Vaccinia virus (VACV) intracellular enveloped virus (IEV) particles are transported to the cell periphery on microtubules where they fuse with the plasma membrane to form cell-associated enveloped virus (CEV). Two IEV-specific proteins, F12L and A36R, are implicated in mediating transport of IEV. Without F12L, virus morphogenesis halts after formation of IEV, and CEV is not formed, whereas without A36R, IEV was reported not to be transported, yet CEV was formed, To address the roles of A36R and F12L in IEV transport, viruses with deletions of either F12L (vDF12L) or A36R (vDA36R) were labelled with enhanced green fluorescent protein (EGFP) fused to the core protein A5L, and used to follow CEV production with time. Without F12L, CEV production was inhibited by >99 %, whereas without A36R, CEV were produced at~60 % of wild-type levels at 24 h post-infection. Depolymerization of microtubules, but not actin, inhibited CEV formation in vDA36R-infected cells. Moreover, vDA36R IEV labelled with EGFP fused to the B5R protein co-localized with microtubules, showing that the A36R protein is not required for the interaction of IEV with microtubules. Time-lapse confocal microscopy confirmed that both wild-type and vDA36R IEV moved in a stop-start manner at speeds consistent with microtubular movement, although the mean length of vDA36R IEV movement was shorter. These data demonstrate that VACV IEV is transported to the cell surface using microtubules in the absence of A36R, and therefore IEV must attach to microtubule motors using at least one protein other than A36R.
Hepatitis C virus (HCV) RNA loads are measured sporadically in HCV-positive individuals. However, the prognostic value of these isolated measurements for predicting progression to acquired immune deficiency syndrome (AIDS) and all-cause mortality in coinfected individuals remains unclear. In this study, the prognostic value of a single HCV RNA load measurement taken early after human immunodeficiency virus (HIV) seroconversion was investigated in a cohort of 96 male patients with inherited bleeding disorders. Dates of HIV seroconversion had been estimated for all patients, and at least 4 HCV RNA load measurements per patient were done retrospectively after HIV seroconversion. HCV RNA load stabilized at 4 years after HIV seroconversion, and this point was used for analysis. There was a significant correlation between increased age and early HCV RNA load (r=0.25; P=.01). Adjusting for HIV RNA levels, CD4 cell counts, and the age effect, HCV RNA load >5.90 log(10) copies/mL was predictive of progression to AIDS and all-cause mortality over a period of at least 15 years.
Little is known about the natural history of hepatitis C virus (HCV) RNA concentrations over the course of infection. The aim of this study was to describe the natural history of HCV RNA concentrations in 85 HIV negative men with bleeding disorders infected with HCV for up to 30 years. HCV RNA concentrations were measured in yearly serum samples using a branched DNA assay. HCV RNA concentrations increased over time in this cohort. Two years after exposure to HCV, 53% of patients had undetectable concentrations and no patients had levels >7 log(10)(genome Eq/ml); by 20 years, these proportions had changed to 23% and 32% respectively. The RNA concentration correlated strongly with alanine aminotransferase (ALT; correlations of 0.41-0.71 depending on stage of infection) and aspartate aminotransferase (AST; 0.20-0.51) levels. Patients with haemophilia A had significantly higher HCV concentrations than those with other disorders. An effect of HCV genotype on HCV RNA concentrations became nonsignificant after excluding patients who were persistently HCV PCR negative and who could not be genotyped. The correlation of HCV RNA concentrations with other markers of liver function, such as ALT, means that studies with clinical outcomes are required to assess whether HCV RNA concentrations provide additional prognostic information to that provided by these other markers.
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