Molecular investigation of the evolutionary history and diversity of primate T-lymphotropic virus types 1 and 3

The Primate T-lymphotropic viruses (PTLV) comprise a group of complex retroviruses that infect both humans (HTLV) and simians (STLV) and have been associated with leukaemia or lymphoma and with neurological disorders. PTLVs have a peculiar replication strategy: their way of life is mainly determined by clonal expansion of the infected cells, rather than by the error-prone reverse transcription process. As a consequence PTLVs are, unlike HIV and RNA viruses, characterised by an extra-ordinary genomic stability. Due to this mitotic spread, thereby using the cell replication machinery, this virus seems to have evolved partially in concert with its host, in particular with its hosts' migrations. In the first part of this work the slow evolutionary rate of PTLV type 1 has been quantified to subsequently date events in the PTLV-1 history. By superimposing an anthropological-documented host migration event on an equivalent event in the reconstructed viral phylogeny, a calibration for the PTLV-1 evolutionary rate can be provided. In this way it has been demonstrated through different estimated HTLV-1 rates that HTLV-1 disseminated in Latin America as a consequence of a post-Columbian introduction of the virus from Africa (± 400 years ago). By investigating the origin of African PTLV-1 it has been shown that the spread of PTLV-1 in Africa must have occurred at least 27,300 ± 8,200 ya and the interspecies transmissions that resulted in the African HTLV-1 subtypes appeared to have emerged in a range of 21,100 to 3,000 ya. The HTLV-1 evolutionary rate has also been estimated with recourse to anthropological events using pedigree data of HTLV-1 vertically infected family members. The low number of observed mutations confirmed the genetic stability of the virus. They also created a large variance in the estimated rates, ranging almost from rates of cellular genes to those of the slowest evolving RNA viruses. The Asian PTLV-1 evolution has been further unraveled in a second part of the study. The full genome sequencing and analysis of the currently most divergent Macaca arctoides STLV-1 revealed a host species-dependent clustering in a ladder-like topology, which seem to reflect macaque migration waves. The analysis of novel strains in orang-utans, siamang and Sulawesi macaques confirmed this clustering pattern. Molecular clock analysis showed vicariance can not explain this phenomenon, but rather preferential viral host-switching between closely related macaques in a more distant past. A third and last part was focused on the identification of novel STLV-3 strains. The discovery of STLV-3 infection in 2 out of 121 Cercopithecus nictitans from Cameroon and in 5 of 23 Ethiopian Theropithecus gelada has been described. The genetic diversity between all known STLV-3 strains has been analysed through phylogenetic inference. By means of molecular clock analysis a time frame for the emergence of STLV-3 in Africa of 110.000 to 73.000 year ago could be inferred. The different studies described in this work corroborate the low evolutionary rate of PTLV and suggest that Central Africa is the cradle of PTLV infection based on the largest intra- and intertype PTLV diversity observed in this area