Geographic distribution of HTLV-I and identification of a new high-risk population.

Epidemiologic studies indicate that human T-cell lymphotropic virus type I (HTLV-I), the causative agent of most cases of adult T-cell leukemia/lymphoma (ATLL) in Southeast Japan and the Caribbean islands and the probable cause of a progressive neurological disorder often referred to as tropical spastic paraparesis, occurs with unusual geographic clustering. The current large-scale serosurvey was undertaken to improve our understanding of HTLV-I prevalence in different parts of the world. We analyzed 43,445 serum samples collected from various geographic locales worldwide; 76% of these sera came from clinically healthy donors. Samples were initially screened by an enzyme-linked immunosorbent assay (ELISA) and 4,353 were further evaluated by means of competition assays. In this study, which did not include sera from endemic areas of Japan, a high prevalence of infection was observed in several countries in the Caribbean basin. A significant age-sex difference was observed between populations in the Caribbean and non-endemic regions of Japan. The reason for the male excess in non-endemic areas of Japan will require further study, while the female excess in the Caribbean basin is compatible with the previously described pattern for other HTLV-I-endemic areas. A newly recognized area of possible endemicity was southern Florida, where evidence of infection with HTLV-I or a related virus was found in a group of native Americans whose sera were collected in 1968. In certain parts of the world, particularly sub-Saharan Africa, important problems in determining specificity of reactivity occurred, probably because of cross-reacting antibodies. No pattern was detected that could explain the cross-reactivity solely on the basis of geographic areas, specific patterns of non-viral parasitic infection, or methods of handling the specimens. It is possible that these cross-reactivities are antibodies to proteins from HTLV-I-related retroviruses yet to be discovered.

Molecular epidemiology of HTLV-I-associated non-Hodgkin's lymphomas in Jamaica.

As part of epidemiologic studies of human T-lymphotropic virus (HTLV)-I-associated malignancies in Jamaica, the authors evaluated 26 patients with non-Hodgkin's lymphoma for the presence of integrated HTLV-I provirus in their malignant cells. Fifteen of 26 patients had integrated provirus. All 15 also were HTLV-I antibody positive. Eleven patients did not have integrated provirus, and all 11 were antibody negative. All of the antibody-positive cases had onset of their disease in adulthood (age range, 21-57 years) as opposed to the broad age range of negative cases (4-66 years). Clinical features which were more common in provirus positive than negative patients included leukemic phase, skin involvement, and hypercalcemia, which are all features frequently seen in HTLV-I-associated adult T-cell leukemia/lymphoma (ATLL). The presence of skin involvement, circulating malignant cells, abnormal liver function tests, or the presence of two or more of these four features were statistically significantly different between virus-positive and virus-negative cases. Although the survival of positive cases (6 months) was shorter than that of negative cases (9 months), this was not statistically significant. The only significant determinant of survival was hypercalcemia, with those who developed hypercalcemia at some point in their disease course, independent of their HTLV-I status, surviving a mean of 5 months as compared to a mean of 17.5 months in those who never became hypercalcemic. The six HTLV-I-positive lymphomas that underwent cell typing were all primarily OKT4 positive, whereas two HTLV-I antibody-negative cases that were typed were B-cell lymphomas.

Transmission of HTLV-I and HIV among homosexual men in Trinidad.

Risk for human T-cell lymphotropic virus type (HTLV-I) and human immunodeficiency virus (HIV) infection was evaluated in 100 homosexual or bisexual men from Trinidad. High seropositivity for HTLV-I (15% vs 2.4% in the general population) was linked to duration of homosexuality and numbers of partners, suggesting that HTLV-I, like HIV, can be transmitted by homosexual sex. Forty percent of homosexuals compared with 0.19% of the general population were seropositive for HIV, and sexual contact with US homosexual men and prior history of gonorrhea were major risk factors. The seroprevalence of HIV was three times higher than that for HTLV-I, suggesting that HIV is more efficiently transmitted, especially since HIV appears to have been recently introduced into Trinidad. Altered immune status was prominent in individuals infected with HIV and coinfected with HIV and HTLV-I. Whether HIV/HTLV-I coinfection amplifies clinical effects is a hypothesis that will require further evaluation.

Seroepidemiologic studies of human T-cell leukemia/lymphoma virus type I in Jamaica.

