Effect of bottlenecking on evolution of the nonstructural protein 3 gene of hepatitis C virus during sexually transmitted acute resolving infection.
Sexual partners of patients infected with the hepatitis C virus (HCV) often have detectable HCV-specific T-cell responses in the absence of seroconversion, suggesting unapparent, spontaneously resolving infection. To determine whether differences in the evolutionary potential of bottlenecked inoculum may explain the low rate of HCV persistence after sexual exposure, we have investigated changes in the entire HCV nonstructural 3 (NS3) gene over time in a chronic carrier and compared his viral quasispecies with that of the acute-phase isolate of his sexual partner, who developed acute resolving hepatitis C. The overall rate of accumulation of mutations, estimated by regression analysis of six consecutive consensus NS3 sequences over 8 years, was 1.5 x 10(-3) mutations per site per year, with small intersample fluctuations related to changes in environmental conditions. Comparison of quasispecies parameters in one isolate of the chronic carrier with those of the acute-phase isolate of the infected partner revealed a higher heterogeneity and lower proportion of nonsynonymous mutations in the former. All NS3 sequences from the acute-phase isolate clustered with a single sequence from the chronic isolate, despite complete HLA mismatch between the patients, suggesting bottlenecking during transmission. The low risk of viral persistence after sexual exposure to HCV may be related to the selection of a limited number of viral particles carrying a particular combination of mutations which may further limit the potential of a relatively homogeneous quasispecies to rapidly diversify and overcome the immune response of the exposed host.
Quer
Josep
J
Liver Unit, Department of Internal Medicine, Hospital Universitari Vall d'Hebron, Pg Vall d'Hebron 119-129, 08035 Barcelona, Spain. jquer@ir.vhebron.net.
Esteban
Juan Ignacio
JI
Cos
Joan
J
Sauleda
Sílvia
S
Ocaña
Laura
L
Martell
María
M
Otero
Teresa
T
Cubero
Maria
M
Palou
Eduard
E
Murillo
Pedro
P
Esteban
Rafael
R
Guàrdia
Jaume
J
D000208:Acute Disease; D000328:Adult; D000595:Amino Acid Sequence; D019143:Evolution, Molecular; D005260:Female; D014644:Genetic Variation; D016174:Hepacivirus / Q000235:genetics / Q000502:physiology*; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D015229:Sexually Transmitted Diseases, Viral / Q000821:virology*; D017361:Viral Nonstructural Proteins / Q000235:genetics*; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases