Carcinogenic HPV Variants Play the Race Card

SEATTLE, Aug. 2 -- The human papillomavirus has a long racial memory.

That's the conclusion of researchers here, who found that variants of two carcinogenic HPV types tend to linger longer in women whose ancestors came from the same geographic region where the viral variants first arose.

Many of the more than 100 known HPV types have viral isolates on the L1 gene that differ by less than 2% in the viruses' DNA sequence. These viral isolates are referred to as variants, and appear to be related to the geographic origin of the variant. Thus, there can be variants of any given HPV type that are associated with, say, African, European, or Asian ancestry.

African American women infected with HPV types 16 or 18, the two most closely associated with cervical cancer risk, tend to be infected with HPV variants that first cropped up in Africa, and white women tend to be infected with variants that first saw the light of day in Europe, reported Long Fu Xi, M.D., Ph.D., from the pathology department of the University of Washington here, and colleagues.

The investigators also found clues to natural immunity against HPV, noting that African American women who are infected with an European HPV variant tend to clear that variant from their bodies more rapidly, and that the virus tends to persist in the black women when it's a type of African origin, the investigators wrote in the Aug. 2 issue of the Journal of the National Cancer Institute.

"Given that women with persistent, compared with transient, HPV 16 or HPV 18 infections are at increased risk of cervical cancer, future studies should be conducted to examine possible mechanisms involving variant-specific immune evasion and their potential clinical and therapeutic implications," they wrote.

The investigators studied 1,114 women in the United States who were taking part in the Atypical Squamous Cells of Undetermined Significance/Low-Grade Squamous Intraepithelial Lesion Triage Study and who were positive for HPV 16 and/or HPV 18 at enrollment. The race of the women was determined by self-report.

The investigators characterized HPV samples by sequencing the virus' E6 gene and part of the long control region in order to determine which samples belonged to which group of established variants.

The women were tested with cervical cytology and HPV DNA typing every six months for two years.

The authors found that among 97 African-American women infected with HPV 18, about two-thirds (63.9%, 95% confidence interval, 53.5% to 73.4%) were infected with African variants. Similarly, among 168 white women with HPV 18 infections, 54.2% (95% CI, 46.3% to 61.9%) were infected with European variants.

Among 162 black women infected with HPV 16, about one-fourth (26.5%, 95% CI, 19.9% to 34.0%) were infected with viral types of African origin, whereas only 4.3% (95% CI, 2.8% to 6.3%) of 584 HPV 16-infected white women had viruses of African origin.

"The likelihood of remaining HPV 18 positive was statistically significantly higher in white women infected with European [variants] than in white women infected with African variants (P = 0.04); the reverse was observed in African American women (P = 0.03)," the authors wrote.

They found a similar pattern for persistence of HPV 16 variants - that is, the likelihood of remaining positive was higher for white women infected with a European variant, and lower for African-American women infected with a European variant compared with African-American women infected with African variants.

The evidence suggests that the differences in viral persistence and viral clearance patterns could be related to the virus' ability to adapt to host immunity, the investigators speculated, an idea supported by the authors of an accompanying editorial. But the editorialists also questioned the significance of the finding in light of other research suggesting that infections that cross racial lines may be more carcinogenic.

"The implication of these results is that variants of these highly pathogenic types of HPV have co-evolved with their host and that co-existence has selected for variants with increased duration of infectivity, a presumably selectable trait," wrote the editorialists, Robert D. Burk, M.D., of Albert Einstein Medical College, and Rob DeSalle, Ph.D., of the American Museum of Natural History, both in New York.

"Although these observations have intriguing biologic ramifications, the issue of clinical importance is whether there is an increased risk for cervical cancer associated with specific variants in individuals of a particular genotype, for which race is a surrogate," they continued.

But if infection with a geographically-related HPV type equates with longer clearance time and presumably greater risk for cervical cancer as suggested, that idea is not borne out by other studies showing the a stronger link between cancer and HPV 16 infection in white women carrying non-European variants, as well as greater risk for cancer among white women from Costa Rica and Mexico infected with non-European variants. Dr. Burk and Dr. DeSalle noted. Another study found that African women with cervical cancer were more commonly affected with a European variant of HPV 16.

"Thus, it appears that the HPVs that did not co-evolve with a specific race are more pathogenic," they wrote.