Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

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


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.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: Multiple infections per cell decrease sensitivity to drug.
Figure 2: Cell-to-cell spread reduces sensitivity to drugs.
Figure 3: Co-culture infection dynamics.


  1. 1

    Pierson, T., McArthur, J. & Siliciano, R. F. Reservoirs for HIV-1: mechanisms for viral persistence in the presence of antiviral immune responses and antiretroviral therapy. Annu. Rev. Immunol. 18, 665–708 (2000)

    CAS  Article  Google Scholar 

  2. 2

    Jung, A. et al. Recombination: multiply infected spleen cells in HIV patients. Nature 418, 144 (2002)

    ADS  CAS  Article  Google Scholar 

  3. 3

    Dixit, N. M. & Perelson, A. S. HIV dynamics with multiple infections of target cells. Proc. Natl Acad. Sci. USA 102, 8198–8203 (2005)

    ADS  CAS  Article  Google Scholar 

  4. 4

    Dimitrov, D. S. et al. Quantitation of human immunodeficiency virus type 1 infection kinetics. J. Virol. 67, 2182–2190 (1993)

    CAS  PubMed  PubMed Central  Google Scholar 

  5. 5

    Sattentau, Q. Avoiding the void: cell-to-cell spread of human viruses. Nature Rev. Microbiol. 6, 815–826 (2008)

    CAS  Article  Google Scholar 

  6. 6

    Martin, N. et al. Virological synapse-mediated spread of human immunodeficiency virus type 1 between T cells is sensitive to entry inhibition. J. Virol. 84, 3516–3527 (2010)

    CAS  Article  Google Scholar 

  7. 7

    Sourisseau, M., Sol-Foulon, N., Porrot, F., Blanchet, F. & Schwartz, O. Inefficient human immunodeficiency virus replication in mobile lymphocytes. J. Virol. 81, 1000–1012 (2007)

    CAS  Article  Google Scholar 

  8. 8

    Dang, Q. et al. Nonrandom HIV-1 infection and double infection via direct and cell-mediated pathways. Proc. Natl Acad. Sci. USA 101, 632–637 (2004)

    ADS  CAS  Article  Google Scholar 

  9. 9

    Dixit, N. M. & Perelson, A. S. Multiplicity of human immunodeficiency virus infections in lymphoid tissue. J. Virol. 78, 8942–8945 (2004)

    CAS  Article  Google Scholar 

  10. 10

    Del Portillo, A. et al. Multiploid inheritance of HIV-1 during cell-to-cell infection. J. Virol. 85, 7169–7176 (2011)

    CAS  Article  Google Scholar 

  11. 11

    Buzón, M. J. et al. HIV-1 replication and immune dynamics are affected by raltegravir intensification of HAART-suppressed subjects. Nature Med. 16, 460–465 (2010)

    Article  Google Scholar 

  12. 12

    Chun, T. W. et al. Relationship between residual plasma viremia and the size of HIV proviral DNA reservoirs in infected individuals receiving effective antiretroviral therapy. J. Infect. Dis. 204, 135–138 (2011)

    CAS  Article  Google Scholar 

  13. 13

    Doitsh, G. et al. Abortive HIV infection mediates CD4 T cell depletion and inflammation in human lymphoid tissue. Cell 143, 789–801 (2010)

    CAS  Article  Google Scholar 

  14. 14

    Paredes, R. et al. Pre-existing minority drug-resistant HIV-1 variants, adherence, and risk of antiretroviral treatment failure. J. Infect. Dis. 201, 662–671 (2010)

    CAS  PubMed  PubMed Central  Google Scholar 

  15. 15

    Levy, D. N., Aldrovandi, G. M., Kutsch, O. & Shaw, G. M. Dynamics of HIV-1 recombination in its natural target cells. Proc. Natl Acad. Sci. USA 101, 4204–4209 (2004)

    ADS  CAS  Article  Google Scholar 

  16. 16

    Gratton, S., Cheynier, R., Dumaurier, M. J., Oksenhendler, E. & Wain-Hobson, S. Highly restricted spread of HIV-1 and multiply infected cells within splenic germinal centers. Proc. Natl Acad. Sci. USA 97, 14566–14571 (2000)

