Human T-lymphophotropic virus (HTLV), formerly called human T-cell lymphotropic virus or human T-cell leukemia/lymphoma virus, is a member of the Deltaretrovirus genus. The Deltaretroviruses belong to the Retroviridae family and include bovine leukemia virus (BLV) and simian T-lymphotropic virus (STLV), aside HTLVs.1

Retroviruses were not isolated from humans prior to 1979. Hence, HTLV (type 1) was the first human retrovirus to be isolated1 from a patient with cutaneous T-cell lymphoma. HTLV (type 2) was isolated a few years later from a patient with hairy cell leukemia.2 It was then believed that HTLV-2 could be associated with hairy cell leukemia. However, the failure to isolate HTLV-2 from replicable number of hairy cell leukemia patients proved that it was not the etiological agent of hairy cell leukemia but rather, a passenger agent.

The third and probably the most important retrovirus was discovered a year later and placed in the same genus as HTLV-1 and 2 viruses. Upon subsequent research however, it was renamed human immunodeficiency virus and reclassified under the Lentivirus genus. In 2005, researchers discovered two (2) new HTLV types – HTLV-3 and HTLV-4.3,4 Knowledge about these viruses is limited as few cases have been reported, compared to HTLV 1 and 2.

HTLV 1 is endemic in some parts of the world (Southwestern Japan, South America, the Caribbean Basin, the Middle East, Australo – Melanesia, the West Indies, Jamaica), as well as equatorial Africa,5 where West Africa lies. HTLV-2 is endemic in pockets of populations. With the aim of exposing the possible re-emergence of HTLV in West Africa, this review focuses on the distribution of the virus types, points out the significance of frequent indeterminate reports, while highlighting the need for mandatory routine blood screening prior to blood donation and/or transfusion.

Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) was used to report the identified studies. Google Scholar, CrossRef, NCBI (PubMed), MEDLINE, Research Gate, Mendeley were searched from database inception until February 2018. Abstracts of Conferences and Proceedings, organization websites and reference lists of selected papers were also searched. Search terms were: Worldwide prevalence of HTLV, HTLV in Africa, HTLV in West Africa, HTLV subtypes, HTLV 3 and 4 in Africa, HTLV of African origin, HTLV seroindeterminate results, spread of HTLV. The first 100 sources identified by Crossref and Google Scholar were screened. Duplicate titles were removed (Fig. 1). Eligible studies included original reports from prevalence studies, case studies and cohort studies. Titles and abstracts recovered in the search were screened for study suitability, focusing on the keywords; non-English, non-Human related, and in-vitro studies were excluded at this point and full-text copies of papers that possibly dealt with the review topic were retrieved. Same reports of already reported population by another study were also excluded. The retrieved data were screened and extracted by NCJ and checked independently by A, EE and M for any discordance. Study characteristics are presented in figures and table.

Fig. 1.

PRISMA flow chart of reviewed studies.

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The HTLV-1 and 2 viruses have experienced gradual but considerably consistent increase in prevalence since their discovery. HTLV-1 subtypes are associated with specific regions of the globe (Fig. 2), while HTLV-2 subtypes are related to highly specific subpopulations (e.g. Brazilian Indians) and behaviors such as injection drug use (Fig. 3).

Fig. 2.

Global distribution of HTLV-1 subtypes.

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Source: Gessain and Cassar.5

Fig. 3.

Global distribution and spread of HTLV-2 subtypes.

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There are seven geographical or ethnic-related subtypes of HTLV-1 including the Cosmopolitan subtype A with four (4) subgroups, the Central African subtype B, the Australo – Melanesian subtype C, the Central African/Pygmies subtype D, the Central African subtypes E (also in Southern Africa), F, and G respectively.5 HTLV-2 has four known subtypes – A, B, C, and D.

Levine et al.6 carried out a study on the worldwide distribution of HTLV-1 virus on 43,445 participants (excluding endemic regions of Japan) and reported a prevalence rate of 3.7%. According to the study, the highest prevalence rate of 11.2% was seen in Hawaii, which was closely followed by West/Central Africa with a prevalence rate of 10.0%. The Caribbean basin had a prevalence rate of 5.1% while the other countries captured in the study had prevalence rates lower than 3.7% – South Africa (3.5%), Central/South America (2.9%), non-endemic regions of Japan (2.8%), Middle East (2.2%), Asia (excluding Japan – 1.4%), Continental North America (1.2%), with Europe having the least prevalence rate of 1.0%. The prevalence of HTLV-1 is different for different parts of the world. It is generally categorized into three strata – regions of low (less than 1%), average or moderate (1% to 5%), and high (greater than 5%) prevalence rates. Europe has been captured in many epidemiological studies, with most of the studies focusing on the United Kingdom, France and Spain.5 Most of the people diagnosed with HTLV were either born in – or had genetic affiliations with Afro – Caribbean and African origin, indicating that HTLV infections and/or transmission may be linked to human migration. In Asia, the prevalence of HTLV-1 has been reported to be between 0.098% and 2.12% in endemic areas of Iran and 0.3% and 37.0% in endemic areas of Japan.5,7,8 Irrespective of the fact that Japan is being bordered by PR China, North and South Korea, the Philippines, Northern Mariana Islands, and the Republic of China (Taiwan), these countries are largely free from HTLV infection, suggesting that the virus is not transmitted by migrants from these regions, thus ruling out human migration as the cause of endemicity in Japan.

