CpG Suppression in HIV-1 Versus HIV-2: Correlation with Pathogenicity and Possible Implications for the Design of Antiretroviral Vaccines

Abstract

The remarkable process by which a single cell, a fertilized egg, develops into an adult human being with more than 200 different cell types relies on the ability of cells to control gene expression. In every human cell there are within the chromosomes approximately 100,000 genes. Yet, each specialized cell of the human body usually expresses only a small subset of these 100,000 genes. Unless something goes wrong, most genes are switched off. DNA methylation represents a major mechanism by which cells undergo such selective gene silencing (Sager and Kitchin 1975). In animal cells, virtually all of this methylation occurs in CpG dinucleotides, and methylation of specific CpG dinucleotides is associated with transcriptional inactivation in many genes.

The use of DNA methylation in the control of gene expression in vertebrate cells must provide strong advantages, for it is not without its consequences. One such evolutionary consequence of DNA methylation in vertebrate cells results from the “spontaneous” deamination of methylated cytosines, creating thymidine. This results, over long evolutionary periods, in CpG suppression, the replacement of methylated CpG dinucleotides in vertebrate DNA with their deamination product TpG. CpG dinucleotides in the DNA of higher vertebrates thus occur at a frequency of about 1% of all dinucleotides, compared to an expected frequency of 4% based on G + C content (Cedar 1984).

This propensity for 5-methylcytosine to undergo deamination has severe consequences for human health. A large percentage of mutations in cancer and other diseases can be traced to replacement of 5-methylcytosine with...