Viral commensalism in humans?

In this issue of the Journal, Matsumoto et al. [1] asked whether human T lymphotropic virus type 1 (HTLV-1) antibody status is associated with the risk of developing gastric cancer. In a cohort of 5000 patients aged 40 years who were enrolled during 1989 –1992 in an HTLV-1– endemic area, they identified 1812 subjects who underwent endoscopy of the upper gastrointestinal tract before 2003. Of those who were free of gastric cancer on that examination, 497 HTLV-1 antibody positive patients were selected and matched with 497 control patients who were HTLV-1 antibody negative. Both groups were followed for 9.5 years to determine who would develop gastric cancer. The major finding of the study was that gastric cancer developed less frequently among HTLV-1–positive subjects than among HTLV-1–negative subjects (2.8% vs. 7.0%). The findings are convincing because no sources of differential bias were obvious, the results confirm and are similar to those of a previous study [2], the time courses in KaplanMeier analysis are internally consistent, and the results for men and women were parallel with similar levels of inverse association (odds ratio, 0.38). Thus, the inverse association between HTLV-1 infection and development of gastric cancer that was uncovered in this prospective study should be considered correct. What do these findings mean? First, the findings may be flawed by confounders, but we could not find any. Second, it is possible that a preexisting host property that predisposes to HTLV-1 infection may lower the risk for gastric cancer development and that HTLV-1 positivity is just a marker for that host phenotype. Although this is plausible, there is no obvious mechanism to account for this possibility, especially when considering the transmission of HTLV-1 and the major gastric cancer–modifying agent, H. pylori. Third, HTLV-1 infection may offer protection against gastric cancer. If this is correct, what could be the protective mechanisms? To address this possibility, we must consider the relationship of HTLV-1 with H. pylori. We now know that gastric colonization with H. pylori, especially cagA-positive strains, is the major risk factor for typical (noncardia) gastric cancer [3], with attributable risk of 80%. Could there be an interaction between HTLV-1 and H. pylori? This study and several previous studies provide evidence that HTLV-1– positive hosts carry H. pylori less often than do HTLV-1-negative hosts [1, 4, 5]. Thus, one potential explanation is that the immunological context created by HTLV-1 is inhibitory to H. pylori. This explanation, although attractive, probably is not sufficient, because the size of the H. pylori positivity rate differences with respect to HTLV-1 status may not be sufficiently large to account for the magnitude of the inverse association. An alternative possibility is that the immunologic context provided by HTLV-1 alters the host-H. pylori interaction in a way that lessens the risk of oncogenesis. This could occur by reduction of the extent or distribution of gastric inflammatory responses to H. pylori or, possibly, of the progression of inflammation into atrophy and intestinal metaplasia. Since HTLV-1 is acquired early in life [1, 2], its acquisition could affect the milieu in which a subsequent H. pylori colonization takes root; a precedent for early life phenomena to affect H. pylori–associated risk of gastric cancer decades later recently has been reported [6]. The interactions of HTLV-1 and humans are complex. Only 0.1%–3% of HTLV-1 infections result in T cell leukemia. Most often infection is chronic and indolent with little viral replication, exceeded by larger amounts of latent, integrated provirus [7]. HTLV-1 infection also is associated with some degree of immunosuppression [8, 9], possibly because of its propensity to establish a clinically silent low-grade infection in T lymphocytes distorting cytokine production [10]. HTLV-1 also stimulates polyclonal activation of lymphocytes without infecting Received 25 February 2008; accepted 25 February 2008; electronically published 9 June 2008. Potential conflicts of interest: none reported. Financial support: National Institutes of Health (grant RO1 GM 63270) and Diane Belfer Program in Human and Microbial Ecology (to M.J.B.); grants P01 AI 057127 and P30 AI 027742 (to F.T.V.). Reprints or correspondence: Dr. Martin J. Blaser, Dept. of Medicine, NYU School of Medicine, 550 First Ave., OBV A606, New York, NY 10016 ([email protected]). The Journal of Infectious Diseases 2008; 198:1–3 © 2008 by the Infectious Diseases Society of America. All rights reserved. 0022-1899/2008/19801-0001$15.00 DOI: 10.1086/588705 E D I T O R I A L C O M M E N T A R Y