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. 1998 Sep 21;188(6):1047-54.
doi: 10.1084/jem.188.6.1047.

Hierarchical and redundant lymphocyte subset control precludes cytomegalovirus replication during latent infection

B Polić  1 , H Hengel, A Krmpotić, J Trgovcich, I Pavić, P Luccaronin, S Jonjić, U H Koszinowski
Affiliations

Hierarchical and redundant lymphocyte subset control precludes cytomegalovirus replication during latent infection

B Polić et al. J Exp Med. .

Abstract

Reactivation from latent cytomegalovirus (CMV) infection is often associated with conditions of immunosuppression and can result in fatal disease. Whether the maintenance of systemic CMV latency is mainly governed by factors of the infected cell or by immune control functions is unknown. Likewise, the putative immune control mechanisms which could prevent the induction and spread of recurrent CMV infection are not clearly identified. We took advantage of latently infected B cell-deficient mice and a sensitive method for virus detection to study CMV reactivation after ablation of lymphocyte subsets. A crucial role of both T lymphocytes and natural killer (NK) cells was demonstrated. Within 5 d after depletion of lymphocytes, productive infection occurred in 50% of mice, and 14 d later 100% of mice exhibited recurrent infection. A hierarchy of immune control functions of CD8(+), NK, and CD4(+) cells was established. Reactivation was rare if only one of the lymphocyte subsets was depleted, but was evident after removal of a further subset, indicating a functional redundancy of control mechanisms. The salivary glands were identified as the site of most rapid virus shedding, followed by the detection of recurrent virus in the lungs, and eventually in the spleen. Our findings document a previously unknown propensity of latent CMV genomes to enter productive infection immediately and with a high frequency after immune cell depletion. The data indicate that only the sustained cellular immune control prevents CMV replication and restricts the viral genome to a systemic state of latency.

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Figures

Figure 1
Figure 1
MCMV recurrence after depletion of T lymphocytes and NK cells. (A) Latently infected μMT/μMT B cell–deficient mice and heterozygous μMT/+ mice were immunodepleted of CD4+, CD8+, and NK1.1+ cells 12 wk p.i. Infectious virus in the salivary glands, lungs, and spleen was determined after immunodepletion as indicated. Shown are the titers of recurrent virus in the salivary glands (top), lungs (middle), and spleen (bottom) of homozygous (•) and heterozygous (○) mice. DL, Detection limit. (B) The percentage of mice in which recurrent virus was detected in the salivary glands (solid line) was used to generate a mathematical model describing the probability of recurrence over time (see Materials and Methods). Broken line, A linear function differentiated from the Poisson distribution as a curve P(t) = (t − t 0)/T 0, for (t − t 0)/T 0 < 0.5. Arrow, The time point at which recurrent virus is predicted in 100% of mice.
Figure 1
Figure 1
MCMV recurrence after depletion of T lymphocytes and NK cells. (A) Latently infected μMT/μMT B cell–deficient mice and heterozygous μMT/+ mice were immunodepleted of CD4+, CD8+, and NK1.1+ cells 12 wk p.i. Infectious virus in the salivary glands, lungs, and spleen was determined after immunodepletion as indicated. Shown are the titers of recurrent virus in the salivary glands (top), lungs (middle), and spleen (bottom) of homozygous (•) and heterozygous (○) mice. DL, Detection limit. (B) The percentage of mice in which recurrent virus was detected in the salivary glands (solid line) was used to generate a mathematical model describing the probability of recurrence over time (see Materials and Methods). Broken line, A linear function differentiated from the Poisson distribution as a curve P(t) = (t − t 0)/T 0, for (t − t 0)/T 0 < 0.5. Arrow, The time point at which recurrent virus is predicted in 100% of mice.
Figure 2
Figure 2
Recurrent infection after selective depletion of T cell subsets. (A) Latently infected B cell–deficient mice were depleted of CD4+ and/or CD8+ T lymphocytes. Virus titration of the spleen, lungs, and salivary glands was performed 2 wk later. Shown are percentages of mice with infectious virus in at least one of the organs analyzed. (B) Recurrent virus in mice depleted of CD4+ and CD8+ T cells. Titers of individual mice (•) and median values (horizontal lines) are shown. Dashed line, Detection limit of infectious virus.
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