Geographic distribution, clinical epidemiology and genetic diversity of the human oncogenic retrovirus HTLV-1 in Africa, the world's largest endemic area.

The African continent is considered the largest high endemic area for the oncogenic retrovirus HTLV-1 with an estimated two to five million infected individuals. However, data on epidemiological aspects, in particular prevalence, risk factors and geographical distribution, are still very limited for many regions: on the one hand, few large-scale and representative studies have been performed and, on the other hand, many studies do not include confirmatory tests, resulting in indeterminate serological results, and a likely overestimation of HTLV-1 seroprevalence. For this review, we included the most robust studies published since 1984 on the prevalence of HTLV-1 and the two major diseases associated with this infection in people living in Africa and the Indian Ocean islands: adult T-cell leukemia (ATL) and tropical spastic paraparesis or HTLV-1-associated myelopathy (HAM/TSP). We also considered most of the book chapters and abstracts published at the 20 international conferences on HTLV and related viruses held since 1985, as well as the results of recent meta-analyses regarding the status of HTLV-1 in West and sub-Saharan Africa. Based on this bibliography, it appears that HTLV-1 distribution is very heterogeneous in Africa: The highest prevalences of HTLV-1 are reported in western, central and southern Africa, while eastern and northern Africa show lower prevalences. In highly endemic areas, the HTLV-1 prevalence in the adult population ranges from 0.3 to 3%, increases with age, and is highest among women. In rural areas of Gabon and the Democratic Republic of the Congo (DRC), HTLV-1 prevalence can reach up to 10-25% in elder women. HTLV-1-associated diseases in African patients have rarely been reported in situ on hospital wards, by local physicians. With the exception of the Republic of South Africa, DRC and Senegal, most reports on ATL and HAM/TSP in African patients have been published by European and American clinicians and involve immigrants or medical returnees to Europe (France and the UK) and the United States. There is clearly a huge underreporting of these diseases on the African continent. The genetic diversity of HTLV-1 is greatest in Africa, where six distinct genotypes (a, b, d, e, f, g) have been identified. The most frequent genotype in central Africa is genotype b. The other genotypes found in central Africa (d, e, f and g) are very rare. The vast majority of HTLV-1 strains from West and North Africa belong to genotype a, the so-called 'Cosmopolitan' genotype. These strains form five clades roughly reflecting the geographic origin of the infected individuals. We have recently shown that some of these clades are the result of recombination between a-WA and a-NA strains. Almost all sequences from southern Africa belong to Transcontinental a-genotype subgroup.

Epidemiological Evidence of Nosocomial and Zoonotic Transmission of Human T-Cell Leukemia Virus-1 in a Large Survey in a Rural Population of Central Africa.

BACKGROUND: Central Africa is one of the largest areas of high endemicity for human T-cell leukemia virus-1 (HTLV-1). However, no preventive measures are yet implemented to reduce its transmission, which can be sexual, from mother-to-child, or through contaminated blood products. Rare zoonotic transmissions from nonhuman primates (NHPs) have also been reported in this region. Here we investigated the HTLV-1 prevalence and associated risk factors in a rural population in Cameroon. METHODS: From 2019 to 2021, we performed a cross-sectional survey in the eastern region of Cameroon. HTLV-1 infection was first screened by ELISA, then tested by western blot and envelope gene targeted polymerase chain reaction. Risk factors associated with HTLV-1 infection were identified by logistic regression in univariable and multivariable analyses. RESULTS: Among 3400 participants, HTLV-1 prevalence was 1.1% (95% confidence interval [CI], .7-1.5). Factors independently associated with HTLV-1 infection were Pygmy ethnicity (adjusted odd ratio [aOR], 2.9; 95% CI, 1.3-6.2), history of surgery (aOR, 6.3; 95% CI, 2.2-17.8), and NHP bite (aOR, 6.6; 95% CI, 2.2-19.8). CONCLUSIONS: These results suggest both iatrogenic and zoonotic transmission of HTLV-1 in Cameroon. Further studies are needed to assess the risk of nosocomial transmission of HTLV-1, to guide public health authorities in implementing preventive measures to control HTLV-1 transmission.

The genomic landscape of contemporary western Remote Oceanians.