The prevalence of HTLV-I antibodies was evaluated in Jamaica among persons with various malignant, infectious, autoimmune and hematologic disorders and in clinically normal persons. Results document that: (1) the prevalence of HTLV-I antibodies in this population increases with age; (2) overall, there is no significant difference in the antibody prevalence between males and females; (3) antibody-positive individuals are born in all major regions of the island and geographical variance in antibody prevalence by place of birth was not prominent; (4) there is further confirmation of the high prevalence of HTLV-I antibody-positive lymphomas in Jamaica; and (5) the prevalence of HTLV-I antibodies in hemophiliacs, patients with chronic lymphocytic leukemia (CLL), myelogenous leukemias, and patients with breast cancer is higher than in the age-matched population without malignancies, although none of these differences were statistically significant. The increased prevalence in hemophiliacs is most likely related to their frequent transfusion with blood products, but it has not yet been determined whether the prevalence in patients with other diseases is related to their diseases or other as yet undefined factors in common.

Apparent transmission of human T-cell leukemia virus type III to a heterosexual woman with the acquired immunodeficiency syndrome.

A 24-year-old woman developed the acquired immunodeficiency syndrome with lymphadenopathy, oral candidiasis, and Kaposi's sarcoma. Her only known risk factor for the syndrome was sexual contact with an asymptomatic Haitian man. The woman had serologic evidence for infection with human T-cell lymphotropic virus type III, and this virus was recovered from the saliva of her sexual partner. Epidemiologic and virologic studies of the cases of such patients provide further evidence of a primary pathogenetic role for this retrovirus in the acquired immunodeficiency syndrome.

Natural antibodies to human T-cell leukemia/lymphoma virus in healthy Venezuelan populations.

Serum samples of 769 healthy Venezuelan donors were assayed for natural antibodies to HTLV-I by the ELISA technique. Specific HTLV-I antibody prevalence was 6.8% but varied from 1% in Caracas to 13.7% in the Amazonas region and the State of Zulia. Adults infected with Trypanosoma cruzi had the highest HTLV-I antibody prevalence of 15%. Areas of high antibody prevalence were correlated most strongly with the presence of arthropod-borne diseases and to a lesser extent with socio-economic factors. Genetic factors were not correlated with antibody prevalence. Antibodies were seen in children as young as 3 years of age in the most endemic areas. Antibody titers increased with age, suggesting continuous exposure to the virus. The data provide clues for elucidation of the geographic variation in HTLV-I antibody prevalence seen Venezuela and other HTLV-I endemic areas. In addition, they further confirm the Caribbean region as being endemic for HTLV-I and extend this region to inland areas of South America.

Antibodies against human T-cell leukemia/lymphoma virus (HTLV) and expression of HTLV p19 antigen in relatives of a T-cell leukemia patient originating from Surinam.

Serum and peripheral blood cell samples from eleven relatives of a T-cell leukemia patient with human T-cell leukemia/lymphoma virus (HTLV)-associated disease, were investigated for the presence of HTLV antibody and antigen expression. In addition to the patient, three family members were seropositive and a wide range in HTLV antibody titer was observed. The father of the patient showed the highest titer (173,000) and carried HTLV p19+ cells in his peripheral blood. Upon induction of proliferation of these cells by short-term culture in the presence of phytohemagglutinin (PHA) and 12-O-tetradecanoyl phorbol-13-acetate (TPA), an increase from 1% to 28% HTLV p19+ cells was observed confirming previous findings that HTLV p19 expression was correlated with proliferative activity of the host cells. In none of the other seronegative or seropositive relatives of the patient HTLV p19 expression was revealed when tested in freshly isolated mononuclear cells, upon short-term incubation in PHA + TPA or after prolonged culture for 2 or 3 passages in medium containing T-cell growth factor. The results from HLA typing studies did not provide any evidence for HTLV related abnormalities in haplotype expression. Our data confirmed the earlier notion of a prevalence of HTLV infection within families of patients with HTLV-associated disease. It is furthermore obvious from our results that a normal individual may possess high titer HTLV antibody and circulating HTLV p19+ cells without showing signs of disease.

Association of the human type C retrovirus with a subset of adult T-cell cancers.

