PubMed Health⌕ Search

PubMed · 15498589

Virus evolution within patients increases pathogenicity.

Abstract

Viruses like the human immunodeficiency virus (HIV), the hepatitis B virus (HBV), the hepatitis C virus (HCV) and many others undergo numerous rounds of inaccurate reproduction within an infected host. The resulting viral quasispecies is heterogeneous and sensitive to any selection pressure. Here we extend earlier work by showing that for a wide class of models describing the interaction between the virus population and the immune system, virus evolution has a well-defined direction toward increased pathogenicity. In particular, we study virus-induced impairment of the immune response and certain cross-reactive stimulation of specific immune responses. For eight different mathematical models, we show that virus evolution reduces the equilibrium abundance of uninfected cells and increases the rate at which uninfected cells are infected. Thus, in general, virus evolution makes things worse. An idea for combating HIV infection, however, is constructing a virus mutant that could outcompete the existing infection without being pathogenic itself.

Explore related subjects

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

Yoh Iwasa, Franziska Michor, Martin A Nowak. 2005-01-07. Virus evolution within patients increases pathogenicity.. https://doi.org/10.1016/j.jtbi.2004.07.016

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related citations

T-cell epitope repertoire as predicted from human and viral genomes.

During thymic education, strongly self-reactive T cells are selected against, while weakly self-reactive cells are positively selected. However, the probability of an antigen being self derived and the number of self-peptides have never been properly defined. We merge algorithms for: cleavage prediction, TAP binding probability estimates and MHC binding properties to estimate the number and distribution of all MHC binding peptides. We show that the number of self-peptides with a high affinity to a given human MHC-I molecule is between 200 and almost 200,000 and is much less than the estimated total number of peptide sequences. This result suggests that MHC molecules are selected through evolution in order to reduce the number of self-peptides presented. The number of viral peptides presented is also low and varies between zero and a few hundred per virus for a given HLA allele. These low numbers explain the need for multiple alleles within an individual. We show that six codominantly expressed MHC-I alleles are sufficient to present at least one or two peptides per virus for the vast majority of viruses. Viruses can escape detection either by using peptides that cannot be presented on MHC molecules or by using peptides whose presented segments overlap significantly with self. Most viral families (such as influenza, HIV, Hepatitis and HPV) present as many peptides as predicted from their genome length, and overlap minimally with the human self-peptide repertoire. However, a few latent viruses, such as herpes and adenovirus share considerable peptide sequence homology with their human hosts.

Antigens, Viral↗

Hypervariable region 1 variant acting as TCR antagonist affects hepatitis C virus-specific CD4+ T cell repertoire by favoring CD95-mediated apoptosis.

We have described previously that hypervariable region 1 (HVR1) variants of hepatitis C virus (HCV) frequently act as T cell receptor (TCR) antagonists for HVR1-specific helper T cells. These naturally occurring HVR1-antagonistic sequences interfered with the effects of HVR1-agonistic sequences such as TCR down-regulation and early activatory signals. By taking advantage of these findings, in this paper, we have analyzed the fate of these HVR1-specific antagonized CD4+ T cells. We present the evidence that TCR antagonism renders agonist-activated T cells susceptible to bystander CD95-mediated killing by suppressing the expression of cellular Fas-associated death domain-like interleukin-1beta-converting enzyme-like inhibitor proteins. To verify whether the TCR repertoire of a HVR1-specific T cell population could be modified consequently, we used a HVR1-agonistic sequence to induce in vitro CD4+ T cells and another HVR1 sequence with antagonistic property to mediate suppressive phenomena. HVR1-specific T cells were cultured with the agonist alone or with the agonist plus the antagonist. HVR1 specificity and T cell repertoires were followed over time by analyzing TCR beta-variable gene segment by "spectratyping". The results showed that the specificity for the agonist was rapidly spoiled after culture in the presence of the antagonist, and the TCR repertoire was strongly modified as a result of CD95-mediated apoptosis of agonist-specific clonal expansions. These data support the hypothesis that in HCV infection, the generation of TCR antagonists may reshape the T cell repertoire, representing an efficacious immune evasion strategy of a highly mutant pathogen.

Antigens, Viral↗