The Vanuatu archipelago served as a gateway to Remote Oceania during one of the most extensive human migrations to uninhabited lands ∼3,000 years ago. Ancient DNA studies suggest an initial settlement by East Asian-related peoples that was quickly followed by the arrival of Papuan-related populations, leading to a major population turnover. Yet there is uncertainty over the population processes and the sociocultural factors that have shaped the genomic diversity of ni-Vanuatu, who present nowadays among the world's highest linguistic and cultural diversity. Here, we report new genome-wide data for 1,433 contemporary ni-Vanuatu from 29 different islands, including 287 couples. We find that ni-Vanuatu derive their East Asian- and Papuan-related ancestry from the same source populations and descend from relatively synchronous, sex-biased admixture events that occurred ∼1,700-2,300 years ago, indicating a peopling history common to the whole archipelago. However, East Asian-related ancestry proportions differ markedly across islands, suggesting that the Papuan-related population turnover was geographically uneven. Furthermore, we detect Polynesian ancestry arriving ∼600-1,000 years ago to Central and South Vanuatu in both Polynesian-speaking and non-Polynesian-speaking populations. Last, we provide evidence for a tendency of spouses to carry similar genetic ancestry, when accounting for relatedness avoidance. The signal is not driven by strong genetic effects of specific loci or trait-associated variants, suggesting that it results instead from social assortative mating. Altogether, our findings provide an insight into both the genetic history of ni-Vanuatu populations and how sociocultural processes have shaped the diversity of their genomes.

Genomic insights into population history and biological adaptation in Oceania.

The Pacific region is of major importance for addressing questions regarding human dispersals, interactions with archaic hominins and natural selection processes1. However, the demographic and adaptive history of Oceanian populations remains largely uncharacterized. Here we report high-coverage genomes of 317 individuals from 20 populations from the Pacific region. We find that the ancestors of Papuan-related ('Near Oceanian') groups underwent a strong bottleneck before the settlement of the region, and separated around 20,000-40,000 years ago. We infer that the East Asian ancestors of Pacific populations may have diverged from Taiwanese Indigenous peoples before the Neolithic expansion, which is thought to have started from Taiwan around 5,000 years ago2-4. Additionally, this dispersal was not followed by an immediate, single admixture event with Near Oceanian populations, but involved recurrent episodes of genetic interactions. Our analyses reveal marked differences in the proportion and nature of Denisovan heritage among Pacific groups, suggesting that independent interbreeding with highly structured archaic populations occurred. Furthermore, whereas introgression of Neanderthal genetic information facilitated the adaptation of modern humans related to multiple phenotypes (for example, metabolism, pigmentation and neuronal development), Denisovan introgression was primarily beneficial for immune-related functions. Finally, we report evidence of selective sweeps and polygenic adaptation associated with pathogen exposure and lipid metabolism in the Pacific region, increasing our understanding of the mechanisms of biological adaptation to island environments.

Epidemiology and Genetic Variability of HHV-8/KSHV among Rural Populations and Kaposi's Sarcoma Patients in Gabon, Central Africa. Review of the Geographical Distribution of HHV-8 K1 Genotypes in Africa.

Human herpesvirus 8 (HHV-8) is the etiological agent of all forms of Kaposi's sarcoma (KS). K1 gene studies have identified five major molecular genotypes with geographical clustering. This study described the epidemiology of HHV-8 and its molecular diversity in Gabon among Bantu and Pygmy adult rural populations and KS patients. Plasma antibodies against latency-associated nuclear antigens (LANA) were searched by indirect immunofluorescence. Buffy coat DNA samples were subjected to polymerase chain reaction (PCR) to obtain a K1 gene fragment. We studied 1020 persons; 91% were Bantus and 9% Pygmies. HHV-8 seroprevalence was 48.3% and 36.5% at the 1:40 and 1:160 dilution thresholds, respectively, although the seroprevalence of HHV-8 is probably higher in Gabon. These seroprevalences did not differ by sex, age, ethnicity or province. The detection rate of HHV-8 K1 sequence was 2.6% by PCR. Most of the 31 HHV-8 strains belonged to the B genotype (24), while the remaining clustered within the A5 subgroup (6) and one belonged to the F genotype. Additionally, we reviewed the K1 molecular diversity of published HHV-8 strains in Africa. This study demonstrated a high seroprevalence of HHV-8 in rural adult populations in Gabon and the presence of genetically diverse strains with B, A and also F genotypes.

