Molecular determinants of HIV-1 subtype C coreceptor transition from R5 to R5X4.
The molecular mechanism(s) underlying transition from CCR5 to CXCR4 usage of subtype C viruses remain largely unknown. We previously identified a subtype C HIV-1 infected child whose virus demonstrated CXCR4 usage along with CCR5 upon longitudinal follow-up. Here we delineated the molecular determinants of Env involved in expanded coreceptor usage. Residue changes in three positions of Env V3 domain are critical for the dual tropic phenotype. These include: substitution of arginine at position 11, MG or LG insertion between positions 13 and 14, and substitution of threonine at the position immediately downstream of the GPGQ crown. Introducing these mutations into V3 region of a heterologous R5 virus also conferred dual tropism. Molecular modeling of V3 revealed a possible structural basis for the dual tropic phenotype. Determining what defines a subtype C X4 virus will lead to a better understanding of subtype C HIV-1 pathogenesis, and will provide important information relevant to anti-retroviral therapy.
Zhang
Hong
H
Nebraska Center for Virology, University of Nebraska, Lincoln, NE 68583-0900, USA.
Tully
Damien C
DC
Zhang
Tiejun
T
Moriyama
Hideaki
H
Thompson
Jesse
J
Wood
Charles
C
D000595:Amino Acid Sequence; D019943:Amino Acid Substitution / Q000235:genetics; D002675:Child, Preschool; D015497:HIV-1 / Q000235:genetics / Q000502:physiology*; D006801:Humans; D007223:Infant; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016254:Mutagenesis, Insertional; D017434:Protein Structure, Tertiary; D015728:Receptors, HIV / Q000378:metabolism*; D017422:Sequence Analysis, DNA; D056189:Viral Tropism; D053585:Virus Attachment; D054299:env Gene Products, Human Immunodeficiency Virus / Q000235:genetics* / Q000378:metabolism*
D015728:Receptors, HIV; D054299:env Gene Products, Human Immunodeficiency Virus