The global distribution of human T-lymphotropic virus 2 (HTLV-2) is not as widespread as HTLV 1, as it is found to be present in pockets of populations. The virus is common among intravenous drug users (IDUs) in Eire, Spain, Italy and Scandinavia, less common in the UK, and rare in Germany and France.9,10 Subtypes A and B are endemic in IDUs and indigenous people of in North, South and Central (Latin) America, Europe and Asia (Vietnam, Italy and Spain),10 and occur sporadically in parts of West and Central Africa – Ghana, Gabon, Cameroon, where it was first isolated and Democratic Republic of Congo (DR Congo) among the pigmy tribes.2 Subtype C, which is a distinct molecular subtype, was isolated from the Amazon region of the Brazilian sub-cluster, while subtype D, distinct and genetically different from the other subtypes was isolated from Central African Congolese Efe Bambuti pygmy.10 It is possible that HTLV-2 was introduced into the IDUs population of the United States during the 1970s, and into Europe, slightly later.

Both HTLV-1 and 2 have been found to be involved in increasing epidemic in some factions of the world. However, HTLV-2 spread and/or prevalence is more common than HTLV-1 in the United States, although the overall prevalence is 200 per 100,000 population.11 Generally, the highest prevalence of HTLV-1 is found in Japan (37%) while Latin America is estimated to have the lowest prevalence (0.024–1.00%). Ample epidemiological studies in Turkey are lacking hence, the inability to categorize its stratum of prevalence. On the other hand, HTLV-2 (subtype C) is most endemic among the indigenous people of Brazil, hence, the Brazilian Amazon is the highest area of its endemicity in the world.9 An alarmingly high HTLV-2 prevalence of up to 61% has been found in Venezuela among the Yaruro and Guahibo populations9,10 while up to 3.8% prevalence has been found in Peruvian Amazon.

Seroprevalence of HTLV-1 is more predominant in females than males, indicating that females are more at risk of the retroviral infection.1 Vertical transmission however, accounts for higher male predisposition to HTLV-1 seropositivity at childhood. The ratio of adult T-cell leukemia/lymphoma (ATLL) is 2:1 in males and females while the reverse is the case for HTLV-1-associated myelopathy (HAM)/tropical spastic paraparesis (TSP).12 It is rather difficult to determine the gender distribution of HTLV-2 because of the peculiarity of the study populations, although it has been associated with the female gender in the United States.9 The prevalence of the viruses is higher in older age, majorly due to their long latency period. The time of expression of the viruses leading to malignant or neurological disorders, however, varies with individuals. ATLL is mostly rapidly progressive and fatal, with median survival time of two years. HAM/TSP may ensue as early as five months after transfusion-transmitted HTLV-1 infection.

There seems to be an overall decline in the worldwide distribution of HTLV-1 virus from 10–20 million to 5–10 million.5 The reason for such wide gap and difference in distribution may be due to the fact that large regions had not been investigated, few population-based studies are available, and the assays used for HTLV-1 serology were not specific enough at the time of early epidemiological studies.5 It should however, be noted that there is still a large amount of data yet to be captured in some areas of the world, as highly populated regions including East Africa, China, India, and the Maghreb, are hitherto yet to be exhaustively surveyed. Hence, the worldwide distribution of HTLV-1 may be slightly or well above 10 million infected individuals. Furthermore, the true prevalence of HTLV-1 worldwide has not been covered previously as epidemiological studies mostly cover only blood donors, pregnant women, or hospital based studies of different selected patients or high-risk groups such as IDUs, HIV, and other hematologic patients, neurologic patients or prostitutes, rather than the general population (villages, towns, cities, states, provinces regions or geo-political zones of a country).

