title: Evolutionary study of leporid CD4 reveals a hotspot of genetic variability within the D2 domain.
abstract: CD4 is the major receptor on T helper cells involved in the uptake of human immunodeficiency virus (HIV) or simian immunodeficiency virus (SIV) into their host cells. Evolutionary studies of CD4 in primates revealed signatures of positive selection in the D1 domain that interacts with primate exogenous lentivirus gp120 proteins. Here, we studied the evolution of CD4 in lagomorphs by comparing sequences obtained for the genera Oryctolagus, Sylvilagus, Lepus, and Ochotona. Our results reveal an overall higher divergence in lagomorphs compared to primates with highest divergence in the D2 domain. A detailed analysis of a small fragment of 33 nucleotides coding for amino acids 169 to 179 in the D2 domain showed dramatic amino acid alterations with a dN/dS value of 3.2 for lagomorphs, suggesting that CD4 is under strong positive selection in this particular region. Within each leporid genus, no significant amino acid changes were observed for the D2 domain which indicates that the genetic differentiation occurred in the ancestor of each genus before the species radiation. The rabbit endogenous lentivirus type K (RELIK) found in leporids shares high structural similarity with HIV which suggests a possible interaction between RELIK and CD4. The presence of RELIK in the studied leporids, the high structural similarity to modern-day exogenous lentiviruses and the absence of exogenous lentiviruses in leporids, allows us to hypothesize that this endogenous retrovirus, that was most probably exogenous in the past, drove the divergent evolution of leporid CD4.
authors.affiliation: InBIO-Research Network in Biodiversity and Evolutionary Biology, CIBIO, Campus de Vairão, Universidade do Porto, Campus Agrário de Vairão, Rua Padre Armando Quintas, nr.7, 4485-661, Vairão, Portugal.|Departamento de Biologia, Faculdade de Ciências, Universidade do Porto, 4169-007, Porto, Portugal.|Institute of Medical Virology, University Hospital Frankfurt, Frankfurt, Germany.
authors.forename: Patricia
authors.initials: P
authors.lastname: de Sousa-Pereira
authors.affiliation: InBIO-Research Network in Biodiversity and Evolutionary Biology, CIBIO, Campus de Vairão, Universidade do Porto, Campus Agrário de Vairão, Rua Padre Armando Quintas, nr.7, 4485-661, Vairão, Portugal.
authors.forename: Joana
authors.initials: J
authors.lastname: Abrantes
authors.affiliation: Institute of Medical Virology, University Hospital Frankfurt, Frankfurt, Germany.
authors.forename: Hanna-Mari
authors.initials: HM
authors.lastname: Baldauf
authors.affiliation: Institute of Medical Virology, University Hospital Frankfurt, Frankfurt, Germany.|Max von Pettenkofer-Institute for Virology, Ludwig-Maximilians-University Munich, Munich, Germany.
authors.forename: Oliver T
authors.initials: OT
authors.lastname: Keppler
authors.affiliation: InBIO-Research Network in Biodiversity and Evolutionary Biology, CIBIO, Campus de Vairão, Universidade do Porto, Campus Agrário de Vairão, Rua Padre Armando Quintas, nr.7, 4485-661, Vairão, Portugal. pjesteves@cibio.up.pt.|Departamento de Biologia, Faculdade de Ciências, Universidade do Porto, 4169-007, Porto, Portugal. pjesteves@cibio.up.pt.|CITS - Centro de Investigação em Tecnologias de Saúde, CESPU, Gandra, Portugal. pjesteves@cibio.up.pt.
authors.forename: Pedro J
authors.initials: PJ
authors.lastname: Esteves
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D005075:Biological Evolution; D015704:CD4 Antigens / Q000235:genetics*; D014644:Genetic Variation / Q000235:genetics*; D006801:Humans; D007793:Lagomorpha / Q000145:classification* / Q000235:genetics*; D000072417:Protein Domains; D011817:Rabbits; D017386:Sequence Homology, Amino Acid
chemical_list: D015704:CD4 Antigens
keywords: CD4; Leporids; Positive selection; RELIK