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

Abstract

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).

Keywords: Africa; Evolution; Genotypes; HTLV-1; Molecular epidemiology; Mutation rate.

Fig. 1

Geographical distribution of the seven main molecular genotypes of HTLV-1 (a–g) and major pathways for the spread of the virus through the movements of infected populations

Fig. 2

Map of Africa showing the general distribution of HTLV-1 genotypes across the continent. The proportion of the different HTLV-1 genotypes and subgroups is presented for each African country. This figure incorporates the information from papers of molecular epidemiology available on PubMed [, , –, , , –, , , –144]. It also incorporates results from two manuscripts in preparation (Cassar et al. and Filippone et al.), notably concerning the situation in Benin, Sierra Leone, Western Sahara, and Madagascar, where no data were available to our knowledge. Countries without indications have no informative published data on HTLV-1 genotypes between 1994 and 2019. The size of the circles is proportional to the number of strains identified. The smallest size corresponds to 1 characterized strain, the intermediate sizes to a maximum of 5 or 29 strains and the largest to a minimum of 30 strains. HTLV-1a-North African (HTLV-1 a-NA), HTLV-1a-Senegalese (HTLV-1 a-Sen), HTLV-1a-West African (HTLV-1 a-WA), HTLV-1b and HTLV-1a-Transcontinental (HTLV-1 a-TC) are the most common throughout the continent in North, West, Central and the Austral parts respectively. HTLV-1 d, -e, -f and-g have been identified in Central Africa (Cameroon, Central African Republic, and Gabon)

Fig. 3

Phylogenetic representation of the HTLV-1 genotypes and subgroups. An alignment of complete LTR sequences (774-nt long) from 178 HTLV-1 strains was obtained. The unrooted phylogenetic tree was generated with the neighbor-joining method using the GTR model (gamma = 0.4953). Branch lengths are drawn to scale, with the bar indicating 0.01 nucleotide replacement per site. Numbers on each node indicate the percentage of bootstrap samples (of 1000 replicates). HTLV-1 genotypes (a–g) and subgroups (within HTLV-1a and HTLV-1c) are presented. References strains (presented in the table) are indicated in the tree, except Mel1 and Ethio10 for which the complete LTR sequence is not available

Fig. 4

Diverse clusters can be identified within the HTLV-1a-TC subgroup. An alignment of LTR sequences (519-nt long) from 91 HTLV-1a-TC strains was obtained. Sequences from HTLV-1a-Jpn were used as outgroup. The phylogenetic tree was generated with the neighbor-joining method using the GTR model (gamma = 0.4953). Horizontal branch lengths are drawn to scale, with the bar indicating 0.01 nucleotide replacement per site. Values correspond to the approximate likelihood-ratio test for each clade