REVIEWS The impact of differential antiviral immunity in children and adults Andrew J. Prendergast1, Paul Klenerman2 and Philip J. R. Goulder3 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. infancy Infancy The period from fetal development to early is one Antiretroviral drugs given to mother and infant The first year of life. of vulnerability to maternal transmission of viral infec- decrease transmission substantially. Nonetheless, more tions. Mother-to‑child transmission of viruses can occur than 1,000 infant infections occur daily, predominantly in utero, at birth (intrapartum) or postnatally. Viral in sub-Saharan Africa, as a result of suboptimal ante- infections acquired at this time are often characterized natal HIV testing, inadequate coverage of prevention by higher levels of viral replication, a greater risk of per- strategies for mother-to‑child transmission and the sistent (chronic) infection and more severe disease com- overall benefits of prolonged breastfeeding (that is, in pared with those acquired in later life. In this Review, we developing countries, breastfeeding reduces the risk of focus on chronic infections with three viruses — HIV, death from gastrointestinal and respiratory tract infec- hepatitis B virus (HBV) and cytomegalovirus (CMV) — tions, which is sufficient to outweigh the increased risk each of which can be acquired through mother-to‑child of death from HIV transmission by breast milk)1. transmission. These viruses cause a substantial burden HIV-infected infants progress to disease more rap- of disease globally and illustrate the differences between idly than adults (TABLE 1). Without treatment, the median the antiviral immune response in early life and in adult- times to AIDS and death in adults are approximately 10 3 1Centre for Paediatrics, hood. In each case, host control of the virus is highly and 11 years from infection, respectively . In infected chil- + Blizard Institute, Queen Mary dependent on age at acquisition. We discuss how differ- dren without treatment, the CD4 T cell count declines University of London, Newark ences in antiviral immunity between children and adults rapid­ly from birth, leading to severe infections and Street, London E1 2AT, UK. fundamentally influence the pathogenesis, time course delayed growth and neurological development. Mortality 2 NIHR Biomedical Research and clinical outcome of these infections (TABLE 1), and exceeds 50% by 2 years of age4. As with other chronic viral Centre and Nuffield Department of Medicine, we consider how knowledge of the differential immune infections, the timing of HIV acquisition affects disease University of Oxford, responses between early and later life might inform outcome. A recent pooled analysis of 12,112 infants born Peter Medawar Building, therapeutic strategies to improve the outcome of chronic to HIV-infected women estimated 1‑year mortality for South Parks Road, viral infections in childhood. perinatally infected children to be 52%, compared with Oxford OX1 3SY, UK. 5 3Department of Paediatrics, 26% for postpartum-infected children . In one cohort that University of Oxford, Viral transmission and disease burden distinguished between in utero, intrapartum and post­natal Peter Medawar Building, HIV. Approximately 34 million people are living with infections, the median times from infection to death were South Parks Road, HIV today, of whom 3.4 million are children1. Without 208, 380 and >500 days, respectively6. Viral loads are high Oxford OX1 3SY, UK. interventions to prevent mother-to‑child transmission, (with a median of 105–107 copies of viral RNA per ml Correspondence to P.J.R.G. e-mail: philip.goulder@ 30–40% of infants with HIV-positive mothers acquire plasma) in almost all HIV-infected infants, but they paediatrics.ox.ac.uk HIV, and this can occur in utero (5–10%), intrapartum tend to be lower in postnatally infected infants com- doi:10.1038/nri3277 (15%) or postnatally through breastfeeding (15%)2. pared with those infected in utero or intrapartum, which 636 | SEPTEMBER 2012 | VOLUME 12 www.nature.com/reviews/immunol © 2012 Macmillan Publishers Limited. All rights reserved REVIEWS Active immunization indicates that immune maturation after birth might The clinical presentation of HBV infection ranges 7,8 The induction of immunity by improve viral control and slow disease progression . from asymptomatic infection to