Methylation of human papillomavirus genomes in cells of anal epithelia of HIV-infected men.
Intra-anal malignancies disproportionately affect individuals who engage in anal intercourse because of infection with human papillomaviruses (HPVs), with an increased risk attributed to infection with HIV because of a declining immunity against HPVs. Long-term persistence of HPVs suggests yet other mechanisms that determine the clinical outcome, however. Because methylation of HPV DNA represses oncogene expression in cervical samples, we investigated whether this mechanism also occurs in HIV-positive men and studied the methylation of CpG dinucleotides overlapping with the HPV-16 enhancer and promoter in 16 anal samples. Similar to cervical infections, the average methylation frequency was 12.3%, with heterogeneities between clones from different and the same samples. In low-grade anal intraepithelial neoplasia (AIN), methylation was high in CpGs overlapping the viral enhancer but rare in promoter positions, whereas methylation was high in promoter regions in high-grade AIN, especially in samples with a high load of viral genomes. The viral replication origin was never methylated. We also detected de novo methylation at methylated (me) CpA, meCpT, and meCpC dinucleotides. Our study expands the observation and mapping of HPV DNA methylation to anal infections and the HIV-positive patient population. As observed at the cervix, DNA methylation may force HPVs into latency with functional replication but repressed transcription. Escape from this repression is a prerequisite for neoplastic progression; however, methylation resumes because of chromosomal integration of HPV genomes but spares some HPV genomes in each cell that maintain the transformed phenotype. DNA methylation, taken together with virus load, may be useful to diagnose the emergence of a population of tumor cells.
Wiley
Dorothy J
DJ
School of Nursing, University of California Los Angeles, Los Angeles, CA, USA.
Huh
John
J
Rao
Jian Yu
JY
Chang
Christopher
C
Goetz
Matthew
M
Poulter
Melinda
M
Masongsong
Emmanuel
E
Chang
Ching I
CI
Bernard
Hans-Ulrich
HU
D001003:Anal Canal / Q000821:virology; D001483:Base Sequence; D001706:Biopsy; D019175:DNA Methylation; D017931:DNA Primers; D004279:DNA, Viral / Q000235:genetics / Q000302:isolation & purification; D015226:Dinucleoside Phosphates / Q000032:analysis; D004742:Enhancer Elements, Genetic; D016679:Genome, Viral; D015658:HIV Infections / Q000150:complications*; D018451:Homosexuality, Male; D006801:Humans; D007413:Intestinal Mucosa / Q000473:pathology / Q000821:virology*; D008297:Male; D027383:Papillomaviridae / Q000235:genetics*; D016133:Polymerase Chain Reaction; D017735:Virus Latency; D014779:Virus Replication
D017931:DNA Primers; D004279:DNA, Viral; D015226:Dinucleoside Phosphates; C015772:CpG dinucleotide