Immunity in Chimpanzees Chronically Infected with Hepatitis C Virus: Role of Minor Quasispecies in Reinfection

Abstract

We have previously reported that chimpanzees chronically infected with hepatitis C virus (HCV) could be reinfected, even with the original infecting strain. In this study we tested the hypothesis that this might reflect the presence of minor quasispecies to which there was little or no immunity. To evaluate this hypothesis, we sequenced multiple clones taken at intervals after primary infection and rechallenge from four chronically infected chimpanzees. The inoculum used in these studies (HCV-H, genotype 1a) revealed 17 separate variants among 46 clones sequenced. Following challenge, each of the four challenged animals showed marked alterations of their quasispecies distribution. The new variants, which appeared 1 to 6 weeks after challenge, were either identical to or closely resembled variants present in the challenge inoculum. These results, paralleled by an increase in viremia in some of the challenged animals, suggest that quasispecies in the challenge inoculum were responsible for signs of reinfection and that there was little immunity. However, the newly emerged quasispecies completely took over infection in only one animal. In the remaining three chimpanzees the prechallenge quasispecies were able to persist. The natural evolution of infection within chimpanzees resulted in variants able to compete with the inoculum variants. Whether through reexposure or the natural progression of infection, newly emerged quasispecies are likely to play a role in the pathogenesis of chronic HCV infection.

Memory in Retroviral Quasispecies: Experimental Evidence and Theoretical Model for Human Immunodeficiency Virus

“…9,31,44 -46 For retroviruses such as HIV-1, the level of complexity of the replicating quasispecies at any one time is expected to be greater than for non-retroviral riboviruses because proviral sequences (maintained with the minimal occurence of point mutations associated with cellular genes) 13 can be activated to perturb the dynamics of replicating retroviral particles. Evidence of re-emergence of ancestral viral sequences was previously obtained for HIV-1, 19,21,47 hepatitis C virus 48 and hepatitis B virus 49 (review by Domingo et al 3 ).…”

Viruses as Quasispecies: Biological Implications

“…(Based on Domingo 2000, with permission) integration of proviral DNA in cellular DNA, which results in reservoirs that may re-emerge at a later stage of infection Briones et al, personal communication). Reemergence (or raise to dominance) of ancestral (minority) genomes in vivo has been documented with several viral infections (Borrow et al 1997;Wyatt et al 1998;Karlsson et al 1999;Briones et al 2000;Lau et al 2000;García-Lerma et al 2001;Imamichi et al 2001;Kijak et al 2002;Charpentier et al 2004), providing additional support for the concept of memory in viruses both in cell culture and in vivo.…”

HCV selection and HVR1 evolution in a chimpanzee chronically infected with HCV‐1 over 12 years

“…This result suggests that the chimpanzee selected a minor strain of the virus for persistent HCV infection, which is consistent with the bottle-neck theory of viral transmission. 53 An alternative explanation is that the undetected mixed subtype HCV infection increased the genetic variation of the original virus strain. 52,54,55 Mixed infection with distinct viral strains from the same subtype may also induce an increase in genetic variation.…”