    ADS  CAS  Article  Google Scholar 

  17. 17

    Collins, K. L., Chen, B. K., Kalams, S. A., Walker, B. D. & Baltimore, D. HIV-1 Nef protein protects infected primary cells against killing by cytotoxic T lymphocytes. Nature 391, 397–401 (1998)

    ADS  CAS  Article  Google Scholar 

  18. 18

    Wu, Y., Beddall, M. H. & Marsh, J. W. Rev-dependent indicator T cell line. Curr. HIV Res. 5, 394–402 (2007)

    CAS  Article  Google Scholar 

  19. 19

    Chen, B. K., Gandhi, R. T. & Baltimore, D. CD4 down-modulation during infection of human T cells with human immunodeficiency virus type 1 involves independent activities of vpu, env, and nef. J. Virol. 70, 6044–6053 (1996)

    CAS  PubMed  PubMed Central  Google Scholar 

  20. 20

    Ribeiro, R. M. et al. Estimation of the initial viral growth rate and basic reproductive number during acute HIV-1 infection. J. Virol. 84, 6096–6102 (2010)

    CAS  Article  Google Scholar 

  21. 21

    Nowak, M. A. & May, R. M. Virus Dynamics: Mathematical Principles of Immunology and Virology (Oxford Univ. Press, 2000)

    MATH  Google Scholar 

  22. 22

    Mathias, A. A. et al. Bioequivalence of efavirenz/emtricitabine/tenofovir disoproxil fumarate single-tablet regimen. J. Acquir. Immune Defic. Syndr. 46, 167–173 (2007)

    CAS  Article  Google Scholar 

  23. 23

    Bailey, J. R. et al. Residual human immunodeficiency virus type 1 viremia in some patients on antiretroviral therapy is dominated by a small number of invariant clones rarely found in circulating CD4+ T cells. J. Virol. 80, 6441–6457 (2006)

    CAS  Article  Google Scholar 

  24. 24

    Kieffer, T. L. et al. Genotypic analysis of HIV-1 drug resistance at the limit of detection: virus production without evolution in treated adults with undetectable HIV loads. J. Infect. Dis. 189, 1452–1465 (2004)

    CAS  Article  Google Scholar 

  25. 25

    Cu-Uvin, S. et al. Genital tract HIV-1 RNA shedding among women with below detectable plasma viral load. AIDS 24, 2489–2497 (2010)

    Article  Google Scholar 

  26. 26

    North, T. W. et al. Viral sanctuaries during highly active antiretroviral therapy in a nonhuman primate model for AIDS. J. Virol. 84, 2913–2922 (2010)

    CAS  Article  Google Scholar 

  27. 27

    Rong, L. & Perelson, A. S. Modeling latently infected cell activation: viral and latent reservoir persistence, and viral blips in HIV-infected patients on potent therapy. PLOS Comput. Biol. 5, e1000533 (2009)

    ADS  MathSciNet  Article  Google Scholar 

  28. 28

    Grossman, Z. et al. Ongoing HIV dissemination during HAART. Nature Med. 5, 1099–1104 (1999)

    CAS  Article  Google Scholar 

  29. 29

    Frenkel, L. M. et al. Multiple viral genetic analyses detect low-level human immunodeficiency virus type 1 replication during effective highly active antiretroviral therapy. J. Virol. 77, 5721–5730 (2003)

    CAS  Article  Google Scholar 

  30. 30

    Rhee, S. Y. et al. Human immunodeficiency virus reverse transcriptase and protease sequence database. Nucleic Acids Res. 31, 298–303 (2003)

    CAS  Article  Google Scholar 

Download references


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




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.

Corresponding author

Correspondence to David Baltimore.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Information

The file contains Supplementary Figures 1-14 with legends, Supplementary Text and Data 1-3, Supplementary Tables 1-2 and additional references. (PDF 1203 kb)

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Sigal, A., Kim, J., Balazs, A. et al. Cell-to-cell spread of HIV permits ongoing replication despite antiretroviral therapy. Nature 477, 95–98 (2011).

Download citation

Further reading


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing