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Little is known about the in vivo development of resistance to human immunodeficiency virus type 1 (HIV-1) CCR5 antagonists. We studied 29 subjects with virologic failure from a phase IIb study of the CCR5 antagonist vicriviroc (VCV) and identified one individual with HIV-1 subtype C who developed VCV resistance. Studies with chimeric envelopes demonstrated that changes within the V3 loop were sufficient to confer VCV resistance. Resistant virus showed VCV-enhanced replication, cross-resistance to another CCR5 antagonist, TAK779, and increased sensitivity to aminooxypentane-RANTES and the CCR5 monoclonal antibody HGS004. Pretreatment V3 loop sequences reemerged following VCV discontinuation, implying that VCV resistance has associated fitness costs.The human immunodeficiency virus type 1 (HIV-1) envelope third variable loop (V3) is the major structural element of gp120 that determines coreceptor recognition and specificity (9,15,16). Vicriviroc (VCV; Schering-Plough) and maraviroc (Selzentry; Pfizer) are allosteric noncompetitive antagonists that bind to similar sites on CCR5 and antagonize the gp120-CCR5 interaction (19). To date, data on resistance to these agents have come largely from in vitro selection studies. Phenotypically, resistance manifests as a plateau in the maximum achievable suppression of viral replication (19). This plateau, referred to as the percent maximal inhibition, correlates with viral adaptation to the use of the inhibitor-bound form of CCR5 for entry (13,21). Genotypically, VCV resistance has been associated with a variety of amino-acid-changing mutations throughout the envelope gene (env) that most often involve V3 but whose effect on drug susceptibility depends on the env backbone into which they are introduced (5). In vitro data suggest that resistance to the closely related CCR5 antagonist AD101 does not confer a significant loss of viral fitness (1, 8). In vivo resistance to the CCR5 antagonists remains poorly defined.To study the emergence of VCV resistance in vivo, we monitored subjects enrolled in ACTG 5211, a 48-week study of VCV in 118 HIV-1-infected, treatment-experienced subjects (3). Among the 90 subjects receiving VCV, we studied all 29 who experienced protocol-defined virologic failure. We amplified full-length HIV-1 env from plasma samples collected during the period from study entry through week 48. These env sequences were used to generate pseudovirions for examining VCV susceptibility and coreceptor usage in the PhenoSense entry susceptibility and Trofile assays (Monogram Biosciences), respectively (20,22). In 28 of 29 subjects analyzed, no evidence of decreased VCV susceptibility was observed (data not shown). Samples from the remaining subject demonstrated increasing VCV resistance over 28 weeks (Fig. 1). This subject, randomly assigned to receive 10 mg of VCV daily, experienced protocol-defined virologic failure at week 16 but continued VCV treatment through week 28 (see Fig. S1 in the supplemental material). Samples from 13 of the 29 subjects showed the emergence...

Hepatitis C virus (HCV) modulates intrahepatic cholesterol biosynthetic pathways to promote viral replication. Chronic HCV infection is associated with altered metabolism, including dyslipidemia and insulin resistance, which contributes to disease progression and influences response to therapy. To further understand the impact of HCV infection on host metabolism, we examined changes in serum lipid profiles and intrahepatic expression of lipid-related genes during interferon (IFN)-free treatment of chronic HCV, genotype-1 infection with sofosbuvir and ribavirin (RBV), and explored associations with treatment outcome. Serum lipids (total cholesterol, low density lipoprotein (LDL), high density lipoprotein (HDL), triglycerides) and hemoglobin A1C (HbA1C) were measured during treatment, while gene expression of lipid-related genes was assessed using paired pre- and end of treatment (EOT) liver biopsies from 8 patients (n=7 sustained virologic response (SVR), n=1 relapse) and unpaired EOT liver biopsies from 25 patients (n= 17 SVR, n=8 relapse). Serum LDL concentration and particle size increased early in therapy, while triglyceride concentration and very low density lipoprotein (VLDL) particle size decreased concomitantly, irrespective of treatment outcome. While LDL increased in patients regardless of treatment outcome, average LDL concentration was lower at baseline and post-treatment in patients who relapsed. Analysis of paired liver biopsies revealed altered expression of genes associated with lipid transport, assembly, and signaling. In unpaired EOT liver biopsies, intrahepatic expression of fatty acid metabolism and lipid transport genes was lower in patients who experienced treatment relapse. Conclusion Clearance of HCV using an IFN-free antiviral regimen results in rapid changes in peripheral and intrahepatic metabolic pathways, implicating a direct effect of HCV replication on lipid homeostasis.

The discovery of a novel HCV GT8 confirms the circulation of this newly identified lineage in the human population.

A decrease in hepatic collagen is the most prominently associated with improvement of PROs in NASH patients with F2-F3 treated with SEL. Furthermore, serum cytokines are associated with baseline PROs and with treatment-emergent changes in PROs in patients with NASH.