Prevalence of HTLV-I in arctic regions

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Int. J. Cancer: 36,651-655 (1985) 0 1985 Alan R. Liss, Inc. PREVALENCE OF HTLV-I IN ARCTIC REGIONS Marjorie ROBERT-GUROFF~, Jeffrey CLARK3, Anne P. LANIER~, Gunhild BECK MAN^, Mads MELBYE~, Peter EBBESEN~, William A. BLATTNER3 and Robert c. GALLO Laboratory of Tumor Cell Biology and 3Environmental Epidemiology Branch, National Cancer Institute, Bethesda, MD 20205; 4Arctic Investigations Laboratory, Centers for Disease Control, Anchorage, AK 99501, Department of Medical Genetics, University of Umea, Umea, Sweden; 61nstitute of Cancer Research, Radiumstationen, DK-8OOO Aarhus C, Denmark. Sera of native inhabitants of Arctic regions were In 1982 we reported the isolation of a new HTLV assayed for antibodies to HTLV-I by the ELlSA tech- subtype, termed HTLV-11, from cells of a patient with firm antibody specificity. Residents of 7 widely separated Alaskan villages exhibited prevalence rates anaraman et al. t 1982). HTLV-11 is readily distin- of 0 to I ~ o / ~ for HTLV-I antibodies. L~~~ than I 01~ of guishable from HTLV-I by immunologic and molecular Greenland Eskimos were HTLV-I antibody-positive. biologic Criteria, but iS ak0 Clearly related to the pro- Residents of 3 northern Swedish regions ranged in totype virus by these same criteria. An additional HTLV-I antibody prevalence from 0 to 5%. Sera of HTLV-I1 isolate has been obtained from cells of an healthy native inhabitants of Alaska and northern intravenous drug user, who died of AIDS (Hahn et al., Sweden were similarly assayed for antibodies to 1984). However, except in sera of i.v. drug abusers HTLV-II. No additional sera were shown to be positive (Tedder et al., 1984; Robert-Guroff, unpublished), no for HTLV-II antibodies. While some of the HTLV-I evidence of widespread infection by HTLV-II has been antibody-positive sera exhibited cross-reactivity with HTLV-II antigens, competition experiments using dis- found in any seroepidemiologic studies. Moreover, rupted ~ ~ ~ v - 1 1 or purified HTLV-I p24 as test anti- HTLV-11 has not been associated with a m particular gens indicated that the primary antibody response in human malignancy, including hairy-cell leukemia or all cases tested was elicited by HTLV-I. Our results AIDS. In the course of our studies with HTLV-11, we show that HTLV-I distribution is not restricted to en- learned that the patient from whose cells HTLV-I1 was demic areas in warm, humid climates, but extends to originally isolated had lived for Some time in an Es- Arctic regions. Within these regions, HTLV-I exhibits kimo village in Alaska @layney 1983). This the same restricted distribution seen in other areas howledge provided a second stimulus to investigate where virus infection is prevalent. The Arctic does not HTLV in Arctic regions. we therefore studied Sera of seem to be a reservoir for HTLV-II infection. The origin of HTLV-I in Arctic is not known. one Alaskan Eskimos, Greenland Eskimos, and Swedish may speculate that foreign visitors introduced the vi- Lapps to determine the Prevalence of HTLV-1 and -11 rus into Aleut and Lapp populations, and that it has in these populations. been maintained there and restricted in i t s distribu- tion as a result of close familial relationships. nique followed by Ompetition experiments to On- rarely encountered T-cell hairy-cell leukemia (Kaly- MATERIAL AND METHODS The human T-cell leukemia (lymphotropic) virus sera type I (HTLV-I) has been causally associated with an Sera of 333 Alaskan Eskimos, originally collected aggressive malignancy of mature T-cells in adults typ- in 1975 and 1981 and stored at -60C until testing, ified by adult T-cell leukemia (ATL) (Gallo et al., were selected from 7 Eskimo communities widely dis- 1983; Robert-Guroff and Gallo, 1983) first described tributed throughout the state. Persons from all age in Japan (Uchiyama et al., 1977). Both HTLV-I and groups were tested in villages 1 and 2, while only ATL have been shown to be endemic in certain regions those between the ages of 40 and 59 were tested in the of the world, especially the southwestern islands of other 5 communities. In this latter group, random Japan (Hinuma et al., 1982; Robert-Guroff et al., samples were chosen from available sera in order to 1983), the Caribbean islands (Blattner et al., 1982, provide an equal distribution by sex and 10-year age 1983; Gessain et al., 1984), the countries surrounding group. Sixteen additional sera from close relatives of the Caribbean basin (Merino et al., 1984; Robert- an antibody-positive Eskimo and 