title: Changes in the V3 region of gp120 contribute to unusually broad coreceptor usage of an HIV-1 isolate from a CCR5 Delta32 heterozygote.
abstract: Heterozygosity for the CCR5 Delta32 allele is associated with delayed progression to AIDS in human immunodeficiency virus type 1 (HIV-1) infection. Here we describe an unusual HIV-1 isolate from the blood of an asymptomatic individual who was heterozygous for the CCR5 Delta32 allele and had reduced levels of CCR5 expression. The primary virus used CCR5, CXCR4, and an unusually broad range of alternative coreceptors to enter transfected cells. However, only CXCR4 and CCR5 were used to enter primary T cells and monocyte-derived macrophages, respectively. Full-length Env clones had an unusually long V1/V2 region and rare amino acid variants in the V3 and C4 regions. Mutagenesis studies and structural models suggested that Y308, D321, and to a lesser extent K442 and E444, contribute to the broad coreceptor usage of these Envs, whereas I317 is likely to be a compensatory change. Furthermore, database analysis suggests that covariation can occur at positions 308/317 and 308/321 in vivo. Y308 and D321 reduced dependence on the extracellular loop 2 (ECL2) region of CCR5, while these residues along with Y330, K442, and E444 enhanced dependence on the CCR5 N-terminus compared to clade B consensus residues at these positions. These results suggest that expanded coreceptor usage of HIV-1 can occur in some individuals without rapid progression to AIDS as a consequence of changes in the V3 region that reduce dependence on the ECL2 region of CCR5 by enhancing interactions with conserved structural elements in G-protein-coupled receptors.
authors.affiliation: Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Paul R
authors.initials: PR
authors.lastname: Gorry
authors.forename: Rebecca L
authors.initials: RL
authors.lastname: Dunfee
authors.forename: Megan E
authors.initials: ME
authors.lastname: Mefford
authors.forename: Kevin
authors.initials: K
authors.lastname: Kunstman
authors.forename: Tom
authors.initials: T
authors.lastname: Morgan
authors.forename: John P
authors.initials: JP
authors.lastname: Moore
authors.forename: John R
authors.initials: JR
authors.lastname: Mascola
authors.forename: Kristin
authors.initials: K
authors.lastname: Agopian
authors.forename: Geoffrey H
authors.initials: GH
authors.lastname: Holm
authors.forename: Andrew
authors.initials: A
authors.lastname: Mehle
authors.forename: Joann
authors.initials: J
authors.lastname: Taylor
authors.forename: Michael
authors.initials: M
authors.lastname: Farzan
authors.forename: Hui
authors.initials: H
authors.lastname: Wang
authors.forename: Philip
authors.initials: P
authors.lastname: Ellery
authors.forename: Samantha J
authors.initials: SJ
authors.lastname: Willey
authors.forename: Paul R
authors.initials: PR
authors.lastname: Clapham
authors.forename: Steven M
authors.initials: SM
authors.lastname: Wolinsky
authors.forename: Suzanne M
authors.initials: SM
authors.lastname: Crowe
authors.forename: Dana
authors.initials: D
authors.lastname: Gabuzda
mesh_terms: D000595:Amino Acid Sequence; D000914:Antibodies, Viral; D065100:CCR5 Receptor Antagonists; D002460:Cell Line; D002478:Cells, Cultured; D015699:HIV Envelope Protein gp120 / Q000737:chemistry / Q000378:metabolism*; D015658:HIV Infections / Q000097:blood / Q000276:immunology / Q000821:virology*; D015497:HIV-1 / Q000235:genetics / Q000254:growth & development* / Q000302:isolation & purification; D006579:Heterozygote; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000821:virology; D008297:Male; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism*; D019713:Receptors, CCR5 / Q000235:genetics* / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors; D015728:Receptors, HIV / Q000502:physiology*; D016415:Sequence Alignment; D017422:Sequence Analysis, DNA; D017384:Sequence Deletion
chemical_list: D000914:Antibodies, Viral; D065100:CCR5 Receptor Antagonists; D015699:HIV Envelope Protein gp120; C059762:HIV envelope protein gp120 (305-321); D010446:Peptide Fragments; D019713:Receptors, CCR5; D019718:Receptors, CXCR4; D015728:Receptors, HIV