To determine whether the human T-cell lymphoma-leukemia virus (HTLV) is associated with particular cancers, patient sera were surveyed for HTLV-specific antibodies. An association was seen with aggressive cancers of mature T-cells, specifically Japanese adult T-cell leukemia (ATL) and T-cell lymphosarcoma cell leukemia (TLCL), a similar cancer of Caribbean blacks. Ninety to 100% of these patients possessed HTLV-specific antibody. Forty-seven and 20% of relatives of ATL and TLCL patients, respectively, and 12 and 4% of healthy donors from ATL and TLCL endemic areas were also antibody positive. Visceral organ involvement, hypercalcemia, and skin manifestation, features of ATL and TLCL, were often seen in other antibody-positive patients. Childhood cancers, most cutaneous T-cell and all non-T-cell leukemias and lymphomas, myeloid leukemias, Hodgkin's disease, and solid tumors were not associated with HTLV. Healthy United States donors and European patients with non-malignant diseases were antibody negative. HTLV is thus associated with a subtype of adult T-cell leukemia-lymphoma, clustered in viral endemic areas, with apparent racial and geographic predilection.

Retroviruses in human leukemia.

After decades of work, a retrovirus of true human origin has been isolated first from a U.S. adult case of T-cell lymphoma and then from cases from various regions of the world. This virus, named HTLV-I, is strongly associated with a malignant leukemia-lymphoma of mature T-cells. This disease was first clinically characterized in Japan but subsequently found to cluster in the Caribbean region, areas of the U.S. and in other countries. This retrovirus-associated malignancy has an adult onset and usually a rapidly fatal course. Lymphadenopathy, hepatosplenomegaly, cutaneous infiltration and hypercalcemia are found. HTLV-I has been characterized in detail and shown to be an exogenous retrovirus. HTLV-I infection is detected in normal populations and is endemic in restricted areas of Japan, the Caribbean, South America, and the U.S. Cases of ATL tend to cluster in these areas. Future studies will focus on learning (1) how HTLV-I is transmitted from individual to individual; (2) the nature of the mechanism by which HTLV-I transforms T-cells; (3) whether we can use probes from HTLV-I to detect other (related) retroviruses in other human neoplasms.

Human T-cell leukaemia/lymphoma virus-associated lymphoreticular neoplasia in Jamaica.

19 (34%) of 56 Jamaicans with lympho-proliferative neoplasia had antibody to the human T-cell leukaemia/lymphoma virus (HTLV) in their sera. 17 of those positive had either non-Hodgkin's lymphoma (NHL) or chronic lymphocytic leukaemia. Of 16 consecutive patients presenting with NHL, 11 (69%) were HTLV seropositive. Virus-positive patients with NHL, among whom females were over-represented, had the clinical features and poor survival typical of adult T-cell leukaemia/lymphoma. HTLV-associated leukaemia/lymphoma is a distinct clinicopathological entity, and the high incidence in this series suggests that HTLV is an important cause of lymphoreticular neoplasia in Jamaica.

Epidemiology of human T-cell leukemia/lymphoma virus.

Human T (thymus-derived)-cell leukemia/lymphoma virus (HTLV) is the first retrovirus consistently isolated from humans. Seroepidemiologic testing for antibodies to HTLV document the following. (1) HTLV is associated with a spectrum of mature T-cell lymphoreticular neoplasms. (2) HTLV is strongly associated with clusters of adult T-cell leukemia in Japan and a related syndrome, lymphosarcoma T-cell leukemia in the Caribbean. (3) Virus-positive infections from other areas of the world share similar clinicopathologic features, with some overlap with cutaneous T-cell lymphoma (CTCL). Antibodies to HTLV are lacking in most persons with CTCL. (4) Virus-associated malignancy clusters in geographic areas where HTLV infection is prevalent, and virus positivity varies by country, region within country, age, and possibly race and sex. Although preliminary, the epidemiologic data suggest that HTLV is etiologically linked to a specific subtype of mature T-cell malignancy.

Human T-cell leukemia/lymphoma virus: the retrovirus of adult T-cell leukemia/lymphoma.

