  
Vol 90 (12) ◽  
pp. 5665-5676 ◽  
Author(s):  
Aya Ishizaka ◽  
Hidenori Sato ◽  
Hitomi Nakamura ◽  
Michiko Koga ◽  
Tadashi Kikuchi ◽  
...  
Keyword(s):  
Antiretroviral Therapy ◽  
Immune Activation ◽  
Viral Suppression ◽  
Immune Status ◽  
Viral Persistence ◽  
Chronic Immune Activation ◽  
Viral Reservoirs ◽  
Increased Risk ◽  
Infected Cells ◽  
Hiv 1

ABSTRACTHIV-1 patients continue to remain at an abnormal immune status despite prolonged combination antiretroviral therapy (cART), which results in an increased risk of non-AIDS-related diseases. Given the growing recognition of the importance of understanding and controlling the residual virus in patients, additional virological markers to monitor infected cells are required. However, viral replication in circulating cells is much poorer than that in lymph nodes, which results in the absence of markers to distinguish these cells from uninfected cells in the blood. In this study, we identified prematurely terminated short HIV-1 transcripts (STs) in peripheral blood mononuclear cells (PBMCs) as an efficient intracellular biomarker to monitor viral activation and immune status in patients with cART-mediated full viral suppression in plasma. STs were detected in PBMCs obtained from both treated and untreated patients. ST levels in untreated patients generally increased with disease progression and decreased after treatment initiation. However, some patients exhibited sustained high levels of ST and low CD4+cell counts despite full viral suppression by treatment. The levels of STs strongly reflected chronic immune activation defined by coexpression of HLA-DR and CD38 on CD8+T cells, rather than circulating proviral load. These observations represent evidence for a relationship between viral persistence and host immune activation, which in turn results in the suboptimal increase in CD4+cells despite suppressive antiretroviral therapy. This cell-based measurement of viral persistence contributes to an improved understanding of the dynamics of viral persistence in cART patients and will guide therapeutic approaches targeting viral reservoirs.IMPORTANCECombination antiretroviral therapy (cART) suppresses HIV-1 load to below the detectable limit in plasma. However, the virus persists, and patients remain at an abnormal immune status, which results in an increased risk of non-AIDS-related complications. To achieve a functional cure for HIV-1 infection, activities of viral reservoirs must be quantified and monitored. However, latently infected cells are difficult to be monitored. Here, we identified prematurely terminated short HIV-1 transcripts (STs) as an efficient biomarker for monitoring viral activation and immune status in patients with cART-mediated full viral suppression in plasma. This cell-based measurement of viral persistence will contribute to our understanding of the impact of residual virus on chronic immune activation in HIV-1 patients during cART.

scholarly journals High Levels of Chronic Immune Activation in the T-Cell Compartments of Patients Coinfected with Hepatitis C Virus and Human Immunodeficiency Virus Type 1 and on Highly Active Antiretroviral Therapy Are Reverted by Alpha Interferon and Ribavirin Treatment

2009 ◽  
Vol 83 (21) ◽  
pp. 11407-11411 ◽  
Author(s):  
Veronica D. Gonzalez ◽  
Karolin Falconer ◽  
Kim G. Blom ◽  
Olle Reichard ◽  
Birgitte Mørn ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cells ◽  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Antiretroviral Therapy ◽  
Immune Activation ◽  
Chronic Immune Activation ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT Chronic immune activation is a driver of human immunodeficiency virus type 1 (HIV-1) disease progression. Here, we describe that subjects with chronic hepatitis C virus (HCV)/HIV-1 coinfection display sharply elevated immune activation as determined by CD38 expression in T cells. This occurs, despite effective antiretroviral therapy, in both CD8 and CD4 T cells and is more pronounced than in the appropriate monoinfected control groups. Interestingly, the suppression of HCV by pegylated alpha interferon and ribavirin treatment reduces activation. High HCV loads and elevated levels of chronic immune activation may contribute to the high rates of viral disease progression observed in HCV/HIV-1-coinfected patients.

scholarly journals Human Endogenous Retrovirus Expression Is Inversely Associated with Chronic Immune Activation in HIV-1 Infection

PLoS ONE ◽  
2012 ◽  
Vol 7 (8) ◽  
pp. e41021 ◽  
Author(s):  
Christopher E. Ormsby ◽  
Devi SenGupta ◽  
Ravi Tandon ◽  
Steven G. Deeks ◽  
Jeffrey N. Martin ◽  
...  
Keyword(s):  
Immune Activation ◽  
Endogenous Retrovirus ◽  
Human Endogenous Retrovirus ◽  
Chronic Immune Activation ◽  
Hiv 1

Low Haemoglobin in Haemophilia Children Is Associated with Chronic Immune Activation

1991 ◽  
Vol 85 (2) ◽  
pp. 62-65 ◽  
Author(s):  
Dietmar Fuchs ◽  
Gilbert Reibnegger ◽  
Ernst Werner ◽  
Helmut Vinazzer ◽  
Helmut Wachter
Keyword(s):  
Immune Activation ◽  
Chronic Immune Activation

Chronic Immune Activation After Sirolimus Conversion in Kidney Transplant Recipients.

2014 ◽  
Vol 98 ◽  
pp. 112-113 ◽  
Author(s):  
L. Gallon ◽  
R. Gehrau ◽  
J. Leventhal ◽  
M. Ansari ◽  
L. Xu ◽  
...  
Keyword(s):  
Kidney Transplant ◽  
Immune Activation ◽  
Chronic Immune Activation ◽  
Transplant Recipients ◽  
Kidney Transplant Recipients
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