Evolution of Hepatitis C Virus during mother-to-child transmission
Previous work in the laboratory of Dr. Christopher Walker at The Columbus
Children's Research Institute (CCRI, Columbus, OH) demonstrated that the
evolution of mutations in the Hepatitis C virus (HCV) accumulate within regions
of the virus that are recognized by cytotoxic T lymphocytes (CTL). These
immunogenic virus peptides are termed "epitopes" and are presented by infected
cells within major histocompatibility complexes (MHC molecules) on the cell
surface. These MHC molecules help the immune system recognize "self" from
"non-self" by displaying peptides from normal tissue ("self" which CTL ignore),
as well as foreign epitopes ("non-self" i.e. virus particles, which trigger CTL
to kill the infected cell).
These studies initially were done in an animal model, wherein the nucleotide
sequence of the virus and the MHC type of the animal is known. These studies
now are being extended into a human system, examining the evolution of HCV upon
transmission of the virus from mother to child (termed vertical transmission).
This is a relatively rare occurrence, and it allows Cawthon, Walker and
co-workers to examine and characterize the virus present in the mother, which
has adapted to "escape" the immune system by making changes in its nucleotide
sequence that code for protein epitopes that no longer bind the appropriate MHC
molecule (rendering the virus "invisible" to cytotoxic T lymphocytes). What
happens, however, when the virus passes to a newborn, which expresses only half
of the maternal MHC alleles, and has a "new" set of paternal MHC alleles, which
can select for new virus mutations? If a maternal allele that selected for a
mutation in the mother's virus is not passed on to the child, will the mutation
revert to wild type? If the child and the mother share an allele that selects
for a viral mutation, will that mutation remain intact in the child? Will new
mutations arise in response to the paternal alleles the child has
inherited, which the virus has never "seen"? The CCRI investigators are
attempting to answer these and other questions with the help of Willam
Hildebrand's lab, which is tissue-typing our mother/child pairs (identifying MHC
alleles), as well as the help of the OUHSC LGB DNA sequencing personnel, who are
performing sequencing reactions of hundreds of virus fragments that the CCRI
investigators are isolating from the plasma of our mother/child pairs. These
data will allow us to understand how HCV adapts upon vertical transmission, and
also how infants and young children respond to HCV infection acquired at birth.