52 sera from healthy Guroff et al., 1984), and parts of subsaharan Africa Alaskan natives or from Alaskan natives with various (Hunsmann et al., 1983; Biggar et al., 1984; Saxinger malignancies were also included in the study. Sera of et al., 1984~) . All these endemic areas have in com- 504 Greenland Eskimos (Ebbesen et al., 1981; Melbye mon warm, humid climates. While HTLV-I is ineffi- et al., 1984) were obtained in 1978 and stored frozen ciently transmitted, with the primary route thought to until use. The sera represented all age groups between involve intimate contact and infected cells rather than 11 and 80, but the majority represented persons be- cell-free virus, it has been speculated that parasitic tween ll and 40 years of age. Males and females were infestations involving insect vectors common in tropi- equally represented in each age group. Two hundred cal and semitropical endemic areas might play a role sera were obtained from Swedish Lapps between the in the life cycle of the virus and in its persistence in ages of 11 and 70, although the majority ranged in age populations inhabiting these areas. In spite of climato- logic differences, parasitic infestations also occur with high frequency in some Arctic populations. Therefore, as part of a geographic seroepidemiologic survey, we undertook an investigation of the prevalence of HTLV- I in Arctic regions. zTO whom reprint requests should be addressed Received: June 18, 1985. 652 ROBERT-GUROFF ET AL from 50 to 70. Males and females were equally repre- sented. One hundred sera were obtained from healthy individuals residing near the Swedish-Finnish border. Most of the people represented were between 11 and 40 years of age, although a few sera were from adults of 40 to 60 years. Again, males and females were equally represented. Sera from 100 healthy donors in Vasterbotten County, Sweden, represented primarily males between the ages of 21 and 50. immunologic Assays Sera were analyzed for antibodies to HTLV-I and -11 by the previously described ELISA technique (Sax- inger and Gallo, 1983) with either disrupted HTLV-I or HTLV-I1 as test antigen. Confirmation that ob- served antibody reactivities were specific for either virus was obtained by competition assays using ex- tracts of the appropriate virus-producing cells as com- petitor as well as extracts of non-virus-producing cells and fetal calf serum (Robert-Guroff et al . , 1982). In some cases, sera reacted specifically with both HTLV- I and HTLV-I1 antigens. In order to determine which virus elicited the primary antibody response, competi- tion experiments were carried out in the ELISA system using HTLV-I p24-coated Bio-EnzaBeads (Litton Bio- netics, Kensington, MD) as the test antigen and HTLV- I-producing HUT102 cell extract or HTLV-II-produc- ing C3-44 cell extract as competitor. In cases where serum reactivity against HTLV-I p24 was minimal, similar competition experiments were carried out us- ing disrupted HTLV-I1 as test antigen. The bead assay was carried out as follows. Limiting dilutions of sera were incubated with the HTLV-I-coated Bio-Enza- Beads in 250 pl PBS containing 20% normal goat serum, 0.05% Tween-20, 2% Trasylol (Mobay, New York, NY), and serial dilutions of competing proteins at the indicated concentrations. The beads were incu- bated with gentle agitation for 1 hr at room tempera- ture and then washed as described in the Litton Bio- EnzaBead manual in PBS-Tween. The beads were then incubated for 1 hr at room temperature with an appro- priate dilution of peroxidase-conjugated goat anti-hu- man IgG in PBS-Tween containing 1% normal goat serum. Following washing, the last 3 washes being in PBS without detergent, the beads were incubated in peroxidase substrate solution consisting of 0.005 % H202 and 0.05 % orthophenylenediamine in citrate buffer, PH 5.0, for 20 min at room temperature in the dark. The reaction was stopped by the addition of 50 p1 4N H2S04 per well. Results were expressed as a percentage of the control absorbance reading obtained in the absence of any competitor. When disrupted HTLV-I1 was used as the test antigen, the competition experiments were carried out similarly on limiting dilutions of sera in the presence of competitors, and the standard ELISA technique was used throughout the procedure. Sera were judged to possess antibody elic- ited primarily by HTLV-I if, when tested against HTLV-I p24, extracts of C3-44 cells did not fully compete for the reactivity, or the competition curve had a lesser slope than that obtained following compe- tition with HUT102 cell extract. Against