Letters to the Editor

AFRICAN GREEN MONKEYS ARE INFECTED WITH ADULT T-CELL LEUKAEMIA VIRUS OR A CLOSELY RELATED AGENT

Serum and peripheral blood leukocytes from the chimpanzees (Pan troglodytes) of the colony of the Laboratory of Central Nervous System Studies, National Institute of Neurological Disorders and Stroke, NIH, were tested for the presence of STLV-I-specific antibodies and proviral DNA. Antibodies were determined by gelatin particle agglutination and Western blot (WB) assays utilizing HTLV-I antigens. Proviral DNA was detected by four PCR assays targeting three different regions of STLV-I genome: the fragments of theenvandpolgenes andLTR.Twenty of twenty-two DNA samples from WB-positive animals were PCR positive. None of the DNA samples from WB-negative (n= 5) and WB-indeterminate (n= 4) animals was PCR positive. The results of the nested and double nestedenvPCR tests were fully concordant; the seminestedLTRPCR test was much less sensitive. The DNA sequences from theenv(483 bp) and thepol(200 bp) genes andLTR(705 bp) were determined for six, two, and two chimpanzee STLV-I isolates, respectively. Phylogenetic analysis revealed that chimpanzee STLV-I isolates can be attributed to three clades. The first of these clades (SS-PTR1/CSA) included STLV-I isolates from the chimpanzees and West African subspecies of African green monkeys (Cercopithecus a. sabaeus). The other clades (S-PTR2 and S-PTR3) included STLV-I isolates only from chimpanzees. However, both S-PTR2 and S-PTR3 clustered together with Central African HTLV-I comprising the human/simian clade (HS-HSA/PTR). This pattern of phylogenetic clustering suggests that interspecies transmission of STLV-I occurred between chimpanzees and African green monkey subspecies as well between chimpanzees and human populations in Central Africa.

Serum and peripheral blood leukocytes from wild yellow baboons (Papio hamadryas cynocephalus) were tested for the presence of STLV-1-specific antibodies and proviral DNA. Fourteen of 30 sera tested positive by radioimmunoprecipitation assay (RIPA) with HTLV-1. Among 36 DNA samples tested by PCR 15 were positive by double nested PCR for a fragment of the STLV-1envgene, the most sensitive assay among PCR tests employed. Of 30 animals that were tested both serologically and by PCR in only 1 case were the results discordant (PCR-positive, antibody-negative). The DNA sequences fromenv(378 bp),pol(212 bp), andLTR(705 bp) were determined for 5, 5, and 2 Mikumi STLV-1 isolates, respectively. The DNA sequences of Mikumi STLV-1 isolates were virtually identical and phylogenetic analysis revealed that they were clearly distinct from previously published baboon STLV-1 sequences, including those STLV-1 isolates presumed to be from yellow baboons. The results of this study suggest that reliable placement of individual STLV-1 within the PTLV-1 phylogeny requires genomic sequences of STLV-1 isolates from wild animals whose taxonomic identity and geographical origin are firmly established and that the LTR is the genomic region of STLV-1 which is the most informative for cladistic analysis of these viruses.

A study of simian T-cell lymphoma/leukemia virus infection, conducted on 747 nonhuman primates belonging to 14 different species in Central and Western Africa, indicated that 4 species (Cercopithecus aethiops, Erythrocebus patas, Papio doguera, and Cercopithecus mona pogonias) had a high prevalence of seropositivity to simian T-cell lymphoma/leukemia virus type I (STLV-I). The other nonhuman primate species, however, had negative or low levels of ant-HTLV-I antibodies. STLV-I pol and env DNA was detected in 12 of 12 different animals among the seropositive species. However, STLV-I pX DNA could be detected in only 10 of 12 animals. Comparative phylogenetic analyses based on 140 bp sequence of the pol gene indicate that these STLV-I isolates were 0-9% divergent from each other and were 3.5-7% divergent from the prototype related human retrovirus HTLV-I (ATK). The West African STLV-I isolates formed a unique phylogenetic cluster as did most of the Central African STLV-I isolates, save for STLV-I (Tan 90). The phylogenetic data indicate that cross species transmission of HTLV-I and STLV-I continued to occur long after their ancestral strain separated from the progenitor to HTLV-II. Comparative amino acid analyses indicated that there was marked conservation of the TAX protein regardless of host species, while the pol and REX proteins exhibited increasing levels of diversity.

