Modulation of Monocyte Activation and Function during Direct Antiviral Agent Treatment in Patients Coinfected with HIV and Hepatitis C Virus

Abstract

BACKGROUND: The activation phenotype and functional changes in monocyte subsets during HCV elimination in HIV/HCV-coinfected patients were evaluated. METHODS: 22 HIV/HCV-coinfected patients on suppressive combination antiretroviral treatment (cART) achieving HCV elimination after direct-acting antivirals (DAAs) therapy and 10 HIV-monoinfected patients were included. Activation phenotype (10 markers) and polyfunctionality (intracellular IL1α, IL1β, IL6, IL8, TNFα and IL10 production) in three monocyte subsets (classical, intermediate and nonclassical) were evaluated by flow cytometry before and at the end of treatment. Cell-associated HIV-DNA levels were assayed by droplet digital PCR. RESULTS: After HCV clearance there was a significant increase in classical monocytes and a decrease in intermediate and nonclassical monocytes levels. The activation markers, CD49d, CD40, CX3CR1, decreased after treatment in the monocyte subsets reaching the levels of HIV-monoinfected patients. After LPS stimulation, although polyfunctionality significantly decreased in intermediate and nonclassical monocytes, some combinations such as IL1α-IL1β-IL6+IL8-TNFα-IL10- were remarkably increased at the end of treatment compared to the control group. Cell-associated HIV-DNA levels correlated with activation markers before but not after treatment. CONCLUSIONS: HCV clearance after DAAs treatment in patients on cART exerts an anti-inflammatory profile in monocyte subsets, activation phenotypes and polyfunctionality. However, there is not a complete normalization compared with HIV-monoinfected patients.

HIV-reservoir size is not affected either by HCV coinfection or by direct acting antivirals (DAAs) therapy

“…Secondly, the results of our longitudinal study revealed that HIV-DNA content did not significantly change after HCV eradication, what reinforces the conclusion of our cross-sectional study. The results of our longitudinal study are also in agreement with most previous studies analyzing the evolution of HIV-DNA content after HCV eradication with anti-HCV therapies based on DAAs 7 , 8 , 10 , 11 . In contrast, one study found a significant decrease of HIV-DNA level in HIV/HCV-coinfected patients after HCV eradication 9 .…”

“…This discrepancy could be found in the different cohorts of patients included; the different levels of inflammation and liver fibrosis in the studied patients; the different cell populations used to assess the HIV reservoir; and the different methodologies used to measure the HIV reservoir. Interestingly, our current results (using a very homogeneous cohort of HIV/HCV-coinfected and HIV monoinfected patients with paired parameters and with strict selection criteria; in addition, the use of a highly precise and reproducible methodology to measure the HIV reservoir, as well as the use of a highly purified population of CD4 + T cell) are in agreement with previous 5 and more recent 11 cross-sectional studies in different cohorts of HIV/HCV-coinfected and HIV-monoinfected patients under cART 5 , 11 . Thus, the results of our current cross-sectional study demonstrate that presence of HCV coinfection do not significantly impact on the HIV reservoir size in HIV patients with successful cART.…”

“…Some studies have explored the role of HCV on the HIV reservoir size, but with contradictory results 5 – 12 . In a previous cross-sectional study, we found increased levels of proviral HIV-DNA in HIV/HCV-coinfected patients compared to HIV-monoinfected 12 , but other cross-sectional studies have found opposite results also measuring proviral HIV-DNA, or 2 LTR circles 5 , or total HIV-DNA content 5 , 11 . Interestingly, in longitudinal studies, the evolution of HIV reservoir size after HCV eradication also remains a controversial issue 5 – 11 .…”

“…In a previous cross-sectional study, we found increased levels of proviral HIV-DNA in HIV/HCV-coinfected patients compared to HIV-monoinfected 12 , but other cross-sectional studies have found opposite results also measuring proviral HIV-DNA, or 2 LTR circles 5 , or total HIV-DNA content 5 , 11 . Interestingly, in longitudinal studies, the evolution of HIV reservoir size after HCV eradication also remains a controversial issue 5 – 11 . The variation of HIV-DNA content after anti-HCV treatment with IFN-based regimens could be mediated by the immunomodulatory effects of IFNα and not necessarily to HCV clearance 5 , 6 .…”

“…Given that the current scenario of Direct-Acting Antivirals (DAAs) regimens against HCV is free of IFNα, it is possible to test the direct effect of HCV eradication on the HIV reservoir. A few studies so far have tried to elucidate the role of DAAs in this issue 7 – 11 ; however, no one have excluded patients with previous history of HCV therapy 7 – 11 ; and most of them have evaluated the impact of DAAs but with RBV 7 – 10 .…”