title: An unusual syncytia-inducing human immunodeficiency virus type 1 primary isolate from the central nervous system that is restricted to CXCR4, replicates efficiently in macrophages, and induces neuronal apoptosis.
abstract: Macrophage/microglia cells are the principal targets for human immunodeficiency virus type 1 (HIV-1) in the central nervous system (CNS). Prototype HIV-1 isolates from the CNS are macrophage (M)-tropic, non-syncytia-inducing (NSI), and use CCR5 for entry (R5 strains), but whether syncytia-inducing (SI) CXCR4-using X4 strains might play a role in macrophage/microglia infection and neuronal injury is unknown. To explore the range of features among HIV-1 primary isolates from the CNS, the authors analyzed an HIV-1 strain (TYBE) from cerebrospinal fluid of an individual with acquired immunodeficiency syndrome (AIDS) that was unusual because it was SI. Like other CNS isolates, HIV-1/TYBE replicated to high level in primary human macrophages, but, in contrast to CNS prototypes, TYBE used CXCR4 exclusively to infect macrophages. A functional TYBE env clone confirmed the X4 phenotype and displayed a highly charged V3 sequence typical of X4 strains. Supernatant from TYBE-infected primary human macrophages induced apoptosis of neurons. Thus, TYBE represents a novel type of CNS-derived HIV-1 isolate that is CXCR4-restricted yet replicates efficiently in macrophages and induce neuronal injury. These results demonstrate that HIV-1 variants in the CNS may possess a broader range of biological characteristics than generally appreciated, raise the possibility that X4 strains may participate in AIDS neuropathogenesis, and provide a prototype clade B HIV-1 strain that replicates efficiently in primary macrophages through the exclusive use of CXCR4 as a coreceptor.
authors.affiliation: Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
authors.forename: Yanjie
authors.initials: Y
authors.lastname: Yi
authors.forename: Wei
authors.initials: W
authors.lastname: Chen
authors.forename: Ian
authors.initials: I
authors.lastname: Frank
authors.forename: Joann
authors.initials: J
authors.lastname: Cutilli
authors.forename: Anjali
authors.initials: A
authors.lastname: Singh
authors.forename: Linda
authors.initials: L
authors.lastname: Starr-Spires
authors.forename: Jerrold
authors.initials: J
authors.lastname: Sulcove
authors.forename: Dennis L
authors.initials: DL
authors.lastname: Kolson
authors.forename: Ronald G
authors.initials: RG
authors.lastname: Collman
mesh_terms: D015526:AIDS Dementia Complex / Q000276:immunology / Q000473:pathology / Q000821:virology*; D000595:Amino Acid Sequence; D017209:Apoptosis / Q000276:immunology; D015726:Giant Cells / Q000276:immunology / Q000821:virology*; D015497:HIV-1 / Q000145:classification / Q000254:growth & development*; D006801:Humans; D008264:Macrophages / Q000473:pathology / Q000821:virology*; D008969:Molecular Sequence Data; D009474:Neurons / Q000276:immunology / Q000473:pathology; D019718:Receptors, CXCR4 / Q000502:physiology*; D014759:Viral Envelope Proteins / Q000235:genetics
chemical_list: D019718:Receptors, CXCR4; D014759:Viral Envelope Proteins