High prevalence of human T-cell leukemia virus type-1b genotype among blood donors in Gabon, Central Africa.

BACKGROUND: The African continent is considered to be the largest endemic area of HTLV-1 infection, with at least several million infected individuals. Systematic screening of blood donors can prevent the transmission of HTLV-1 in blood. Gabon is one of the countries with the highest prevalence of HTLV-1 worldwide, and yet the routine testing of blood donors has still not been introduced. METHODS: All blood donations collected between April and July 2017 at the Centre National de Transfusion Sanguine of Gabon were studied. Plasma samples were screened by ELISA for the presence of HTLV-1/2 antibodies. Western blot (WB) and polymerase chain reaction (PCR) tests were used for confirmation. RESULTS: In total, 3123 blood donors were tested, including 1740 repeat and 1378 first-time blood donors (FTBDs). Of them, 132 samples tested positive for HTLV-1/2 by ELISA (4.2%). WB and PCR confirmed HTLV-1 infection for 23 individuals. The overall prevalence of HTLV-1 was 0.74% [95% CI 0.47%-1.10%], 1% in FTBD, and 0.5% in repeat donors. Age and sex-adjusted prevalence was five-fold lower in FTBD than in the general adult population of rural areas of Gabon. All detected HTLV-1 strains belonged to the central African HTLV-1b genotype but were highly diverse. CONCLUSION: We report an overall prevalence of HTLV-1 of 0.74%, one of the highest values reported for blood donors in Africa. Given the high risk of HTLV-1 transmission in blood, it is necessary to conduct cost-effectiveness studies to determine the need and feasibility of implementing screening of HTLV-1 in blood donors in Gabon.

Multiple recombinant events in human T-cell Leukemia virus Type 1: complete sequences of recombinant African strains.

Africa is the largest endemic area for HTLV-1, with many molecular genotypes. We previously demonstrated that some strains from North Africa (a-NA clade) originated from a recombinant event between Senegalese and West African strains. A series of 52 new HTLV-1 strains from 13 North and West African countries were sequenced in the LTR region and/or a env gene fragment. Four samples from French Guyanese of African origin were also added. Furthermore, 7 complete sequences from different genotypes were characterized. Phylogenetic analyses showed that most of the new African strains belong to the Cosmopolitan a-genotype. Ten new strains from the a-NA clade were found in Morocco, Western Sahara, Mali, Guinea, Côte d'Ivoire and Ghana. A new a-G-Rec clade, which arose from a distinct recombination event between Senegalese and West African strains, was identified in Guinea and Ghana. The complete sequences suggest that recombination occur in the LTR as well as the env/pol region of the genome, thus a-NA and a-G-Rec strains have a mosaic profile with genetic segments from either a-WA or a-Sen strains. Our work demonstrates that recombination in HTLV-1 may not be as rare an event as previously proposed.

Molecular epidemiology, genetic variability and evolution of HTLV-1 with special emphasis on African genotypes.

Human T cell leukemia virus (HTLV-1) is an oncoretrovirus that infects at least 10 million people worldwide. HTLV-1 exhibits a remarkable genetic stability, however, viral strains have been classified in several genotypes and subgroups, which often mirror the geographic origin of the viral strain. The Cosmopolitan genotype HTLV-1a, can be subdivided into geographically related subgroups, e.g. Transcontinental (a-TC), Japanese (a-Jpn), West-African (a-WA), North-African (a-NA), and Senegalese (a-Sen). Within each subgroup, the genetic diversity is low. Genotype HTLV-1b is found in Central Africa; it is the major genotype in Gabon, Cameroon and Democratic Republic of Congo. While strains from the HTLV-1d genotype represent only a few percent of the strains present in Central African countries, genotypes -e, -f, and -g have been only reported sporadically in particular in Cameroon Gabon, and Central African Republic. HTLV-1c genotype, which is found exclusively in Australo-Melanesia, is the most divergent genotype. This reflects an ancient speciation, with a long period of isolation of the infected populations in the different islands of this region (Australia, Papua New Guinea, Solomon Islands and Vanuatu archipelago). Until now, no viral genotype or subgroup is associated with a specific HTLV-1-associated disease. HTLV-1 originates from a simian reservoir (STLV-1); it derives from interspecies zoonotic transmission from non-human primates to humans (ancient or recent). In this review, we describe the genetic diversity of HTLV-1, and analyze the molecular mechanisms that are at play in HTLV-1 evolution. Similar to other retroviruses, HTLV-1 evolves either through accumulation of point mutations or recombination. Molecular studies point to a fairly low evolution rate of HTLV-1 (between 5.6E-7 and 1.5E-6 substitutions/site/year), supposedly because the virus persists within the host via clonal expansion (instead of new infectious cycles that use reverse transcriptase).

