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Letter to the Editor

Early Stochastic Dynamics in Human Cytomegalovirus Infection

Dominik Wodarz, Ignacio Rodriguez-Brenes
Richard M. Longnecker, Editor
Dominik Wodarz
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Ignacio Rodriguez-Brenes
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Richard M. Longnecker
Northwestern University
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DOI: 10.1128/JVI.00949-17
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LETTER

While the dynamics of virus infections have been studied extensively in a variety of settings, the very early dynamics during the establishment phase of an infection remain understudied. A recent paper (1) investigated the early dynamics of cytomegalovirus (CMV) infection in a cohort of highly exposed infants. They found that in a relatively large fraction of newly infected individuals, the infection was transient and self-limiting but that in a few cases, the infection was a fully fledged primary infection. This was explained with stochastic mathematical models of the early infection process. The models could account for the data if the basic reproductive ratio of the virus (R0) was close to the extinction threshold of 1 and if the infection was initiated from one or a very few infected founder cells. This explanation is based on the stochastic nature of the dynamics at low population levels, where stochastic extinction is a likely event.

The dynamics underlying this observation, however, might be more complex. We recently examined the very early spread of a modified adenovirus in a two-dimensional monolayer of 293 embryonic kidney epithelial cells (2–4), starting from single infected cells. Two distinct patterns of viral spread were observed under identical conditions. About 50% of growth foci in a culture displayed a robust growth pattern, characterized by a plaque-like expansion of the infected cells. The other infection foci resulted in limited growth, characterized by a relatively slow expansion of infected cells, followed by growth cessation. Stochastic fluctuations around small numbers seemed an unlikely explanation for the limited infections, because these were not terminated early at very small population sizes but rather after a period of sustained, albeit slow, growth. Using mathematical models (4), we found that two simultaneously stable outcomes can be observed under the following assumptions: (i) infected cells can establish an interferon (IFN)-induced antiviral state in surrounding uninfected cells, and (ii) this antiviral state can be overcome to a certain extent at higher infection multiplicities, allowing faster infection growth. Under these assumptions, the model predicted an initial race between the spread of the virus and the spread of the antiviral state to uninfected cells. If early stochastic effects push the populations toward the domain of attraction of the robust infection outcome, the virus wins the race, resulting in a fully fledged infection. Otherwise, the race is won by the IFN-induced antiviral state, leading to limited growth. In accordance with predictions, experimental inhibition of IFN responses resulted in a shift of the outcomes from approximately 50% to significantly larger percentages of robust growth (4).

Similar dynamics may provide an alternative explanation for the observations in CMV-infected infants. Type I IFNs reduce CMV replication (5–8), and CMV can overcome this to an extent (9). This mechanism would not require a value of R0 that is close to the extinction threshold, which might not be evolutionarily robust. Interestingly, an accelerated CMV growth rate was seen at higher virus loads (10), which might be due to increased infection multiplicity, as suggested by our model. Hence, the role of innate immune responses in early CMV dynamics warrants further investigation.

FOOTNOTES

  • For the author reply, see https://doi.org/10.1128/JVI.01006-17.

  • Copyright © 2017 American Society for Microbiology.

All Rights Reserved .

