Correspondence
More on HTLV tax and Mycosis Fungoides
N Engl J Med 1993; 329:2035-2036December 30, 1993
- Article
To the Editor:
Drs. Pancake and Zucker-Franklin (Aug. 19 issue)1 report that about two thirds of the patients with mycosis fungoides in their study appeared to be infected with human T-cell lymphotropic retrovirus type I or type II (HTLV-I or HTLV-II), since circulating mononuclear cells from these patients contained HTLV-related tax sequences. Instead of being widely distributed, these viruses and the diseases caused by them are more common in certain geographic areas and among certain populations2,3. We are not aware that mycosis fungoides has a similar epidemiologic pattern. Could the tax sequences present in circulating cells from many patients with mycosis fungoides be related to an unidentified retrovirus that does not exhibit the epidemiologic patterns of HTLV-I and HTLV-II?
3 ReferencesGeorge A. Youngberg, M.D.
Anand Karnad, M.D.
East Tennessee State University College of Medicine, Johnson City, TN 376141
Pancake BA ,Zucker-Franklin D . HTLV tax and mycosis fungoides. N Engl J Med 1993;329:580-580
Full Text | Web of Science | Medline2
Ito Y . The epidemiology of human T-cell leukemia/lymphoma virus. Curr Top Microbiol Immunol 1985;115:99-112
CrossRef | Web of Science | Medline3
Rosenblatt JD ,Plaeger-Marshall S ,Giorgi JV , et al. A clinical, hematologic, and immunologic analysis of 21 HTLV-II-infected intravenous drug users. Blood 1990;76:409-417
Web of Science | Medline
To the Editor:
Many of the patients with mycosis fungoides and HTLV-I or HTLV-II tax proviral sequences had weak responses to HTLV antibody when commercial reagents were used. These data, although preliminary and controversial,1,2 may raise questions for people identified as seropositive for HTLV-I or HTLV-II, particularly those with weak antibody reactivity. Screening of blood donors in the United States for HTLV-I began in November 1988. Since then, approximately 0.1 percent of screened donors have had repeated reactivity to anti-HTLV-I on enzyme immunoassay, resulting in the notification of and deferral of blood donation by over 40,000 people3. Supplemental testing confirmed the presence of HTLV-I or HTLV-II antibody in only 15 to 20 percent of these people. Over 50 percent were classified as having indeterminate reactivity on the basis of weak gag-related bands on Western blotting.
The Retrovirus Epidemiology Donor Study recently completed an evaluation of the accuracy of HTLV supplemental testing of U.S. blood donors and is prospectively following infected donors. We performed studies using the polymerase chain reaction (PCR) directed at both the pol region (SK110 and SK111 primers) and the tax and rex regions (SK43 and SK44 primers, which were those used by Pancake and Zucker-Franklin) of HTLV-I and HTLV-II on DNA from peripheral-blood mononuclear cells. These studies were performed between October 1990 and December 1991 in blood samples from 699 donors at five U.S. blood centers who had been identified as having HTLV-I reactivity by enzyme immunoassay (unpublished data). Of 115 donors confirmed as seropositive by Western blot analysis, 111 (96.5 percent) had positive tests for HTLV provirus on testing with both primer pairs (35 were positive for HTLV-I, and 76 for HTLV-II), and 4 had negative PCR tests. This suggests that either the virus had been cleared or the number of circulating infected cells was too small to detect. Of 425 donors with indeterminate reactivity, 6 (1.4 percent) had positive PCR tests (1 for HTLV-I and 5 for HTLV-II). When serum samples from these six donors were reanalyzed, HTLV envelope antibodies were detected with the use of recombinant envelope-antigen assays. These donors are, in fact, infected. None of 159 donors with HTLV-I reactivity by enzyme immunoassay and negative supplemental test results had positive PCR tests with either primer pair. We are prospectively following 149 donors infected with HTLV-I and 378 infected with HTLV-II (including 4 of the 6 infected donors initially classified as having indeterminate reactivity by Western blotting). No cases of mycosis fungoides have been identified,4 but prospective follow-up commenced only in 1990.
These data support the concordance of HTLV antibody and PCR test results and the overall accuracy of testing for HTLV-I and HTLV-II by U.S. blood banks. We believe that few donors who have reactivity on enzyme immunoassay but indeterminate or no reactivity in supplemental tests are infected with these viruses (with the few exceptions noted above). So far, our data indicate that mycosis fungoides is rare in those infected with HTLV-I or HTLV-II. We will, however, continue to monitor our cohort for development of this disease.
4 ReferencesMichael P. Busch, M.D., Ph.D.
Irwin Memorial Blood Centers, San Francisco, CA 94118Edward Murphy, M.D., M.P.H.
University of California, San Francisco, CA 94143George Nemo, Ph.D.