The prevalence of human T-lymphotropic virus type 1 & 2 (HTLV-1/2) in South African blood donors.

BACKGROUND AND OBJECTIVES: Donated blood is not currently screened for human T-cell lymphotropic virus (HTLV) in South Africa. Several small studies have detected HTLV-1 in South Africa, but prevalence by geographic region or population group is unavailable. MATERIALS AND METHODS: We performed a large seroprevalence study of South African blood donors during 3 months in 2013. All geographic regions except the Western Cape were included, and Black and Coloured (local term for mixed race) donors were oversampled. Identity-unlinked plasma samples were screened with the Abbott Prism HTLV-1/2 assay, and repeatedly reactive samples were tested by the Inno-LIA HTLV-1/2 Score confirmatory assay. Odds ratios were calculated with multivariable logistic regression. RESULTS: Of 46 752 donors tested, 133 (0·28%) were initially reactive, 111 (0·24%) repeatedly reactive and 57 (0·12%) confirmed positive for HTLV-1; none were HTLV-2 positive. Prevalence was 0·062% weighted to annual blood donations but highly concentrated in the Black population group (OR = 20·24 CI: 2·77-147·88); higher in females than males (OR = 1·81 CI: 1·06-3·08); and in donors aged >50 years compared to ages 16-19 (OR = 6·4 CI: 2·95-13·86). After controlling for age, sex and population group, there was no difference in prevalence between new and repeat blood donors or among geographic regions within South Africa. CONCLUSIONS: We conclude that HTLV-1 infection is widespread among the Black population of South Africa and its epidemiology is similar to other endemic areas. Because South Africa is increasing its recruitment of Black blood donors, the implications for blood screening require further consideration.

Risk factors for HTLV-1 infection in Central Africa: A rural population-based survey in Gabon.

BACKGROUND: Human T-Lymphotropic Virus type 1 (HTLV-1) is a human oncoretrovirus that infects at least 5 to 10 million people worldwide and is associated with severe diseases. Africa appears as the largest HTLV-1 endemic area. However, the risk factors for the acquisition of HTLV-1 remain poorly understood in Central Africa. METHODS: We conducted an epidemiological survey between 2013 and 2017, in rural areas of 6 provinces of Gabon, in a rainforest environment. Epidemiological data were obtained and blood samples were collected after informed consent. Plasma were screened for HTLV-1 antibodies by ELISA and the positive samples were then tested by Western blot (WB). Genomic DNA derived from buffy-coat was subjected to two semi-nested PCRs amplifying either HTLV-1 env gene or LTR region fragments. RESULTS: We recruited 2,060 individuals over 15 years old, including 1,205 men and 855 women (mean age: 49 years). Of these, 299 were found to be ELISA HTLV-1/2 seropositive. According to WB criteria, 136 were HTLV-1 (6.6%), 25 HTLV-1/2 (1.2%) and 9 HTLV seroreactive (0.4%). PCR results showed that 146 individuals were positive for at least one PCR: 104 for the env gene and 131 for the LTR region. Based on both serological and molecular results, 179 individuals were considered infected with HTLV-1, leading to an overall prevalence of 8.7%. The distribution of HTLV-1 infection was heterogeneous across the country. Based on multivariable analyses, female gender, increasing age, ethnicity (Pygmy) and multiple hospitalizations (more than 5 times) were found to be independent risk factors for HTLV-1 infection. Furthermore, a non-human primate bite appeared to be marginally associated with a higher risk of HTLV-1 infection. CONCLUSION: Based on state-of-the-art serological and molecular methods, we have demonstrated that rural adult populations in Gabon are highly endemic for HTLV-1. Our results regarding risk factors should lead to public health actions aiming to reduce HTLV-1 transmission.