HTLV-I1 as test antigen, type-I sera gave competition curves of similar slope when either HUT102 or C3-44 cell ex- tract was used as competitor. Sera were judged to possess antibody elicited by HTLV-I1 if, when tested against HTLV-I1 as test antigen, C3-44 cell extract was a more effective competitor than HUT102 cell extract. Against HTLV-I p24 as test antigen, type I1 sera were more efficiently competed by C3-44 extract or gave similar cornpetition curves with C3-44 and HUT102 cell extracts as competitors. Antibody titers were determined on serial dilutions of test sera in the ELISA system against disrupted HTLV-I and/or -11 as test antigen. Titer is expressed as the reciprocal of the serum dilution at which the absorbance of the test serum equals the absorbance of a standard negative serum diluted 1:20. RESULTS Antibody prevalence to HTLY-I A seroepidemiologic survey of 3 widely separated Arctic regions revealed several discrete areas in which antibodies to HTLV-I were prevalent (Table I). Among Alaskans, average seroprevalence was 3 % and ranged from 0 to 12% in small villages and among several risk groups tested. The villages surveyed were widely separated along the Alaskan coast. Specific antibody was also detected in the husband of a healthy Eskimo with high titer antibody to HTLV-I (Table 11). In other Arctic areas, we detected only one antibody- positive individual in more than 500 Greenland Eski- mos surveyed. However, among sera obtained from 3 different regions in Sweden, we detected a significant antibody prevalence of 5 % in residents near the Swed- ish-Finnish border (Table I). TABLE I - PREVALENCE OF ANTIBODIES TO HTLV-I IN ARCTIC REGIONS Antibody to HTLV-I Region Number Number Positive positive/ % tested Alaska Healthy Eskimos of village: 1 2 3 4 5 6 7 Total Relatives of a healthy antibody- positive Eskimo Alaskan Natives' Random healthy donors With leukemiasllymphomas With other cancers3 Greenland Sweden Healthy Eskimos Healthy Lapps Healthy donors near Swedish- Healthv donors in Vasterbotten Finnish border Counfy 1 I42 017 I 012 1 51106 013 1 0136 3126 91333 1116' 0122 01 14 0116 1 I506 1 1200 51100 0/100 ~ 2 0 0 5 0 0 12 3 6 0 0 0 < 1 < 1 5 0 'The positive family member was the husband of a healthy antibody- positive Eskimo (No. F3412, Table II).-*Alaskan natives include Eski- mos, Indians, and Aleuts.-30ther cancers include nasopharyngeal carci- noma and hepatocellular carcinoma. 653 PREVALENCE OF HTLV-I IN ARCTIC REGIONS TABLE I1 - CROSS-REACTIVITY OF HTLV-I ANTISERA WITH HT1.V-IT ANTIGENS Ageisex of Antibody titers to Serum healthy samples serum HTLV-I HTLV-11 donors Alaskan sera 54159 54171 54 189 54195 54205 (5/81)* 54207 (8183) 542 1 1 54164 F3412 (5175) (4183) (5183) H80424 Swedish sera 50336 5043 1 J0439 50440 5045 1 50479 Greenland sera 40lF 53lM 54lM 511M 421F 48lM 45lM 43lM 59lF 75lM 321F 54lM 29lF 271F 71F 14lM 365 5,120 2,560 4,101 873 1,860 660 5,843 170 124,400 102,400 470,000 1,990 830 106 1,010 150 155 1,370 < 20 < 20 < 20 < 2q N.D. 200 < 20 < 20 < 20 92,000 38,000 110,000 < 20 N.D. < 20 1 , 1 0 0 < 20 < 20 N.D. T7675 30lM 75 N.D. Sera were not analyzed at dilutions lower than l:20.-*Date on which serum sample was ~btained.-~N.D. = not determine~I-~Husband of donor F3412. Cross-reactivity of serum antibodies for antigens of HTLV-I and HTLV-I1 All sera obtained from the healthy individuals resid- ing in the 7 Alaskan villages, and 160 of the Swedish sera representing the 3 different regions, were screened for antibody reactivity with antigens of HTLV-11. We lacked sufficient amounts of Greenland Eskimo sera to carry out this analysis on that population. None of the sera tested against HTLV-I1 antigens reacted specifi- cally, except 5 of the 20 sera already shown to be antibody-positive for HTLV-I (Table 11). Generally, sera with the highest titer exhibited this dual specific- ity. All samples were coded and serial samples were not revealed until the studies were complete. Determination of primary antibody spec$city In order to determine whether antibody present in cross-reactive sera had been elicited by HTLV-I or HTLV-11, we carried out competition experiments against disrupted HTLV-I1 as antigen on wells of mi- crotiter plates, or against purified HTLV-I p24 coated on Bio-EnzaBeads. Figure 1 illustrates some represen- tative competition curves. A pattern typical of a type- I serum is shown in panels (a) and (b); panels (c) and (6) show the competition curves obtained with a stan- dard type-I1 serum. Curves representative of a serum sample of an Alaskan Eskimo are shown in panels (e ) and (f). The Alaskan sera tested in this fashion were shown to have the primary antibody response elicited by HTLV-I. We detected no sera with an antibody response elicited by HTLV-11. The Swedish serum with reactivity for HTLV-I1 was not assayed in this manner. 