Reply to Hisada et al.

    University of California, San Francisco, and Blood Systems Research Institute, San Francisco

    Hisada et al. [1] provide interesting data that support the major finding of the recently published study [2] by my colleagues and me but that do not support some minor findings. Both studies analyzed cross-sectional data from prevalent cohorts and found that proviral load was up to 1 log10 higher in human T lymphotropic virus (HTLV)I carriers than in HTLV-II carriers. Replication of this finding strengthens the conclusion that the magnitude of proviral load may explain the differences in pathogenesis between the 2 retrovirusesdifferences that exist despite the similar genetic sequences of the viruses. It may also explain why both serologic and nucleic-acid assays are less sensitive for HTLV-II than for HTLV-I, a matter that has been only partially addressed by the blood bank community [35]. It would be interesting if Hisada et al. could perform HTLV-II subtyping for their cohort, to test the finding reported by my colleagues and me of a higher proviral load in persons infected with HTLV-II subtype A than in persons infected with HTLV-II subtype B.

    Despite the use by both studies of primers directed at tax gene sequences that are conserved between HTLV-I and HTLV-II, the 1 log10 higher mean proviral loads in Hisada et al.'s study (7-fold for the HTLV-II carriers and 14-fold for the HTLV-I carriers) are most likely the result of technical differences in the quantitative polymerase chain reaction assays used. Testing of shared reagents and reference standards by these and other laboratories, as proposed recently during a workshop at the 11th International Conference on Human Retrovirology: HTLV and Related Viruses [6], may resolve these differences. Alternatively, differences in the subjects studied, such as differences in lymphocyte subsets or intensity of injection drug use, may explain the differences in mean proviral load between the 2 studies.

    Again in contrast to the findings reported by my colleagues and mein this instance of a lower HTLV-II proviral load in women [2]Hisada et al. found no difference in HTLV-II proviral load by sex. We had postulated that a lower proviral load in our female subjects could have been related to a smaller quantity of infectious inoculum received during sexual acquisition of HTLV-II. If this hypothesis is correct, then the preponderance of injection drug use among both male and female members of Hisada et al.'s cohort could have overwhelmed any effect of sexual acquisition. The presumptively larger quantity of HTLV-II inoculum acquired during injection drug useassociated infection would have resulted in a higher proviral load set point in both men and women.

    Taken together, these 2 studies suggest that HTLV-II proviral load is related to both viral (HTLV type and subtype) and host (mode of acquisition, demographics, and immune response) characteristics. Additional research is needed to refine these hypotheses. Prospective studies will be particularly useful in disentangling the viral- and host-specific determinants of proviral load in HTLV carriers.

    References

    1.  Hisada M, Miley WJ, Biggar RJ. Provirus load is lower in human T lymphotropic virus (HTLV)II carriers than in HTLV-I carriers: a key difference in viral pathogenesis J Infect Dis 2005; 191:13824 (in this issue). First citation in article

    2.  Murphy EL, Lee TH, Chafets D, et al. Higher human T lymphotropic virus (HTLV) provirus load is associated with HTLV-I versus HTLV-II, with HTLV-II subtype A versus B, and with male sex and a history of blood transfusion. J Infect Dis 2004; 190:50410. First citation in article

    3.  Liu H, Shah M, Stramer SL, Chen W, Weiblen BJ, Murphy EL. Sensitivity and specificity of human T-lymphotropic virus (HTLV) types I and II polymerase chain reaction and several serologic assays in screening a population with a high prevalence of HTLV-II. Transfusion 1999; 39:118593. First citation in article

    4.  Poiesz BJ, Dube S, Choi D, et al. Comparative performances of an HTLV-I/II EIA and other serologic and PCR assays on samples from persons at risk for HTLV-II infection. Transfusion 2000; 40:92430. First citation in article

    5.  Thorstensson R, Albert J, Andersson S. Strategies for diagnosis of HTLV-I and -II. Transfusion 2002; 42:78091. First citation in article

    6.  Abstracts of the 11th International Conference on Human Retrovirology: HTLV and Related Viruses. 912 June 2003. San Francisco, CA. AIDS Res Hum Retroviruses 2003; 19(Suppl):S781. First citation in article

    7.  Nagai M, Usuku K, Matsumoto W, et al. Analysis of HTLV-I proviral load in 202 HAM/TSP patients and 243 asymptomatic HTLV-I carriers: high proviral load strongly predisposes to HAM/TSP. J Neurovirol 1998; 4:58693. First citation in article

    8.  Etoh K, Yamaguchi K, Tokudome S, et al. Rapid quantification of HTLV-I provirus load: detection of monoclonal proliferation of HTLV-Iinfected cells among blood donors. Int J Cancer 1999; 81:85964. First citation in article

    9.  Taylor GP, Tosswill JH, Matutes E, et al. Prospective study of HTLV-I infection in an initially asymptomatic cohort. J Acquir Immune Defic Syndr 1999; 22:92100. First citation in article

    10.  Manns A, Miley WJ, Wilks RJ, et al. Quantitative proviral DNA and antibody levels in the natural history of HTLV-I infection. J Infect Dis 1999; 180:148793. First citation in article