title: Evidence for adaptive evolution at the divergence between lymphoid and brain HIV-1 nef genes.
abstract: Human immunodeficiency virus type 1 (HIV) infection of the central nervous system frequently causes HIV-associated neurocognitive disorders (HAND). The role of HIV Nef and other accessory proteins in HAND pathogenesis is unclear. To determine whether HIV nef undergoes adaptive selection in brain, we cloned 100 nef sequences (n = 30 brain and n = 70 lymphoid) from four patients with AIDS and HIV-associated dementia (HAD). Normalized nonsynonymous substitutions were more frequent at the divergence of lymphoid and brain sequences, indicating stronger adaptive selection in brain compared to lymphoid tissue. Brain-specific nonsynonymous substitutions were found within an NH(3)-terminal CTL epitope, the PACS1 binding motif, or positions predicted to be important for activation of the myeloid-restricted Src family tyrosine kinase Hck. These results suggest that adaptive selection of HIV nef in brain may reflect altered requirements for efficient replication in macrophages and brain-specific immune selection pressures.
authors.affiliation: Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.
authors.forename: Kevin C
authors.initials: KC
authors.lastname: Olivieri
authors.forename: Kristin A
authors.initials: KA
authors.lastname: Agopian
authors.forename: Joya
authors.initials: J
authors.lastname: Mukerji
authors.forename: Dana
authors.initials: D
authors.lastname: Gabuzda
mesh_terms: D015526:AIDS Dementia Complex / Q000821:virology*; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D001921:Brain / Q000821:virology*; D019143:Evolution, Molecular; D014644:Genetic Variation; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D008214:Lymphocytes / Q000821:virology*; D008969:Molecular Sequence Data; D017434:Protein Structure, Tertiary / Q000235:genetics; D012641:Selection, Genetic; D014779:Virus Replication; D054311:nef Gene Products, Human Immunodeficiency Virus / Q000737:chemistry / Q000235:genetics*
chemical_list: D054311:nef Gene Products, Human Immunodeficiency Virus; C514837:nef protein, Human immunodeficiency virus 1