40 lib 20 0.1 1.0 10 loo B 0.1 1.0 10 100 COMPETING PROTEIN ( p g ) FIGURE 1 - ELISA competition experiments to distinguish sera with primary antibody reactivity to HTLV-I or HTLV-11. Sera in panels (a) , (c) and (e) were tested against disrupted HTLV-I1 as test antigens. Sera in panels (b), (d) and U, were tested against purified HTLV-I p24 on Bio-EnzaBeads. Lim- iting dilutions of sera were assayed as described in Meth- ods in the presence of increasing concentrations of competing cell extracts. Solid symbols represent competition with C3-44 cell lysate (HTLV-I1 producer); open symbols represent competition with HUT102 cell lysate (HTLV-I pro- ducer). Representative sera include a known HTLV-I anti- body-positive serum (0), a known HTLV-I1 antibody- positive serum (D), and serum from an Alaskan Aleut (A). DISCUSSION Given the now well-known distribution of HTLV-I in endemic areas of southwestern Japan, the Caribbean region and Africa, we were surprised to find seroprev- alence rates for HTLV-I as high as 12% in some subgroups of persons residing in Arctic regions. Al- though climatologic features of this study population were distinctive compared to tropical and subtropical regions which typify HTLV-I endemic areas, other features of the groups studied could account for the HTLV-I prevalence rates observed. Because of the Arctic cold, there is considerable residential crowding and relatively poor personal hygiene among the groups studied. As a result, these populations exhibit some of the highest known incidences of several viral and par- 654 ROBERT-GUROFF ET AL. asitic infestations. These conditions could also contrib- ute to transmission of HTLV-I. Nevertheless, the lack of a uniform distribution of seroprevalence suggests point source introduction into the population and sub- sequent limited spread. One suggestion for the intro- duction of the virus into the Alaskan population is a possible interaction with Japanese fishermen who are also carriers of HTLV-I. Another possibility is an interaction with Russian sea-otter hunters who traded with both Chinese and Japanese, and could have thus introduced the virus into Alaska (Laughlin et al., 1979). The origin of the virus into the Swedish Lapp population is also not clear. The Lapp language is remotely related to the Finno-Ugric group of lan- guages. However, the genetic make-up of the Lapps is most probably distinct from that of both Finns and Swedes. Indeed, genetic relatedness to Aleuts has been claimed (Hanihara, 1979). It would also be of interest to analyze sera of the various Russian peoples. So far no reports on the prevalence of HTLV-I among any populations of the USSR have appeared. Antibodies to HTLV-I have been detected in sera of baboons from an experimental colony in Sukhumi, USSR (Saxinger et al. , 19846). Whether this evidence reflects infection from Africa via the migration of Old World primates, or whether this antibody prevalence results from the inoculation of human tumor material into the baboons in the experimental colony is not clear. A virus closely related to HTLV-I has been isolated from the cells of a baboon inoculated with tumor tissue of an infected Sukhumi baboon (Guo et al . , 1984). gent as those previously seen in other geographic areas including Japan (Robert-Guroff et al . , 1983) and Ven- ezuela (Merino et a l . , 1984). Factors which may ac- count for this restricted viral distribution include possible transmission vectors, themselves geographi- cally restricted, and the tight familial transmission of the virus resulting from its low infectivity and neces- sity for close contact or actual transmission of infected cells. A major impetus for this investigation was a sugges- tion that HTLV-I1 might be prevalent in Alaska, based on the anecdotal account of the patient from whose cells the prototype HTLV-I1 isolate was obtained, and who had resided some time in Alaska. In view of the failure to identify any reservoir of HTLV-I1 infection worldwide, it seemed reasonable to investigate this Alaskan connection. The results presented here show that HTLV-I1 is not endemic in Alaska. To date, the m l y group identified with significant antibody prevalence to HTLV-I1 is composed of i.v. drug abu- sers (Tedder et al., 1984; M. Robert-Guroff, unpub- lished). 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