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Cell-to-cell spread of HIV permits ongoing replication despite antiretroviral therapy

Nature volume 477, pages 9598 (01 September 2011) | Download Citation

Abstract

Latency and ongoing replication1 have both been proposed to explain the drug-insensitive human immunodeficiency virus (HIV) reservoir maintained during antiretroviral therapy. Here we explore a novel mechanism for ongoing HIV replication in the face of antiretroviral drugs. We propose a model whereby multiple infections2,3 per cell lead to reduced sensitivity to drugs without requiring drug-resistant mutations, and experimentally validate the model using multiple infections per cell by cell-free HIV in the presence of the drug tenofovir. We then examine the drug sensitivity of cell-to-cell spread of HIV4,5,6,7, a mode of HIV transmission that can lead to multiple infection events per target cell8,9,10. Infections originating from cell-free virus decrease strongly in the presence of antiretrovirals tenofovir and efavirenz whereas infections involving cell-to-cell spread are markedly less sensitive to the drugs. The reduction in sensitivity is sufficient to keep multiple rounds of infection from terminating in the presence of drugs. We examine replication from cell-to-cell spread in the presence of clinical drug concentrations using a stochastic infection model and find that replication is intermittent, without substantial accumulation of mutations. If cell-to-cell spread has the same properties in vivo, it may have adverse consequences for the immune system11,12,13, lead to therapy failure in individuals with risk factors14, and potentially contribute to viral persistence and hence be a barrier to curing HIV infection.

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Acknowledgements

We thank B. K. Chen, A. Del Portillo, J. T. Schiffer, L. Corey, and G. Lustig for discussions. A.S. was supported by the Human Frontier Science Program Long Term Fellowship LT00946. J.T.K. was supported by the UCLA STAR fellowship and T32 AI089398. A.B.B. was supported by the amfAR Postdoctoral Research Fellowship 107756-47-RFVA. This work was supported by the Bill & Melinda Gates Foundation and by the National Institutes of Health (HHSN266200500035C) and a contract from the National Institute of Allergy and Infectious Diseases. We acknowledge the support of the UCLA CFAR Virology Core Lab (P01-AI-28697) and the UCSF-GIVI CFAR (P30-AI-27763).

Author information

Affiliations

  1. Division of Biology, California Institute of Technology, Pasadena, California 91125, USA

    • Alex Sigal
    • , Jocelyn T. Kim
    • , Alejandro B. Balazs
    •  & David Baltimore
  2. Division of Infectious Diseases, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California 90095, USA

    • Jocelyn T. Kim
  3. Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 76100, Israel

    • Erez Dekel
    •  & Avi Mayo
  4. Department of Plant Sciences, Weizmann Institute of Science, Rehovot 76100, Israel

    • Ron Milo

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Contributions

A.S. and D.B. conceived the study. A.S. designed the research; A.S. and J.T.K. performed the experiments with support from A.B.B.; A.S. formulated the basic mathematical model and performed the numerical simulations; R.M., A.M. and E.D. added analytical insights and expanded the model to treat virus number as a random variable; A.S. and D.B. wrote the paper.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to David Baltimore.

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    Supplementary Information

    The file contains Supplementary Figures 1-14 with legends, Supplementary Text and Data 1-3, Supplementary Tables 1-2 and additional references.

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https://doi.org/10.1038/nature10347

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