Kaposi sarcoma, oral malformations, mitral dysplasia, and scoliosis associated with 7q34-q36.3 heterozygous terminal deletion.

Chromosome 7 germline macrodeletions have been implicated in human congenital malformations and developmental delays. We herein report a novel heterozygous macrodeletion of 7q34-q36.3 in a 16-year-old girl originally from West Indies. Similar to previously reported cases of germline chromosome 7q terminal deletions, our patient has dental malposition, and developmental (growth and intellectual) delay. Novel phenotypic features include endemic Kaposi sarcoma (KS), furrowed tongue, thoracolumbar scoliosis, and mild mitral valve dysplasia. The occurrence of human herpes virus 8-driven KS, in a child otherwise normally resistant to other infectious agents and without any other tumoral lesion, points to a very selective immunodeficiency. While defects in organogenesis have been described with such macrodeletions, this is the first report of immunodeficiency and cancer predisposition.

Serological and Molecular Methods to Study Epidemiological Aspects of Human T-Cell Lymphotropic Virus Type 1 Infection.

We estimated that at least 5-10 million individuals are infected with HTLV-1. Importantly, this number is based on the study of nearly 1.5 billion people living in known human T-cell lymphotropic virus type 1 (HTLV-1) endemic areas, for which reliable epidemiological data are available. However, for some highly populated regions including India, the Maghreb, East Africa, and some regions of China, no consistent data are yet available which prevents a more accurate estimation. Thus, the number of HTLV-1 infected people in the world is probably much higher. The prevalence of HTLV-1 prevalence varies depending on age, sex, and economic level in most HTLV-1 endemic areas. HTLV-1 seroprevalence gradually increases with age, especially in women. HTLV-1 has a simian origin and was originally acquired by humans through interspecies transmission from STLV-1 infected monkeys in the Old World. Three main modes of HTLV-1 transmission have been described; (1) from mother-to-child after prolonged breast-feeding lasting more than six months, (2) through sexual intercourse, which mainly, but not exclusively, occurs from male to female and lastly, (3) from contaminated blood products, which contain HTLV-1 infected lymphocytes. In specific areas, such as Central Africa, zoonotic transmission from STLV-1 infected monkeys to humans is still ongoing.The diagnostic methods used to study the epidemiological aspects of HTLV-1 infection mainly consist of serological assays for the detection of antibodies specifically directed against different HTLV-1 antigens. Screening tests are usually based on enzyme-linked immunoabsorbent assay (ELISA), chemiluminescence enzyme-linked immunoassay (CLEIA) or particle agglutination (PA). Confirmatory tests include mostly Western blots (WB)s or innogenetics line immunoassay (INNO-LIA™) and to a lesser extent immunofluorescence assay (IFA). The search for integrated provirus in the DNA from peripheral blood cells can be performed by qualitative and/or quantitative polymerase chain reaction (qPCR). qPCR is widely used in most diagnostic laboratories and quantification of proviral DNA is useful for the diagnosis and follow-up of HTLV-1 associated diseases such as adult T-cell leukemia (ATL) and tropical spastic paraparesis/HTLV-1 associated myelopathy (TSP/HAM). PCR also provides amplicons for further sequence analysis to determine the HTLV-1 genotype present in the infected person. The use of new generation sequencing methodologies to molecularly characterize full and/or partial HTLV-1 genomic regions is increasing. HTLV-1 genotyping generates valuable molecular epidemiological data to better understand the evolutionary history of this virus.

Persistent risk of adult T-cell leukemia/lymphoma after neonatal HTLV-1 infection through exchange transfusion.

A 36-year-old Caucasian male presented with adult T-cell leukemia/lymphoma (ATL). HTLV-1 contamination was attributed to a neonatal exchange transfusion. Remission was achieved but 11 years later he presented with symptoms suggesting ATL relapse. Molecular studies of T-cell clonality and virus integration sites revealed a clonal disease, distinct from the first tumor.

A Novel Human T-lymphotropic Virus Type 1c Molecular Variant in an Indigenous Individual from New Caledonia, Melanesia.

