Provirus Load Is Lower in Human T Lymphotropic Virus (HTLV)–II Carriers than in HTLV‐I Carriers: A Key Difference in Viral Pathogenesis?

To the Editor—Human T lymphotropic virus (HTLV)–I and HTLV-II are closely related retroviruses [1]. In addition to HTLV-I–associated myelopathy (HAM), HTLV-I is associated with adult T cell leukemia (ATL). Some evidence suggests that HTLV-II may be associated with a HAM-like neuropathy [2], but the incidence of HTLV-II–associated neuropathy is low and its association with any malignancy is uncertain. Why the pathogenesis of HTLV-II disease differs from that of HTLV-I disease—despite high homologies of viral sequences—is unclear Provirus load, the amount of integrated virus in the host genome, is a correlate of HTLV-I disease pathogenesis. HTLV-I provirus loads are higher in patients with ATL or HAM than in asymptomatic carriers [1, 3]. Higher provirus load occurs because of greater viral replication and proliferation of HTLV-I–infected clones. Although the association between HTLV-II provirus load and disease pathogenesis is less well studied, a correlation between provirus load and clonal proliferation of HTLV-II–infected cells has been observed [4] In the 1 August 2004 issue of the Journal of Infectious Diseases Murphy et al. [5] reported that HTLV-I provirus load was higher than HTLV-II provirus load in US blood donors. In the study, HTLV-II provirus load was found to be unrelated to age but was higher in men than in women. In this letter, we confirm the finding of a significant difference in provirus load between HTLV-I and HTLV-II carriers Between 1983 and 1990, we recruited injection drug users from methadone maintenance treatment centers in 3 US metropolitan areas in New York, New Jersey, and Louisiana [6]. Cyropreserved peripheral-blood mononuclear cells (PBMCs) were available from 11 HTLV-I and 91 HTLV-II carriers, all of whom were HIV-1 negative. HTLV-I and HTLV-II provirus loads were quantitated by use of a real-time polymerase chain reaction (PCR) assay, with sequences from the tax gene used as a primer. This assay detects HTLV-I and HTLV-II provirus loads with equal sensitivity. For each sample, ∼1 μg of DNA was amplified for 45 cycles by use of AmpliTaq Gold polymerase with an ABI PRISM Sequence Detection System and TaqMan PCR Reagent (PE Applied Biosystems) [7]. Undetectable provirus load was assigned a value of 5 copies/1 × 105 PBMCs, the midpoint between 0 and the detection limit. The log10-transformed provirus loads in the HTLV-I and HTLV-II carriers were compared by the Kruskal-Wallis test. Age, sex, percentage of CD4-positive cells (hereafter, “CD4 percent”), and provirus detection were compared either by the χ2 test or by Fisher’s exact test The mean age and CD4 percent at the time of blood collection did not differ between the HTLV-I and HTLV-II carriers (table 1). Twenty-nine (31.9%) of the 91 HTLV-II carriers had undetectable provirus loads, compared with 2 (18.2%) of the 11 HTLV-I carriers (P=.50). The mean log10 provirus load was lower in the 91 HTLV-II carriers than in the 11 HTLV-I carriers (2.43 vs. 3.43 log10 copies/1 × 105 PBMCs; P=.01). The HTLV-I provirus load reported in our study, which corresponds to 2.7% of lymphocytes being infected, is consistent with what has been reported in asymptomatic HTLV-I carriers in other cohorts [8, 9] but is somewhat higher than the mean reported by Murphy et al. (3.28 log10 copies/1 × 106 PBMCs, which corresponds to 0.19% of lymphocytes being infected) Sex, age, provirus detection, and provirus load (mean, median, and range) in 102 US injection drug users, by human T lymphotropic virus (HTLV) type In contrast to Murphy et al.’s findings, HTLV-II provirus load was not significantly different in 32 men and 59 women in our cohort (2.31 vs. 2.65 log10 copies/1 × 105 PBMCs; P=.30). In a linear regression model in which sex was adjusted for, the mean HTLV-II provirus load decreased by 0.33 log10 copies/1 × 105 PBMCs (95% confidence interval, 0.01–0.65 log10 copies/1 × 105 PBMCs) per every 10-year increment in age (P=.04). HTLV-I provirus load was also similar in 8 men and 3 women (3.31 vs. 3.77 log10 copies/1 × 105 PBMCs; P=.68), but the small number of subjects limited our ability to further analyze the associations between HTLV-I provirus load and CD4 percent and age The discrepancies in the results of the 2 studies could be due to many factors, including differences in the characteristics of the study populations, such as route of infection and drug-use practices. Although the mean ages of the HTLV-II carriers in each study were similar, our population consisted entirely of injection drug users, whereas Murphy et al.’s population included subjects who did not use injection drugs. An association between older age and lower HTLV-II provirus load in our population is of interest. For HTLV-I carriers, HAM incidence appears to peak between 40 and 50 years of age and decreases thereafter. The age-specific incidence of HAM-like neuropathy in HTLV-II carriers has not been established In summary, the results of these 2 studies confirm that a finding of a higher provirus load in HTLV-I carriers than in HTLV-II carriers is not limited to a specific study population and is not a result of varying sensitivities of PCR assays. These findings support the possibility that a lower disease incidence in HTLV-II carriers than in HTLV-I carriers may be due to lower levels of HTLV-II provirus load