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  • Review Article
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The impact of differential antiviral immunity in children and adults

Nature Reviews Immunology volume 12, pages 636–648 (2012)Cite this article

Subjects

Key Points

  • The immune response is adapted at all stages of early life to maximize survival. These adaptations during intrauterine and early extrauterine life favour protection against extracellular pathogens, and leave infants particularly vulnerable to intracellular pathogens, such as viruses that are transmitted perinatally.

  • This Review contrasts the disease outcomes of three viral infections that can be transmitted perinatally — namely, HIV, cytomegalovirus (CMV) and hepatitis B virus (HBV) infections — in infants and adults to illustrate the ontogeny of the immune response to virus infections and the impact of the immune differences between early life and adulthood on these as well as other viral infections.

  • Following HIV infection of children, survival is ∼1 year without treatment, compared with ∼10 years in adult infection. In HBV infection, perinatal transmission results in persistent infection in 90% of cases, compared with 5% in adults. Although perinatally acquired persistent HBV infection is usually asymptomatic in childhood, it carries a high risk of cirrhosis and hepatocellular carcinoma developing in adulthood. Perinatally transmitted CMV infection, by contrast, does not typically cause disease in infants, although excretion of the virus is prolonged compared with adults. Congenital CMV infection occurring in the first trimester of pregnancy can cause disease in a minority of infants infected at this time.

  • The immune response in intrauterine and early neonatal life is tolerogenic. This is reflected by the propensity of naive fetal T cells to differentiate into regulatory T cells following stimulation by non-inherited maternal alloantigens, and by the greater capacity of neonatal innate immune cells to produce the anti-inflammatory and immunomodulatory cytokine interleukin-10 (IL-10) following Toll-like receptor stimulation.

  • T helper 1 (TH1) cell-supporting cytokines — such as type I interferons, interferon-γ and IL-12 — are produced in decreased amounts during childhood, and IL-12 production does not reach adult levels until adolescence. By contrast, TH17 cell-supporting cytokines, such as IL-6 and IL-23, are increased in neonates compared with adults. The apparent skewing of the immune response in fetal and early neonatal life favours defence against extracellular pathogens, and avoids damaging pro-inflammatory TH1 cell responses, but at the expense of effective antiviral immune responses.

  • In spite of the effective strategies that exist for the prevention of mother-to-child transmission of HIV and hepatitis C virus, these are successful only in certain settings. A deeper understanding of the ontogeny of antiviral immunity will be crucial to guide the development of new strategies, including neonatal immunization and the optimal use of antiviral therapies in early life, to combat the disease caused by these viruses.

Abstract

The course of immune maturation has evolved to favour survival at each stage of development in early life. Fetal and neonatal immune adaptations facilitate intrauterine survival and provide early postnatal protection against extracellular pathogens, but they leave infants susceptible to intracellular pathogens such as viruses that are acquired perinatally. This Review focuses on three such pathogens — HIV, hepatitis B virus and cytomegalovirus — and relates the differential impact of these infections in infants and adults to the antiviral immunity that is generated at different ages. A better understanding of age-specific antiviral immunity may inform the development of integrated prevention, treatment and vaccine strategies to minimize the global disease burden resulting from these infections.

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Figure 1: Differential outcomes of viral infections in early and later life.
Figure 2: Changes in lymphocyte subset composition from birth to early adulthood.
Figure 3: Differences between innate immunity in early and later life.
Figure 4: The number of children and adults living with HIV.

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Acknowledgements

We are grateful to the Wellcome Trust, the NIHR Biomedical Research Centre, Oxford, the Oxford Martin School, the UK Medical Research Council and the US National Institutes of Health (grant 5U19A082630-04) for support. We would like to thank also C. Wilson and A. Marchant for critical review of the manuscript.

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Authors and Affiliations

  1. Centre for Paediatrics, Blizard Institute, Queen Mary University of London, Newark Street, London, E1 2AT, UK

    Andrew J. Prendergast

  2. NIHR Biomedical Research Centre and Nuffield Department of Medicine, University of Oxford, Peter Medawar Building, South Parks Road, Oxford, OX1 3SY, UK

    Paul Klenerman

  3. Department of Paediatrics, University of Oxford, Peter Medawar Building, South Parks Road, Oxford, OX1 3SY, UK

    Philip J. R. Goulder

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  1. Andrew J. Prendergast
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  2. Paul Klenerman
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Correspondence to Philip J. R. Goulder.

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Glossary

Infancy

The first year of life.

Active immunization

The induction of immunity by immunogens that activate and expand the endogenous immune repertoire. Such immunogens induce antibodies and cell-mediated immunity, as well as immunological memory that might last for decades.

Passive immunization

Immunity that is provided rapidly by the transfer of immunoglobulins, the maximal activity of which lasts for approximately 2–3 weeks before it wanes owing to catabolic destruction.

Neonates

Infants up to 28 days of age.

Long-term non-progressors

(LTNPs). There is no universally adopted definition of LTNPs, and often the term LTNP is used interchangeably with HIV controller, because control of viraemia is strongly predictive of long-term non-progression of disease. LTNPs are individuals infected with HIV whose plasma viral load is controlled to low levels for extended periods. Stricter definitions of LTNPs include the duration of infection and preservation of CD4+ T cell numbers.

Mucosa-associated invariant T cells

(MAIT cells). A conserved mammalian T cell subset that expresses TCR α-chains with a canonical Vα7.2 junctional sequence in rodents and humans. MAIT cells are specific for an as-yet-undefined antigen that is bound to the monomorphic MHC class I-related molecule MR1. In a similar manner to invariant natural killer T cells, MAIT cells typically express memory T cell markers and natural killer cell receptors, and in adult humans they account for one in six circulating CD8+ T cells.

Follicular helper T cells

CD4+ T helper cells that are specialized to regulate multiple stages of antigen-specific B cell immunity through cognate cell contact and the secretion of cytokines. They localize to B cell follicles during immune responses.

Memory inflation

The gradual accumulation of peptide-specific CD8+ T cells with an effector memory phenotype that occurs after the resolution of certain viral infections (for example, MCMV infection).

Immunosenescence

The decreased function of the immune system with age. In particular, the number of naive T cells decreases as thymic function declines, and the number of terminally differentiated T cells with shortened telomeres increases.

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Prendergast, A., Klenerman, P. & Goulder, P. The impact of differential antiviral immunity in children and adults. Nat Rev Immunol 12, 636–648 (2012). https://doi.org/10.1038/nri3277

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