National Heart, Lung, and Blood Institute, Bethesda, MD 208921
Bazarbachi A ,Saal F ,Laroche L ,Flageul B ,Peries J ,de The H . HTLV-1 provirus and mycosis fungoides. Science 1993;259:1470-1471
CrossRef | Web of Science | Medline2
Whittaker SJ ,Luzzatto L . HTLV-1 provirus and mycosis fungoides. Science 1993;259:1470-1470
CrossRef | Web of Science | Medline3
Centers for Disease Control and Prevention, US.P.H.S. Working Group. Guidelines for counseling persons infected with human T-lymphotropic virus type I (HTLV-I) and type II (HTLV-II). Ann Intern Med 1993;118:448-454
Web of Science | Medline4
Murphy E ,Miller K ,Sacher R , et al. A multicenter study of HTLV-I and -II health effects. Transfusion 1992;32:Suppl:58S-58S abstract.
CrossRef | Web of Science
Author/Editor Response
The authors reply:
To the Editor: The point made by Youngberg and Karnad is well taken. It is possible that patients with mycosis fungoides are infected with a virus representing either a variant of HTLV-I or HTLV-II or even a previously unrecognized retrovirus with a homologous sequence in the conserved HTLV-tax-related DNA region amplified in our studies. We are investigating this possibility. So far, sequence-specific differences have not been correlated with different disease patterns1. In fact, only limited sequence variations among HTLV-I strains isolated from widely different sources have been noted2. Nevertheless, it is recognized that HTLV-infected persons, even those residing in areas where the virus is endemic, may not have detectable antibodies to HTLV structural proteins as measured with commercially available kits3. The same virus (HTLV-I) appears to be responsible for disparate disease entities, such as adult T-cell leukemia and tropical spastic paraparesis. In these conditions, there is a marked variation in antibody titers4. Differences in immunogenetic background (e.g., in the HLA haplotype) may be responsible for the various manifestations of disease among patients infected with the same virus5. Patients with mycosis fungoides should be studied with this possibility in mind.
In response to Busch et al., there is a slight, but important, misunderstanding. Most patients with mycosis fungoides have no reactivity to HTLV antibody, not indeterminate or weakly positive reactivity. We recently studied a seven-year-old child whose parents were from Grenada, where HTLV-I infection is endemic. The child had unequivocal mycosis fungoides limited to 20 percent of his skin. A skin-biopsy sample was positive for HTLV-tax proviral sequences. The child had no detectable serum antibodies to structural proteins of the virus. His mother was asymptomatic and seropositive for antibodies to p19, 21, 26, 28, 32, 42, and 53 of HTLV-I. Tax proviral sequences were identified in her peripheral-blood mononuclear cells. It is likely that the child acquired the virus during breast-feeding, which is a common cause of viral transmission in endemic areas. Since the child was infected early in life, could he have developed a tolerance to the virus? It is appropriate to be concerned about HTLV-antibody-negative blood donors who come from areas where HTLV-I is endemic. Although prospective clinical studies of antibody-positive donors may yield answers in the long run, such studies should also include an assessment of the immune response of the donors over time.
5 ReferencesDorothea Zucker-Franklin, M.D.
Bette A. Pancake, Ph.D.
New York University Medical Center, New York, NY 100161
Yoshida M ,Osame M ,Usuku K ,Matsumoto M ,Igata A . Viruses detected in HTLV-I-associated myelopathy and adult T-cell leukaemia are identical on DNA blotting. Lancet 1987;1:1085-1086
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Ratner L ,Philpott T ,Trowbridge DB . Nucleotide sequence analysis of isolates of human T-lymphotropic virus type 1 of diverse geographical origins. AIDS Res Hum Retroviruses 1991;7:923-941
CrossRef | Web of Science | Medline3
Ehrlich GD ,Glaser JB ,Abbott MA , et al. Detection of anti-HTLV-I Tax antibodies in HTLV-I enzyme-linked immunosorbent assay-negative individuals. Blood 1989;74:1066-1072
Web of Science | Medline4
Osame M ,Matsumoto M ,Usuku K , et al. Chronic progressive myelopathy associated with elevated antibodies to human T-lymphotropic virus I and adult-T-cell leukemialike cells. Ann Neurol 1987;21:117-122
CrossRef | Web of Science | Medline5
Usuku K ,Sonoda S ,Osame M , et al. HLA haplotype-linked high immune responsiveness against HTLV-I in HTLV-I-associated myelopathy: comparison with adult T-cell leukemia/lymphoma. Ann Neurol 1988;23:Suppl:S143-S150
CrossRef | Web of Science | Medline
- Citing Articles (2)
Citing Articles
1
Susan L. Stramer, Edward P. Notari IV, Shimian Zou, David E. Krysztof, Jaye P. Brodsky, Gary E. Tegtmeier, Roger Y. Dodd. (2011) Human T-lymphotropic virus antibody screening of blood donors: rates of false-positive results and evaluation of a potential donor reentry algorithm. Transfusion 51:4, 692-701
CrossRef2
CAROLE A. ANGEL, DAVID N. SLATER, JANICE A. ROYDS, STUART N. P. NELSON, STANLEY S. BLEEHEN. (1996) ABSENCE OF EPSTEIN-BARR VIRAL ENCODED RNA (EBER) IN PRIMARY CUTANEOUS T-CELL LYMPHOMA. The Journal of Pathology 178:2, 173-175
CrossRef
