Abstract
HIV/HCV coinfected individuals under highly active antiretroviral therapy (HAART) represent an interesting model for the investigation of the role played by the immune system in driving the evolution of the HCV quasispecies. We prospectively studied the intra-host evolution of the HCV heterogeneity in 8 coinfected subjects, selected from a cohort of 32 patients initiating HAART: 5 immunological responders (group A) and 3 immunological non-responders (group B), and in two HCV singly infected controls not assuming drugs (group C). For all these subjects at least two serial samples obtained at the first observation (before HAART) and more than 1 year later, underwent clonal sequence analysis of partial E1/E2 sequences, encompassing the whole HVR1. Evolutionary rates, dated phylogenies and population dynamics were co-estimated by using a Bayesian Markov Chain Monte Carlo approach, and site specific selection pressures were estimated by maximum likelihood-based methods. The intra-host evolutionary rates of HCV quasispecies was 10 times higher in subjects treated with HAART than in controls without immunodeficiency (1.9 and 2.3×10−3 sub/site/month in group A and B and 0.29×10−3 sub/site/month in group C individuals). The within-host Bayesian Skyline plot analysis showed an exponential growth of the quasispecies populations in immunological responders, coinciding with a peak in CD4 cell counts. On the contrary, quasispecies population remained constant in group B and in group C controls. A significant positive selection pressure was detected in a half of the patients under HAART and in none of the group C controls. Several sites under significant positive selection were described, mainly included in the HVR1. Our data indicate that different forces, in addition to the selection pressure, drive an exceptionally fast evolution of HCV during HAART immune restoration. We hypothesize that an important role is played by the enlargement of the viral replicative space.
Highlights
Hepatitis C virus is an RNA virus infecting more than 170 million people throughout the world
In order to investigate the forces acting on the evolution of HCV QS during highly active antiretroviral therapy (HAART) and clarify the effect of a restored immune response on viral diversification, we studied the within-host dynamics of the QS populations in a subgroup of these showing an immunological response to HAART or not
Studies of the impact of HAART on liver disease in patients with HIV/HCV coinfection generally suggested its beneficial effect on the progression of fibrosis [34,35], but an uncommon increase in transaminase levels accompanied by higher HCV viremia levels was reported [36,37]
Summary
Hepatitis C virus is an RNA virus infecting more than 170 million people throughout the world. Patients with HIV/ HCV coinfection represent a fruitful setting for studying the role played by the immune response in the heterogeneity of HCV QS as it is generally accepted that immunosuppression is associated to a reduced HCV QS complexity [7,8]. Some authors have suggested a correlation between the increase of CD4 cell counts during therapy and the heterogeneity of HCV quasispecies population [10,11,12], but other authors did not observe significant relationships between HCV heterogeneity and CD4+ cell numbers, suggesting that changes in T-cell functions caused by HAART may play a role in conditioning the evolution of HCV QS [13,14]
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