Characterization of the three HERV-H proviruses with an open envelope reading frame encompassing the immunosuppressive domain and evolutionary history in primates

The HERV-H family is one of the largest human endogenous retrovirus families, with approximately 1000 elements. Using a direct coupled in vitro transcription/translation approach (PTT for protein truncation test) and an extended series of primers on human genomic DNA, on monochromosomal hybrids and on a BAC library, we could demonstrate that there are only three envelopes with a large open reading frame encompassing the immunosuppressive (ISU) domain, corresponding to 62-, 60-, and 59-kDa potential translational products. The associated proviruses, HERV-H/env62, HERV-H/env60, and HERV-H/env59 were sequenced together with their flanking DNA and mapped by FISH, and their entry times within the primate lineage were determined. Analysis of the LTR sequences revealed numerous recombinational and/or homogenization events in the course of evolution, with divergences between 5′ and 3′ LTRs higher than expected for a simple time-dependent genetic drift. PTT-analyses further revealed that the three large envelopes in humans are prematurely stopped in the majority of primates, and sequencing of the largest envelope gene, from HERV-H/env62, in five human individuals revealed two polymorphic sites. The results are consistent with the absence of a strong selective pressure for the conservation of a functional envelope gene of possible benefit for the host, but do not exclude somatic effects possibly associated with the immunosuppressive domain carried by these genes.