DOI: 10.1128/jvi.01303-08. Baseline Resistance of Primary Human Immunodeficiency Virus Type 1 Strains to the CXCR4 Inhibitor AMD3100 [Penn]

Baseline Resistance of Primary Human Immunodeficiency Virus Type 1 Strains to the CXCR4 Inhibitor AMD3100

10.1128/jvi.01303-08

Crossref journal-article

American Society for Microbiology

Journal of Virology (235)

Abstract

ABSTRACT We screened a panel of R5X4 and X4 human immunodeficiency virus type 1 (HIV-1) strains for their sensitivities to AMD3100, a small-molecule CXCR4 antagonist that blocks HIV-1 infection via this coreceptor. While no longer under clinical development, AMD3100 is a useful tool with which to probe interactions between the viral envelope (Env) protein and CXCR4 and to identify pathways by which HIV-1 may become resistant to this class of antiviral agents. While infection by most virus strains was completely blocked by AMD3100, we identified several R5X4 and X4 isolates that exhibited plateau effects: as the AMD3100 concentration was increased, virus infection and membrane fusion diminished to variable degrees. Once saturating concentrations of AMD3100 were achieved, further inhibition was not observed, indicating a noncompetitive mode of viral resistance to the drug. The magnitude of the plateau varied depending on the virus isolate, as well as the cell type used, with considerable variation observed when primary human T cells from different human donors were used. Structure-function studies indicated that the V1/V2 region of the R5X4 HIV-1 isolate DH12 was necessary for AMD3100 resistance and could confer this property on two heterologous Env proteins. We conclude that some R5X4 and X4 HIV-1 isolates can utilize the AMD3100-bound conformation of CXCR4, with the efficiency being influenced by both viral and host factors. Baseline resistance to this CXCR4 antagonist could influence the clinical use of such compounds.

Bibliography

Harrison, J. E., Lynch, J. B., Sierra, L.-J., Blackburn, L. A., Ray, N., Collman, R. G., & Doms, R. W. (2008). Baseline Resistance of Primary Human Immunodeficiency Virus Type 1 Strains to the CXCR4 Inhibitor AMD3100. Journal of Virology, 82(23), 11695â11704.

Authors 7

Jessamina E. Harrison (first)
Jonathan B. Lynch (additional)
Luz-Jeannette Sierra (additional)
Leslie A. Blackburn (additional)
Neelanjana Ray (additional)
Ronald G. Collman (additional)
Robert W. Doms (additional)

References 61 Referenced 16

10.1128/jvi.66.5.2934-2942.1992
10.1371/journal.ppat.0020010
10.1093/jac/dkl027
10.1128/JVI.72.3.2509-2515.1998
10.1128/jvi.70.10.7318-7321.1996
10.1038/nrd1134
10.1128/AAC.38.4.668
10.1128/jvi.70.2.689-696.1996
10.1128/AAC.41.12.2616
10.1038/nm0198-072
10.1016/S0092-8674(00)81393-8
10.1016/S0140-6736(07)61052-6
10.1016/S0092-8674(00)80577-2
10.1016/j.bcp.2006.05.010
10.1126/science.1070441
10.1128/JVI.79.21.13250-13261.2005
10.1172/JCI7403
10.1189/jlb.0306148
10.1016/j.virol.2006.11.025
10.1097/00002030-200109070-00010
10.1089/aid.2005.21.171
10.1128/JVI.78.14.7582-7589.2004
10.1097/01.qai.0000137371.80695.ef
10.1073/pnas.95.19.11360
10.1126/science.1145373
10.1128/JVI.77.24.13042-13052.2003
10.1016/j.virol.2007.02.022
10.1089/08892220152741414
10.1128/JVI.78.6.2790-2807.2004
10.1371/journal.ppat.0030117
10.1128/JVI.77.2.1610-1613.2003
10.1128/JVI.75.12.5457-5464.2001
10.1073/pnas.96.9.5215
10.1128/JVI.00385-07
10.1128/JVI.78.16.8654-8662.2004
10.1006/viro.2000.0807
10.1016/j.virol.2005.04.035
10.1016/j.virol.2004.07.019
10.1083/jcb.151.2.413
10.1038/nm0796-760
10.1089/088922204322749567
10.1128/JVI.01793-07
10.1128/JVI.79.7.4347-4356.2005
10.1016/j.virol.2006.11.004
10.1128/jvi.71.4.3219-3227.1997
Ray, N., and R. W. Doms. 2006. HIV-1 coreceptors and their inhibitors. Curr. Top. Microbiol. Immunol.303:97-120. / Curr. Top. Microbiol. Immunol. (2006)
10.1128/JVI.02413-06
10.1073/pnas.252469399
10.1097/00002030-200109070-00004
Rucker, J., B. J. Doranz, A. L. Edinger, D. Long, J. F. Berson, and R. W. Doms. 1997. Cell-cell fusion assay to study role of chemokine receptors in human immunodeficiency virus type 1 entry. Methods Enzymol.288:118-133. / Methods Enzymol. (1997)
10.1016/S0166-3542(97)00025-9
10.1084/jem.186.8.1383
10.1128/jvi.69.7.4453-4462.1995
10.1128/JVI.74.2.693-701.2000
10.1128/JVI.72.5.4478-4484.1998
10.1038/384184a0
10.1128/JVI.02006-06
10.1084/jem.185.9.1681
10.1128/JVI.73.9.7117-7125.1999
10.1080/753312758
10.1128/JVI.79.3.1480-1486.2005

Dates

Type	When
Created	16 years, 11 months ago (Sept. 18, 2008, 10:38 a.m.)
Deposited	3 years, 5 months ago (March 5, 2022, 7:07 a.m.)
Indexed	1 year, 3 months ago (May 17, 2024, 8:49 a.m.)
Issued	16 years, 9 months ago (Dec. 1, 2008)
Published	16 years, 9 months ago (Dec. 1, 2008)
Published Print	16 years, 9 months ago (Dec. 1, 2008)

Funders 0

None

BibTeX

@article{Harrison_2008, title={Baseline Resistance of Primary Human Immunodeficiency Virus Type 1 Strains to the CXCR4 Inhibitor AMD3100}, volume={82}, ISSN={1098-5514}, url={http://dx.doi.org/10.1128/jvi.01303-08}, DOI={10.1128/jvi.01303-08}, number={23}, journal={Journal of Virology}, publisher={American Society for Microbiology}, author={Harrison, Jessamina E. and Lynch, Jonathan B. and Sierra, Luz-Jeannette and Blackburn, Leslie A. and Ray, Neelanjana and Collman, Ronald G. and Doms, Robert W.}, year={2008}, month=dec, pages={11695–11704} }

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  "URL": "http://dx.doi.org/10.1128/JVI.01303-08",
  "relation": {},
  "ISSN": [
    "0022-538X",
    "1098-5514"
  ],
  "subject": [],
  "container-title-short": "J Virol",
  "published": {
    "date-parts": [
      [
        2008,
        12
      ]
    ]
  },
  "assertion": [
    {
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      "group": {
        "name": "publication_history",
        "label": "Publication History"
      }
    },
    {
      "value": "2008-09-09",
      "order": 1,
      "name": "accepted",
      "label": "Accepted",
      "group": {
        "name": "publication_history",
        "label": "Publication History"
      }
    },
    {
      "value": "2008-12-01",
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}