REFERENCES

  1. 1.↵
    1. Mayer BT,
    2. Krantz EM,
    3. Swan D,
    4. Ferrenberg J,
    5. Simmons K,
    6. Selke S,
    7. Huang ML,
    8. Casper C,
    9. Corey L,
    10. Wald A,
    11. Schiffer JT,
    12. Gantt S
    . 2017. Transient oral human cytomegalovirus infections indicate inefficient viral spread from very few initially infected cells. J Virol91:e00380-17. doi:10.1128/JVI.00380-17.
    OpenUrlAbstract/FREE Full Text
  2. 2.↵
    1. Hofacre A,
    2. Wodarz D,
    3. Komarova NL,
    4. Fan H
    . 2012. Early infection and spread of a conditionally replicating adenovirus under conditions of plaque formation. Virology423:89–96. doi:10.1016/j.virol.2011.11.014.
    OpenUrlCrossRefPubMed
  3. 3.↵
    1. Wodarz D,
    2. Hofacre A,
    3. Lau JW,
    4. Sun Z,
    5. Fan H,
    6. Komarova NL
    . 2012. Complex spatial dynamics of oncolytic viruses in vitro: mathematical and experimental approaches. PLoS Comput Biol8:e1002547. doi:10.1371/journal.pcbi.1002547.
    OpenUrlCrossRefPubMed
  4. 4.↵
    1. Rodriguez-Brenes IA,
    2. Hofacre A,
    3. Fan H,
    4. Wodarz D
    . 2017. Complex dynamics of virus spread from low infection multiplicities: implications for the spread of oncolytic viruses. PLoS Comput Biol13:e1005241. doi:10.1371/journal.pcbi.1005241.
    OpenUrlCrossRef
  5. 5.↵
    1. Orange JS,
    2. Biron CA
    . 1996. Characterization of early IL-12, IFN-αβ, and TNF effects on antiviral state and NK cell responses during murine cytomegalovirus infection. J Immunol156:4746–4756.
    OpenUrlAbstract
  6. 6.↵
    1. Yeow WS,
    2. Lawson CM,
    3. Beilharz MW
    . 1998. Antiviral activities of individual murine IFN-α subtypes in vivo: intramuscular injection of IFN expression constructs reduces cytomegalovirus replication. J Immunol160:2932–2939.
    OpenUrlAbstract/FREE Full Text
  7. 7.↵
    1. Presti RM,
    2. Pollock JL,
    3. Dal Canto AJ,
    4. O'Guin AK,
    5. Virgin HWT
    . 1998. Interferon gamma regulates acute and latent murine cytomegalovirus infection and chronic disease of the great vessels. J Exp Med188:577–588. doi:10.1084/jem.188.3.577.
    OpenUrlAbstract/FREE Full Text
  8. 8.↵
    1. Cheeseman SH,
    2. Rubin RH,
    3. Stewart JA,
    4. Tolkoff-Rubin NE,
    5. Cosimi AB,
    6. Cantell K,
    7. Gilbert J,
    8. Winkle S,
    9. Herrin JT,
    10. Black PH,
    11. Russell PS,
    12. Hirsch MS
    . 1979. Controlled clinical trial of prophylactic human-leukocyte interferon in renal transplantation. Effects on cytomegalovirus and herpes simplex virus infections. N Engl J Med300:1345–1349.
    OpenUrlCrossRefPubMedWeb of Science
  9. 9.↵
    1. Miller DM,
    2. Zhang Y,
    3. Rahill BM,
    4. Waldman WJ,
    5. Sedmak DD
    . 1999. Human cytomegalovirus inhibits IFN-α-stimulated antiviral and immunoregulatory responses by blocking multiple levels of IFN-α signal transduction. J Immunol162:6107–6113.
    OpenUrlAbstract/FREE Full Text
  10. 10.↵
    1. Mayer BT,
    2. Matrajt L,
    3. Casper C,
    4. Krantz EM,
    5. Corey L,
    6. Wald A,
    7. Gantt S,
    8. Schiffer JT
    . 2016. Dynamics of persistent oral cytomegalovirus shedding during primary infection in ugandan infants. J Infect Dis214:1735–1743. doi:10.1093/infdis/jiw442.
    OpenUrlCrossRefPubMed
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Early Stochastic Dynamics in Human Cytomegalovirus Infection
Dominik Wodarz, Ignacio Rodriguez-Brenes
Journal of Virology Aug 2017, 91 (18) e00949-17; DOI: 10.1128/JVI.00949-17

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Early Stochastic Dynamics in Human Cytomegalovirus Infection
Dominik Wodarz, Ignacio Rodriguez-Brenes
Journal of Virology Aug 2017, 91 (18) e00949-17; DOI: 10.1128/JVI.00949-17
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KEYWORDS

virus dynamics
stochastic dynamics
cytomegalovirus
Cytomegalovirus Infections

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