Human T (thymus-derived)-cell leukemia/lymphoma virus (HTLV) is a new retrovirus first isolated from T-cell lines from a patient with cutaneous T-cell lymphoma from the southeastern United States. Closely related viruses have since been isolated from several patients with adult T-cell leukemia and lymphoma (and some normal persons) from different areas of the world. HTLV is not a genetically transmitted endogenous virus of humans, but it rather is acquired by postzygotic infection. Natural antibodies to several purified viral proteins have been observed in infected individuals. HTLV is transmissible in vitro to human cord blood T cells, and infection results in an increased growth rate, a reduced requirement for (and often independence from) T-cell growth factor, and an abrogation of the crisis period that usually occurs a month after the establishment of normal T-cell cultures. These data suggest that HTLV is the etiologic agent in some human cases of leukemia and lymphoma.

Antibodies against three purified proteins of the human type C retrovirus, human T-cell leukemia-lymphoma virus, in adult T-cell leukemia-lymphoma patients and healthy Blacks from the Caribbean.

Six black patients of Caribbean origin with adult T-cell leukemia-lymphoma, 18 of their healthy family members and relatives, and 337 healthy black individuals from the Caribbean were investigated for the presence of serum antibodies against human T-cell leukemia-lymphoma virus (HTLV). Three distinct structural proteins of this virus with molecular weights of 24,000, 19,000, and 15,000 were purified, radiolabeled, and used in radioimmune precipitation assays. Five of the patients, three of the family members (two of them spouses), and 11 of the normals had specific antibodies against at least the proteins with molecular weights of 24,000 and 19,000. High antibody titers against these proteins were often associated with antibodies against the protein with a molecular weight of 15,000. In all cases, antibody titers against this protein were considerably lower than those against the proteins with molecular weights of 24,000 and 19,000. HTLV is highly associated with Caribbean adult T-cell leukemia-lymphoma and is also endemic among the normal Caribbean population. By comparison of the frequencies of anti-HTLV positives among family members of patients and the normal population, we conclude that infection by HTLV occurs in a horizontal way and at least in the West Indian black and Japanese population probably without a requirement for uncommon genetic factors.

The human type-C retrovirus, HTLV, in Blacks from the Caribbean region, and relationship to adult T-cell leukemia/lymphoma.

Type-C RNA tumor viruses have been implicated in the etiology of naturally occurring leukemias and lymphomas of animals. Human T-cell leukemia/lymphoma virus (HTLV) is the first human virus of this class consistently identified in association with a specific type of human leukemia/lymphoma. The isolation of HTLV was made possible by the ability to grow mature T-cells in tissue culture usually with T-cell growth factor (TCGF). We now report a cluster of adult T-cell leukemia/lymphoma among Blacks from the Caribbean in which all eight cases are positive for HTLV virus and/or antibody. These patients have disease that appears indistinguishable from Japanese adult T-cell leukemia/lymphoma which, as we have also reported, is associated with HTLV in over 90% of cases. The finding of HTLV antibodies in some of the normal population in the Caribbean and Japan, and the clustering of a specific form of T-cell leukemia/lymphoma in these virus-endemic areas, suggest that HTLV infection may be associated with the occurrence of a distinctive clinico-pathologic entity.

Adult T-cell lymphoma-leukaemia in Blacks from the West Indies.

Six Black patients (five born in the West Indies and one in Guyana), aged 21-55 years, had adult T-cell lymphoma-leukaemia diagnosed in the U.K. This disorder is rare in Europe and the U.S.A., but is more common in Japan. Five patients had severe hypercalcaemia which correlated with disease activity, although osteolytic lesions were found in only one. Other clinical features were lymphadenopathy and a high white blood-cell count (range 27-67 X 10(9)/l) with a predominance of pleomorphic lymphoid cells with pronounced nuclear irregularities prominent at ultrastructural level. The cells in all cases formed rosettes with sheep red blood-cells and lacked terminal transferase. Analysis with OKT monoclonal antibodies in four cases confirmed a mature T-cell phenotype defined as helper/inducer (T4+, T6-, T8-) in three. Combination chemotherapy resulted in short-lived remissions; four patients died and two have survived 3-6 months. The disease in these patients is indistinguishable on clinical and pathological grounds from adult T-cell leukaemia/lymphoma in Japan. Geographical clustering among certain racial groups suggests common aetiological factors in the pathogenesis of this disease. The finding of high titre antibody against the structural core protein (p24) of a new human C-type leukaemia virus (human T-cell leukaemia/lymphoma virus) in all tested cases from this series and data from all but one case from Japan suggest that one such factor may be viral.