title: CD4 and MHC class 1 down-modulation activities of nef alleles from brain- and lymphoid tissue-derived primary HIV-1 isolates.
abstract: Human immunodeficiency virus type 1 (HIV-1) nef undergoes adaptive evolution in the central nervous system (CNS), reflecting altered requirements for HIV-1 replication in macrophages/microglia and brain-specific immune selection pressures. The role of Nef in HIV-1 neurotropism and pathogenesis of HIV-associated dementia (HAD) is unclear. In this study, we characterized 82 nef alleles cloned from brain, cerebral spinal fluid, spinal cord, and blood/lymphoid tissue-derived HIV-1 isolates from seven subjects with HAD. CNS isolate-derived nef alleles were genetically compartmentalized and had reduced sequence diversity compared to those from lymphoid tissue isolates. Defective nef alleles predominated in a brain-derived isolate from one of the seven subjects (MACS2-br). The ability of Nef to down-modulate CD4 and MHC class 1 (MHC-1) was generally conserved among nef alleles from both CNS and lymphoid tissues. However, the potency of CD4 and MHC-1 down-modulation was variable, which was associated with sequence alterations known to influence these Nef functions. These results suggest that CD4 and MHC-1 down-modulations are highly conserved functions among nef alleles from CNS- and lymphoid tissue-derived HIV-1 isolates that may contribute to viral replication and escape from immune surveillance in the CNS.
authors.affiliation: Center for Virology, Burnet Institute, 85 Commercial Rd, Melbourne, 3004 VIC, Australia.
authors.forename: Lachlan R
authors.initials: LR
authors.lastname: Gray
authors.forename: Dana
authors.initials: D
authors.lastname: Gabuzda
authors.forename: Daniel
authors.initials: D
authors.lastname: Cowley
authors.forename: Anne
authors.initials: A
authors.lastname: Ellett
authors.forename: Lisa
authors.initials: L
authors.lastname: Chiavaroli
authors.forename: Steven L
authors.initials: SL
authors.lastname: Wesselingh
authors.forename: Melissa J
authors.initials: MJ
authors.lastname: Churchill
authors.forename: Paul R
authors.initials: PR
authors.lastname: Gorry
mesh_terms: D015526:AIDS Dementia Complex / Q000235:genetics / Q000378:metabolism / Q000821:virology; D000483:Alleles; D000595:Amino Acid Sequence; D001921:Brain / Q000378:metabolism / Q000821:virology*; D015704:CD4 Antigens / Q000378:metabolism*; D002460:Cell Line; D002490:Central Nervous System / Q000378:metabolism / Q000821:virology; D015536:Down-Regulation; D005805:Genes, MHC Class I; D015754:Genes, nef; D015658:HIV Infections / Q000235:genetics / Q000378:metabolism / Q000821:virology; D015497:HIV-1 / Q000235:genetics* / Q000472:pathogenicity; D006801:Humans; D008221:Lymphoid Tissue / Q000378:metabolism / Q000821:virology*; D008297:Male; D008969:Molecular Sequence Data; D010802:Phylogeny; D014779:Virus Replication; D054311:nef Gene Products, Human Immunodeficiency Virus / Q000235:genetics* / Q000378:metabolism / Q000502:physiology
chemical_list: D015704:CD4 Antigens; D054311:nef Gene Products, Human Immunodeficiency Virus; C514837:nef protein, Human immunodeficiency virus 1