Kuru is one of the better-known paradigms of “place diseases,” or diseases occurring in high incidence in geographically restricted or delimited regions. From the study of kuru among the stone age fore in the Eastern Highlands of Papua, New Guinea, came the discovery of unconventional agents or slow viruses that cause neurodegenerative diseases in humans. In a similar fashion, the study of another place disease, a fulminating hematological malignancy in southwestern Japan, called adult T-cell leukemiailymphoma, led to the discovery of and etiological association with an exogenous replication-competent human retrovirus, human T-cell lymphotropic virus type I (HTLV-I). This initial frontier of HTLV-I research was expanded by the serendipitous discovery that endemic tropical spastic paraparesis, also known as Jamaican neuropathy and paraparesia espastica el Pucifico, another place disease in the Caribbean basin and Colombia, was also caused by HTLV-I. A clinically indistinguishable spastic myelopathy, designated HTLV-I-associated myelopathy, was later recognized among HTLV-I-seropositive individuals in southern Japan, and presently, HTLV-I-associated myelopathy and HTLV-I-positive tropical spastic paraparesis are considered to be the same disease. The study of diseases in populations isolated by the virtue of geography, culture, and/or genetics can also provide insights into the evolution and dissemination of the etiological agent. From the studies of HTLV-I infection in an isolated recently contacted group in the fringe highlands of Papua, New Guinea, and among the lifelong residents of the Solomon Islands has come an augmented perspective on the emergence, evolution, and global dissemination of this lymphotropic retrovirus. In addition, these studies in Melanesia have led to the realization that HTLV-I may, in certain instances, serve as a biological marker for the early and recent migrations of human populations.

Simian T-cell leukemia virus (STLV-I) is an oncovirus highly related to human T-cell leukemia virus type I (HTLV-I). To further examine the extent of variability, dissemination patterns, phylogeny, and evolution of these viruses, we analyzed a new STLV-I variant from a naturally infected Cereopithecus aethiops var. tantalus from the Central African Republic. Sequence analyses of its LTR, gag, pol, env, and pX (Orf II) genes indicated that this isolate, STLV-I (Tan 90), is 6% divergent from the prototype HTLV-I (ATK) and is the most divergent African STLV-I characterized to date. Our phylogenetic data indicate that southeast Asian and African STLV-I and HTLV-I strains segregated from each other thousands of years ago and that Japanese HTLV-I strains represent a relatively recent introduction of African or New World isolates. The data also indicate that interspecies transmission occurred several times on different continents over prolonged periods of time.

The hypothesis that the true incidence of c-ALL is relatively uniform throughout the world is not supported by experience in tropical Africa, where ALL is uncommon under five years of age. A high rate of spontaneous somatic mutation in pre-B cells may initiate the development of c-ALL, but its progress could be determined by (i) a leukaemogenic agent causing a second genetic event, (ii) the effects of intense antigenic barrage, either stimulating or suppressing pre-B-cell mitosis, or (iii) genetic determinants. Epidemiological patterns in populations of low, intermediate and high socio-economic status may be classified I–III with increasing incidence of diagnosed T-ALL in children over five years and c-ALL in younger children, and subclassified A and B with decreasing incidence of BL.

There may be two forms of AML, one similar to that seen in industrialized countries, the other occurring at high prevalence in African children of low socio-economic status, often presenting with chloroma, and perhaps associated with immune suppression secondary to malnutrition, malaria and other intercurrent infections. Uncontrolled exposure to petroleum and other chemicals, and the use of alkylating agents in treatment of neoplasms in young patients could emerge as important cause of ANLL in Africa.

There are two varieties of CLL also, one similar to that seen in the western world, the other prevalent in adults below 45 years of age, especially women: transmission of a leukaemogenic agent is postulated, to which women are more susceptible due to immunosuppression during normal pregnancy. The human population and some subhuman primates of subSaharan Africa are the largest reservoir of HTLV-1, which shows association with B-CLL over 50 years of age and ATL.