Parallel Germline Infiltration of a Lentivirus in Two Malagasy Lemurs

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Abstract
Retroviruses normally infect the somatic cells of their host and are transmitted horizontally, i.e., in an exogenous way. Occasionally, however, some retroviruses can also infect and integrate into the genome of germ cells, which may allow for their vertical inheritance and fixation in a given species; a process known as endogenization. Lentiviruses, a group of mammalian retroviruses that includes HIV, are known to infect primates, ruminants, horses, and cats. Unlike many other retroviruses, these viruses have not been demonstrably successful at germline infiltration. Here, we report on the discovery of endogenous lentiviral insertions in seven species of Malagasy lemurs from two different genera—Cheirogaleus and Microcebus. Combining molecular clock analyses and cross-species screening of orthologous insertions, we show that the presence of this endogenous lentivirus in six species of Microcebus is the result of one endogenization event that occurred about 4.2 million years ago. In addition, we demonstrate that this lentivirus independently infiltrated the germline of Cheirogaleus and that the two endogenization events occurred quasi-simultaneously. Using multiple proviral copies, we derive and characterize an apparently full length and intact consensus for this lentivirus. These results provide evidence that lentiviruses have repeatedly infiltrated the germline of prosimian species and that primates have been exposed to lentiviruses for a much longer time than what can be inferred based on sequence comparison of circulating lentiviruses. The study sets the stage for an unprecedented opportunity to reconstruct an ancestral primate lentivirus and thereby advance our knowledge of host–virus interactions. Retroviruses are RNA viruses that are reverse transcribed into DNA and inserted into the host's genome. Though this process happens most frequently in somatic cells (e.g., immune cells for HIV), retroviruses can occasionally be integrated in the genome of the host's germ cells. Such viral insertions may thus be transmitted vertically from parent to offspring, leading to the formation of “endogenous retroviruses.” A substantial fraction of mammalian genomes (about 8% in humans) corresponds to remnants of endogenous retroviruses integrated throughout evolution, providing a fossil record of past viral invasions and important clues on the history of modern retroviruses. In this study, we demonstrate that an endogenous retrovirus related to HIV and other lentiviruses was endogenized independently and quasi-simultaneously in two lineages of Malagasy lemurs around 4.2 million years ago. These are the first endogenous lentiviruses discovered in primates. Based on sequences collected from different lemur species, we reconstructed an apparently intact and complete sequence for this ancestral prosimian lentivirus, which will allow functional analysis and advance our understanding of the biology and origin of lentiviruses, including HIV. Furthermore, our study indicates that lentiviruses may still be circulating in lemurs and that a systematic screening of Malagasy mammals could further our knowledge on the past and present diversity of lentiviruses.