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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

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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.

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Authors and Affiliations

  1. Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA

    Yanjie Yi, Ian Frank, Joann Cutilli, Anjali Singh, Linda Starr-Spires & Ronald G. Collman

  2. Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA

    Wei Chen, Jerrold Sulcove & Dennis L. Kolson

  3. 522 Johnson Pavilion, 36th and Hamilton Walk, 19104-6061, Philadelphia, PA, USA

    Ronald G. Collman

Authors
  1. Yanjie Yi
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  2. Wei Chen
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  3. Ian Frank
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  4. Joann Cutilli
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  5. Anjali Singh
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  6. Linda Starr-Spires
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  7. Jerrold Sulcove
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  8. Dennis L. Kolson
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  9. Ronald G. Collman
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Correspondence to Ronald G. Collman.

Additional information

This work was supported by NIH grants to R.G.C. and D.L.K.

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Yi, Y., Chen, W., Frank, I. et al. 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. Journal of NeuroVirology 9, 432–441 (2003). https://doi.org/10.1080/13550280390218706

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  • DOI: https://doi.org/10.1080/13550280390218706

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