Selection pressure from neutralizing antibodies drives sequence evolution during acute infection with hepatitis C virus.
OBJECTIVE
Despite recent characterization of hepatitis C virus-specific neutralizing antibodies, it is not clear to what extent immune pressure from neutralizing antibodies drives viral sequence evolution in vivo. This lack of understanding is particularly evident in acute infection, the phase when elimination or persistence of viral replication is determined and during which the importance of the humoral immune response has been largely discounted.


METHODS
We analyzed envelope glycoprotein sequence evolution and neutralization of sequential autologous hepatitis C virus pseudoparticles in 8 individuals throughout acute infection.


RESULTS
Amino acid substitutions occurred throughout the envelope genes, primarily within the hypervariable region 1 of E2. When individualized pseudoparticles expressing sequential envelope sequences were used to measure neutralization by autologous sera, antibodies neutralizing earlier sequence variants were detected at earlier time points than antibodies neutralizing later variants, indicating clearance and evolution of viral variants in response to pressure from neutralizing antibodies. To demonstrate the effects of amino acid substitution on neutralization, site-directed mutagenesis of a pseudoparticle envelope sequence revealed amino acid substitutions in hypervariable region 1 that were responsible for a dramatic decrease in neutralization sensitivity over time. In addition, high-titer neutralizing antibodies peaked at the time of viral clearance in all spontaneous resolvers, whereas chronically evolving subjects displayed low-titer or absent neutralizing antibodies throughout early acute infection.


CONCLUSIONS
These findings indicate that, during acute hepatitis C virus infection in vivo, virus-specific neutralizing antibodies drive sequence evolution and, in some individuals, play a role in determining the outcome of infection.
Dowd
Kimberly A
KA
Department of Medicine, Johns Hopkins Medical Institutions, Baltimore, Maryland, USA.
Netski
Dale M
DM
Wang
Xiao-Hong
XH
Cox
Andrea L
AL
Ray
Stuart C
SC
D000208:Acute Disease; D000328:Adult; D000595:Amino Acid Sequence; D005260:Female; D016174:Hepacivirus / Q000235:genetics* / Q000276:immunology; D006526:Hepatitis C / Q000235:genetics* / Q000276:immunology; D018937:Hepatitis C Antibodies / Q000235:genetics* / Q000276:immunology / Q000502:physiology; D006801:Humans; D016014:Linear Models; D008297:Male; D016297:Mutagenesis, Site-Directed; D009500:Neutralization Tests; D011336:Probability; D012494:Sampling Studies; D012680:Sensitivity and Specificity; D014759:Viral Envelope Proteins / Q000235:genetics / Q000378:metabolism*; D014779:Virus Replication / Q000235:genetics; D055815:Young Adult
D018937:Hepatitis C Antibodies; D014759:Viral Envelope Proteins