Maintenance of large subpopulations of differentiated CD8 T-cells two years after cytomegalovirus infection in Gambian infants.

BACKGROUND: In a previously published study, we found that large differentiated subpopulations of CD8 T-cells emerged rapidly after CMV infection in young infants and persisted throughout the following year. Here we describe a follow-up study conducted on the same infants to establish whether the differentiated subpopulations continued through the second year post-infection. METHODOLOGY / PRINCIPAL FINDINGS: CMV-specific cells identified using tetramers remained more activated and differentiated than the overall CD8 population. The large subpopulation of differentiated cytotoxic (CD28(-)CD62L(-)Bcl-2(low)CD95(+)perforin(+)) cells that emerged rapidly after infection remained stable after two years. No similar subpopulation was found in CMV-uninfected infants indicating that two years after infection, CMV remained a major factor in driving CD8 T-cell differentiation. Although markers of activation (CD45R0 and HLA-D) declined throughout the first year, HLA-D expression continued to decline during the second year and CD45R0 expression increased slightly. The age-related increase in IFNgamma response observed during the first year continued but was non-significant during the second year, indicating that the rate of functional improvement had slowed substantially. CONCLUSIONS / SIGNIFICANCE: The large differentiated subpopulations of CD8 T-cells that had emerged immediately after CMV infection persisted through the second year post-infection, while levels of activation and functional capacity remained fairly constant.

Effects of antenatal and postnatal environments on CD4 T-cell responses to Mycobacterium bovis BCG in healthy infants in the Gambia.

The Mycobacterium bovis BCG vaccine has a poor record of efficacy in low-income tropical settings. Against this background, we evaluated the immune response of infants to mycobacterial antigens over the 2 years following BCG vaccination at birth by measuring the gamma interferon (IFN-gamma), interleukin-2 (IL-2), and CD154 responses of CD4 T cells. Similar numbers of cells expressed IFN-gamma in infants, 4- to 5-year-old children, and adults, while CD154 was not expressed at comparable levels until the second year of infancy. The IL-2 response remained relatively low in infants, children, and adults but correlated negatively with mother's body mass index and was highest among infants born to Mandinka mothers. Similarly, infants born in the wet season had a stronger CD154 response than those born in the dry season throughout the 2 years of the study. We conclude that the prenatal and perinatal environments have a lasting effect on the response of infants to the BCG vaccine.

CD4(+) T cell responses to cytomegalovirus in early life: a prospective birth cohort study.

We compared cytomegalovirus (CMV)-specific interferon-gamma (IFN-gamma), interleukin 2 (IL-2), and CD154 CD4(+) T cell responses of infants to those from chronically infected adults and from children aged 4-5 years. Magnitudes of the responses were similar, although coexpression of IFN-gamma plus CD154 occurred more than coexpression of IFN-gamma plus IL-2 or IL-2 plus CD154. Responses remained constant during infancy, although the proportion of IFN-gamma-producing cells increased from infancy to adulthood. Most responding cells in infants were undifferentiated (i.e., CD27(+)CD28(+)), although IFN-gamma-producing cells were disproportionately CD27(-). By 12 months after diagnosis, viremia was rarely detectable, indicating that CMV was controlled despite the slow development of CMV-specific CD4(+) T cell responses.

Cytomegalovirus infection induces T-cell differentiation without impairing antigen-specific responses in Gambian infants.

Cytomegalovirus (CMV) infection induces profound differentiation of T cells, and is associated with impaired responses to other immune challenges. We therefore considered whether CMV infection and the consequent T-cell differentiation in Gambian infants was associated with impaired specific responses to measles vaccination or polyclonal responses to the superantigen staphylococcal enterotoxin B (SEB). While the concentration of undifferentiated (CD27(+) CD28(+) CCR7(+)) T-cells in peripheral blood was unaffected by CMV, there was a large increase in differentiated (CD28(-) CD57(+)) CD8 T-cells and a smaller increase in differentiated CD4 cells. One week post-vaccination, the CD4 cell interferon-gamma (IFN-gamma) response to measles was lower among CMV-infected infants, but there were no other differences between the cytokine responses, or between the cytokine or proliferative responses 4 months post-vaccination. However, the CD8 T cells of CMV-infected infants proliferated more in response to SEB and the antibody response to measles correlated with the IFN-gamma response to CMV, indicating that CMV infection actually enhances some immune responses in infancy.

Cytomegalovirus infection in Gambian infants leads to profound CD8 T-cell differentiation.

Cytomegalovirus (CMV) infection is endemic in Gambian infants, with 62% infected by 3 months and 85% by 12 months of age. We studied the CD8 T-cell responses of infants to CMV following primary infection. CMV-specific CD8 T cells, identified with tetramers, showed a fully differentiated phenotype (CD28(-) CD62L(-) CD95(+) perforin(+) granzyme A(+) Bcl-2(low)). