title: Primary infection by a human immunodeficiency virus with atypical coreceptor tropism.
abstract: The great majority of human immunodeficiency virus type 1 (HIV-1) strains enter CD4+ target cells by interacting with one of two coreceptors, CCR5 or CXCR4. Here we describe a transmitted/founder (T/F) virus (ZP6248) that was profoundly impaired in its ability to utilize CCR5 and CXCR4 coreceptors on multiple CD4+ cell lines as well as primary human CD4+ T cells and macrophages in vitro yet replicated to very high titers (>80 million RNA copies/ml) in an acutely infected individual. Interestingly, the envelope (Env) glycoprotein of this clade B virus had a rare GPEK sequence in the crown of its third variable loop (V3) rather than the consensus GPGR sequence. Extensive sequencing of sequential plasma samples showed that the GPEK sequence was present in virtually all Envs, including those from the earliest time points after infection. The molecularly cloned (single) T/F virus was able to replicate, albeit poorly, in cells obtained from ccr5Δ32 homozygous donors. The ZP6248 T/F virus could also infect cell lines overexpressing the alternative coreceptors GPR15, APJ, and FPRL-1. A single mutation in the V3 crown sequence (GPEK->GPGK) of ZP6248 restored its infectivity in CCR5+ cells but reduced its ability to replicate in GPR15+ cells, indicating that the V3 crown motif played an important role in usage of this alternative coreceptor. These results suggest that the ZP6248 T/F virus established an acute in vivo infection by using coreceptor(s) other than CCR5 or CXCR4 or that the CCR5 coreceptor existed in an unusual conformation in this individual.
authors.affiliation: Duke Human Vaccine Institute, Duke University Medical Center, Durham, North Carolina 27710, USA.
authors.forename: Chunlai
authors.initials: C
authors.lastname: Jiang
authors.forename: Nicholas F
authors.initials: NF
authors.lastname: Parrish
authors.forename: Craig B
authors.initials: CB
authors.lastname: Wilen
authors.forename: Hui
authors.initials: H
authors.lastname: Li
authors.forename: Yue
authors.initials: Y
authors.lastname: Chen
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Pavlicek
authors.forename: Anna
authors.initials: A
authors.lastname: Berg
authors.forename: Xiaozhi
authors.initials: X
authors.lastname: Lu
authors.forename: Hongshuo
authors.initials: H
authors.lastname: Song
authors.forename: John C
authors.initials: JC
authors.lastname: Tilton
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Pfaff
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Henning
authors.forename: Julie M
authors.initials: JM
authors.lastname: Decker
authors.forename: M Anthony
authors.initials: MA
authors.lastname: Moody
authors.forename: Mark S
authors.initials: MS
authors.lastname: Drinker
authors.forename: Robert
authors.initials: R
authors.lastname: Schutte
authors.forename: Stephanie
authors.initials: S
authors.lastname: Freel
authors.forename: Georgia D
authors.initials: GD
authors.lastname: Tomaras
authors.forename: Rebecca
authors.initials: R
authors.lastname: Nedellec
authors.forename: Donald E
authors.initials: DE
authors.lastname: Mosier
authors.forename: Barton F
authors.initials: BF
authors.lastname: Haynes
authors.forename: George M
authors.initials: GM
authors.lastname: Shaw
authors.forename: Beatrice H
authors.initials: BH
authors.lastname: Hahn
authors.forename: Robert W
authors.initials: RW
authors.lastname: Doms
authors.forename: Feng
authors.initials: F
authors.lastname: Gao
mesh_terms: D020816:Amino Acid Motifs; D019943:Amino Acid Substitution / Q000235:genetics; D000075244:Apelin Receptors; D015496:CD4-Positive T-Lymphocytes / Q000821:virology; D002478:Cells, Cultured; D015870:Gene Expression; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D008264:Macrophages / Q000821:virology; D044042:Receptors, Formyl Peptide / Q000235:genetics / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism; D015728:Receptors, HIV / Q000378:metabolism*; D044067:Receptors, Lipoxin / Q000235:genetics / Q000378:metabolism; D018000:Receptors, Peptide / Q000235:genetics / Q000378:metabolism; D056189:Viral Tropism; D054299:env Gene Products, Human Immunodeficiency Virus / Q000235:genetics
chemical_list: C104575:APLNR protein, human; D000075244:Apelin Receptors; C105101:FPR2 protein, human; C103539:GPR15 protein, human; D044042:Receptors, Formyl Peptide; D043562:Receptors, G-Protein-Coupled; D015728:Receptors, HIV; D044067:Receptors, Lipoxin; D018000:Receptors, Peptide; D054299:env Gene Products, Human Immunodeficiency Virus