BACKGROUND: Human T-Lymphotropic Virus type 1 (HTLV-1) is endemic among people of Melanesian descent in Papua New Guinea, Solomon Islands and Vanuatu, and in Indigenous populations from Central Australia. Molecular studies revealed that these Australo-Melanesian strains constitute the highly divergent HTLV-1c subtype. New Caledonia is a French overseas territory located in the Southwest Pacific Ocean. HTLV-1 situation is poorly documented in New Caledonia and the molecular epidemiology of HTLV-1 infection remains unknown. OBJECTIVES: Studying 500 older adults Melanesian natives from New Caledonia, we aim to evaluate the HTLV-1 seroprevalence and to molecularly characterize HTLV-1 proviral strains. STUDY DESIGN: Plasma from 262 men and 238 females (age range: 60-96 years old, mean age: 70.5) were screened for anti-HTLV-1 antibodies by particle agglutination (PA) and indirect immunofluorescence assay (IFA). Serological confirmation was obtained using Western blot assay. DNAs were extracted from peripheral blood buffy coat of HTLV-1 seropositive individuals, and subjected to four series of PCR (LTR-gag; pro-pol; pol-env and tax-LTR). Primers were designed from highly common conserved regions of the major HTLV-1 subtypes to characterize the entire HTLV-1 proviral genome. RESULTS: Among 500 samples, 3 were PA and IFA positive. The overall seroprevalence was 0.6%. The DNA sample from 1 New Caledonian woman (NCP201) was found positive by PCR and the complete HTLV-1 proviral genome (9,033-bp) was obtained. The full-length HTLV-1 genomic sequence from a native woman from Vanuatu (EM5), obtained in the frame of our previous studies, was also characterized. Both sequences belonged to the HTLV-1c Australo-Melanesian subtype. The NCP201 strain exhibited 0.3% nucleotide divergence with the EM5 strain from Vanuatu. Furthermore, divergence reached 1.1% to 2.9% with the Solomon and Australian sequences respectively. Phylogenetic analyses on a 522-bp-long fragment of the gp21-env gene showed the existence of two major clades. The first is composed of strains from Papua New Guinea; the second includes strains from all neighboring archipelagos (Solomon, Vanuatu, New Caledonia), and Australia. Interestingly, this second clade itself is divided into two sub-clades: strains from Australia on one hand, and strains from Solomon Islands, Vanuatu and New Caledonia on the other hand. CONCLUSIONS: The HTLV-1 seroprevalence (0.6%) in the studied adult population from New Caledonia appears to be low. This seroprevalence is quite similar to the situation observed in Vanuatu and Solomon Islands. However it is very different to the one encountered in Central Australia. Taken together, these results demonstrated that Australo-Melanesia is endemic for HTLV-1 infection with a high diversity of HTLV-1c strains and a clear geographic clustering according to the island of origin of HTLV-1 infected persons.

Human T-Lymphotropic Virus type 1 infection in an Indigenous Australian population: epidemiological insights from a hospital-based cohort study.

BACKGROUND: The Human T Lymphotropic Virus type 1 (HTLV-1) subtype C is endemic to central Australia where each of the major sequelae of HTLV-1 infection has been documented in the socially disadvantaged Indigenous population. Nevertheless, available epidemiological information relating to HTLV-1c infection is very limited, risk factors for transmission are unknown and no coordinated program has been implemented to reduce transmission among Indigenous Australians. Identifying risk factors for HTLV-1 infection is essential to direct strategies that could control HTLV-1 transmission. METHODS: Risk factors for HTLV-1 infection were retrospectively determined for a cohort of Indigenous Australians who were tested for HTLV-1 at Alice Springs Hospital (ASH), 1st January 2000 to 30th June 2013. Demographic details were obtained from the ASH patient management database and the results of tests for sexually transmitted infections (STI) were obtained from the ASH pathology database. RESULTS: Among 1889 Indigenous patients whose HTLV-1 serostatus was known, 635 (33.6 %) were HTLV-1 Western blot positive. Only one of 77 (1.3 %) children tested was HTLV-1 infected. Thereafter, rates progressively increased with age (15-29 years, 17.3 %; 30-49 years, 36.2 %; 50-64 years, 41.7 %) reaching 48.5 % among men aged 50-64 years. In a multivariable model, increasing age (OR, 1.04; 95 % CI, 1.03-1.04), male gender (OR, 1.41; 95 % CI, 1.08-1.85), residence in the south (OR, 10.7; 95 % CI, 7.4-15.6) or west (OR, 4.4; 95 % CI, 3.1-6.3) of central Australia and previous STI (OR, 1.42; 95 % CI, 1.04-1.95) were associated with HTLV-1 infection. Infection was acquired by three of 351 adults who were tested more than once during the study period (seroconversion rate, 0.24 (95 % CI = 0.18-2.48) per 100 person-years). CONCLUSIONS: This study confirms that HTLV-1 is highly endemic to central Australia. Although childhood infection was documented, HTLV-1 infection in adults was closely associated with increasing age, male gender and STI history. Multiple modes of transmission are therefore likely to contribute to high rates of HTLV-1 infection in the Indigenous Australian population. Future strategies to control HTLV-1 transmission in this population require careful community engagement, cultural understanding and Indigenous leadership.