fulminant hepa­titis, immunogens that activate and However, viral loads do not typically reach adult levels and age at acquisition determines the likelihood of expand the endogenous (~104 copies per ml) until perinatally infected children symptoms (TABLE 1). Perinatally infected infants are immune repertoire. Such 9 (FIG. 1) immunogens induce antibodies reach 3–5 years of age . usually asymptomatic until late adolescence or early and cell-mediated immunity, as adulthood, whereas later acquisition of HBV leads to well as immunological memory Hepatitis B virus. More than 350 million people are symptoms such as fever, abdominal pain and jaundice that might last for decades. infected with HBV worldwide, and HBV infection in 5–15% of children aged 1–5 years and in 33–50% of accounts for almost half of all cases of cirrhosis, end-stage adolescents and adults15. Liver damage arises from CD8+ Passive immunization 10 Immunity that is provided liver disease and hepatocellular carcinoma . In regions T cell-mediated destruction of infected hepatocytes (dis- rapidly by the transfer of with high endemicity, the major time of infection is early cussed below). The immune response to HBV therefore immunoglobulins, the maximal childhood, with mother-to‑child transmission at birth determines the risk of both viral persistence and clini- activity of which lasts for having a crucial role10. Perinatal HBV acquisition leads to cal disease. Perinatally infected infants have high viral approximately 2–3 weeks (FIG. 1) before it wanes owing to persistent infection in ~90% of cases, whereas equivalent loads and a greater risk of persistence , but a much 11 catabolic destruction. exposure in adults leads to persistence in ~5% of cases . longer asymptomatic period (‘immunotolerant disease’) The incidence of mother-to‑child transmission is mark- compared with older children and adults. However, a edly reduced by active immunization and passive immu- younger age at infection carries a greater long-term risk nization of the child at birth, providing short-term and of developing hepatocellular carcinoma16. long-term protection, respectively, against HBV infec- tion12. However, rare cases of intrauterine trans­mission Cytomegalovirus. Congenital CMV infection is the do occur13, depending on the viral load, and effective most common congenital infection in the developed treatment with antiviral drugs such as lamivudine can world and an important cause of childhood disabil- reduce this risk further14. ity17. Congenital CMV infection occurs in 0.2–6.2% Table 1 | Differential clinical outcomes of chronic viral infections in early and later life Virus Perinatal infection Adult infection HIV • Rapid disease progression, with a typical time to symptomatic • Slower disease progression, typically with many years of clinical disease of several months in sub-Saharan Africa4 latency; median time to AIDS is 10 years3 • Clinical presentation with pneumonia, septicaemia, • Clinical presentation with pneumonia, septicaemia, skin infections, gastroenteritis, opportunistic infections (such as CMV infection oral candidiasis and tuberculosis, or with AIDS-defining illnesses or Pneumocystis jiroveci pneumonia), failure to thrive, oral such as toxoplasmosis, Pneumocystis jiroveci pneumonia, CMV candidiasis, persistent diarrhoea and encephalopathy retinitis, disseminated nontuberculous mycobacterial infections and • More than 50% mortality within 2 years in the absence of ART4 malignancy • A small minority (<5%)180 become long-term non-progressors, • Approximately 40% mortality within 10 years in the absence of ART3 with stable CD4+ T cell counts, low viral loads and minimal • 5–15% become long-term non-progressors; <1% become ‘elite clinical disease, and may only be diagnosed in adolescence controllers’, who control the virus to undetectable levels in the absence of ART181 HBV • Acute infection: almost always asymptomatic15 • Acute infection: may have a prodromal phase with fever, rash and • Chronic infection (>90% of individuals): generally a long arthralgia; infection is asymptomatic or mild in two-thirds of adults; ‘immunotolerant’ phase (up to 20–30 years) with high viral loads one-third develop symptomatic hepatitis with fatigue, nausea and but minimal histological changes in the liver; some individuals jaundice; 1% develop ‘fulminant’ hepatitis with acute liver failure125 develop flares of