The screening of blood donors for HTLV-1/2 infection alongside other mandatory tests before donation has been mandated in many endemic countries – Asia – China, Japan, Taiwan; America: Argentina, Brazil, Canada, Colombia, French West Indies, Jamaica, Peru, USA, and Venezuela; Australia; Europe: New Zealand, Sweden, UK, Uruguay, France, Greece, Ireland, Netherlands, Portugal, Romania, Denmark, Finland, and Norway. Middle East: Israel, Iran, and Saudi Arabia.72 However, routine screening and diagnosis of HTLV-1/2 infection among blood donors in West Africa and other endemic parts of Africa, is rarely practiced, despite the fact that these regions are of moderate to high endemicity.

Two new viruses, genetically related to HTLV-1 and 2 (although more related to their STLV counterparts), were discovered in the same geographical region, the rainforest part of Southern Cameroon, Central Africa.3,4 On isolation from asymptomatic pygmies and Bantus, they were subjected to enzyme immunoassay (EIA) and Western blotting which yielded indeterminate results to both HTLV-1 and 2. Their proviruses were then detected using a series of PCR primers designed to amplify all known HTLVs and STLVs.3,4 The infected individuals were either hunters, or living in the rainforest region (Fig. 4), characterized by existence of non-human primates highly infected with STLVs. It is therefore, not out of place to suggest that they may have diverged via interspecies transmission from non-human primates to humans. The relatedness to other deltaviruses led to their placement in the same genus and family, and the designation of the names HTLV-3 and HTLV-4.

Fig. 4.

Global distribution and spread of HTLVs.

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Fig. 5.

Distribution of HTLV-1 and 2 in West Africa.

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The tax gene of HTLV-3, like HTLV-1, contains a PDZ binding motif while HTLV-4 does not. The motif binds to PDZ domain and promotes virus-mediated T-cell proliferation in vitro and persistence in vivo. PDZ (postsynaptic density 95, PSD-85; Discs large, Dlg; Zonula occludens-1, ZO-1) domains are modular protein interaction domains – formerly known as Discs-large homology regions (DHRs) or GLGF repeats, after a conserved Gly-Leu-Gly-Phe sequence found within the domain – that play a role in protein targeting and protein complex assembly.73 The presence of HTLV-3 and 4 viruses in Cameroon, though not associated with any diseases, is depictive of their possible presence in other West and Central African countries.

There are several reports of indeterminate WB patterns resulting from HTLV reactive sera/plasma samples in Africa. Researchers have suggested cross-reactivity with antigen of Plasmodium falciparum39 and of various infectious agents, as well as low proviral load or co-infection with other infectious agents like HIV. However, most of these indeterminate results in apparently healthy individuals are not HLTV-3 or 4, upon subjection to further confirmatory assays. Persistent increased rate of indeterminate results, which are not HTLV-3 or HTLV-4 upon subjection to further confirmatory assays, ought to be looked into. It should be recalled that HIV-1 and 2 (previously named HTLV-3 and 4) were initially grouped together with HTLV-1 and 2, and were only regrouped after further research. Therefore, further investigative research on these indeterminate cases is warranted, as there is a possibility that the indeterminate WB results encountered with EIA/PA reactive samples could be new HTLV-1, 2, 3 or 4 subtypes, yet-to-be discovered HTLV type or an entirely new undiscovered infectious agents with similar reactivity to EIA.

Although the prevalence rate of HTLV in target risk populations is useful epidemiological data, they may not give a true representation for accurate estimation of HTLV infections in West Africa, as they are mostly restricted to visitations of study participants to the hospitals (hospital – based studies). Most Africans engage in self-medication, as they do not visit the hospitals until they present with severe symptoms. Giving the long latency of the virus, as well as the fact that diagnostic and/or routine screening is hitherto not mandatory, the real prevalence rates of HTLVs may be higher than those found in the reviewed studies. It should be noted that prevalence data from population-based studies have a trend to be more accurate once they are considered healthy individuals. West African lacks recent epidemiological data on HTLV prevalence. Nation-wide general population based studies capturing the communities (apparently healthy population) should therefore be considered, so as to ascertain the true prevalence of these virus types. Furthermore, the significantly high rate of HTLV indeterminate WB serological patterns in African studies calls for concern. Although cross-reactivity with antigens of some other infectious agents have been hypothesized, there are possibilities that such reactions could be resultant from yet-to-be discovered HTLV (sub)types or an entirely unknown virus/infectious agent. It is imperative that routine screening for HTLVs be mandated in West Africa, especially in the health care centers and hospitals that engage in blood donation and/or transfusion, since West Africa is a region of high endemicity of HTLV-1 and 2. It should be noted that West Africa is at risk of HTLV-3 and 4 transmission and subsequent endemicity, given the presence of the virus types in Cameroon, a neighbouring country to Nigeria, a West African country.

The authors declare no conflicts of interest.