Higher HTLV-1c proviral loads are associated with blood stream infections in an Indigenous Australian population.

BACKGROUND: An association between blood stream infections (BSI) and HTLV-1 seropositivity in Indigenous Australians might result from HTLV-1 mediated inflammation and parasite coinfections that provide portals of entry for bacteria. OBJECTIVES: To determine whether BSI risk increases with HTLV-1c proviral load (PVL) and to identify the pathogens responsible in the context of HTLV-1 related conditions. STUDY DESIGN: Indigenous adults admitted to Alice Springs Hospital, central Australia, were recruited as cases or controls according to whether they had a BSI. Clinical data were extracted from case notes and the hospital pathology database. HTLV-1 serology and PVL assays were then performed and risk factors for BSI were determined for HTLV-1 infected subjects. RESULTS: Risk factors were compared between 44 cases and 30 controls who were HTLV-1 Western blot positive. In a multivariable model, high HTLV-1c PVL was predictive of BSI during the study period (OR, 9.10; 95% CI, 2.40-34.4). Median (IQR) HTLV-1c PVL (copies per 100 PBL) was 39-fold higher for patients recording any BSI (0.116 (0.009, 0.277)) relative to those who had no BSI (0.003 (0.000, 0.067))(p=0.0007). Mean (SD) PVL for subjects with no BSI (n=27), 1 BSI (n=37) and ≥2 BSI (n=10) during the study period were 0.120 (0.301), 0.271 (0.622) and 0.500 (0.654) copies per 100 PBL, respectively (p=0.0007). Five BSI were associated with possible complications of HTLV-1; strongyloidiasis (3), infective dermatitis (1), HTLV-1 associated bronchiectasis (1). CONCLUSIONS: Higher HTLV-1c PVL predicts BSI risk; however; most BSI were not associated with recognised complications of HTLV-1 infection.

Epidemic History and Iatrogenic Transmission of Blood-borne Viruses in Mid-20th Century Kinshasa.

BACKGROUND: The human immunodeficiency virus type 1 (HIV-1) pandemic was ignited in Léopoldville (now known as Kinshasa), in the former Belgian Congo. Factors that jump-started its early expansion remain unclear. Nonlethal hepatitis C virus (HCV) and human T-cell lymphotropic virus (HTLV-1) can be used to investigate past iatrogenic transmission. METHODS: We undertook a cross-sectional study of elderly inhabitants of Kinshasa, with serological assays, amplification, and sequencing. Risk factors were assessed through logistic regression. Phylogenetic methods reconstructed the genetic history of HCV. RESULTS: A total of 217 of 839 participants (25.9%) were HCV seropositive; 26 (3.1%) were HTLV-1-seropositive. Amplification products were obtained from 118 HCV-seropositive participants; subtypes 4k (in 47 participants) and 4r (in 38) were most common. Independent risk factors for HCV subtype 4r seropositivity were intramuscular tuberculosis therapy, intravenous injections at hospital A, intravenous injections before 1960, and injections at a colonial-era venereology clinic. Intravenous injections at hospital B and antimalarials were associated with HCV subtype 4k seropositivity. Risk factors for HTLV-1 seropositivity included intravenous injections at hospitals C or D and transfusions. Evolutionary analysis of viral sequences revealed independent exponential amplification of HCV subtypes 4r and 4k from the 1950s onward. CONCLUSIONS: Iatrogenic transmission of HCV and HTLV-1 occurred in mid-20th century Kinshasa, at the same time and place HIV-1 emerged. Iatrogenic routes may have contributed to the early establishment of the pandemic.

Adult T-Cell Leukemia/Lymphoma in a Caucasian Patient After Sexual Transmission of Human T-Cell Lymphotropic Virus Type 1.

Adult T-cell leukemia/lymphoma (ATLL), a T-cell neoplasm caused by human T-cell lymphotropic virus type 1 (HTLV-1), develops in the majority of cases in individuals who were infected with HTLV-1 as young children, by their mother during prolonged breastfeeding. We report the case of a Caucasian French man, whose parents were HTLV-1-seronegative and who developed ATLL after HTLV-1 sexual transmission by a Cameroonian woman. This hypothesis was corroborated by genotyping of the patient's virus, which revealed an HTLV-1B strain, found only in Central Africa, especially in Cameroon. Thus, ATLL may develop after HTLV-1 infection during adulthood, outside breastfeeding.

A Severe Bite From a Nonhuman Primate Is a Major Risk Factor for HTLV-1 Infection in Hunters From Central Africa.

BACKGROUND: HTLV-1 infection is endemic to Central African populations. The risk factors for HTLV-1 acquisition in humans via the interspecies transmission of STLV-1 (its simian counterpart) remain largely unknown. METHODS: We studied 269 individuals (254 men, 15 women) bitten by a nonhuman primate (NHP), mostly during hunting activities. These, Pygmies and Bantus, living in the southern Cameroonian rainforest, were matched for sex, age, and ethnicity with individuals from the same settlements reporting no NHP bites. HTLV-1 serology was performed by Western blot on plasma samples. PCR was carried out for HTLV-1 provirus on buffy-coat DNAs. The amplified products were sequenced and analyzed by phylogenetic analyses. RESULTS: HTLV-1 prevalence was 8.6% (23/269) in individuals with bites, vs 1.5% (4/269) in matched controls (P < .001). Moreover, HTLV-1 infection was linked to bite severity. The 23 HTLV-1-positive bitten individuals reported being bitten by a gorilla (17), chimpanzee (3), or small monkey (3). Thirteen (56%) were coinfected with a simian foamy virus known to be acquired through severe bites. Mother-to-child infection was excluded in 6 HTLV-1-infected bitten individuals. All the HTLV-1-positive hunters bitten by a gorilla or chimpanzee were infected with a subtype B strain similar to that present in apes from the same area. Two hunters bitten by small monkeys (C. agilis in one case) were infected with a HTLV-1 subtype F strain very similar to the STLV-1 strains present in such monkeys. CONCLUSIONS: These results strongly suggest ongoing direct zoonotic acquisition of STLV-1 in humans through severe NHP bites during hunting activities.

Northern African strains of human T-lymphotropic virus type 1 arose from a recombination event.

UNLABELLED: Although recombination is a major source of genetic variability in retroviruses, no recombinant strain had been observed for human T-lymphotropic virus type 1 (HTLV-1), the first isolated human-pathogenic retrovirus. Different genotypes exist for HTLV-1: Genotypes b and d to g are restricted to central Africa, while genotype c is only endemic in Australo-Melanesia. In contrast, the cosmopolitan genotype a is widely distributed. We applied a combination of phylogenetics and recombination analysis approaches to a set of new HTLV-1 sequences, which we collected from 19 countries throughout Africa, the continent where the virus has the largest endemic presence. This led us to demonstrate the presence of recombinants in HTLV-1. Indeed, the HTLV-1 strains currently present in North Africa have originated from a recombinant event between strains from Senegal and West Africa. This recombination is estimated to have occurred around 4,000 years ago. This recombination seems to have been generated during reverse transcription. In conclusion, we demonstrate that, albeit rare, recombination can occur in HTLV-1 and may play a role in the evolution of this retrovirus. IMPORTANCE: A number of HTLV-1 subtypes have been described in different populations, but none of the genetic differences between these subtypes have been ascribed to recombination events. Here we report an HTLV-1 recombinant virus among infected individuals in North Africa. This demonstrates that, contrary to what was thought, recombination can occur and could play a role in the evolution of HTLV-1.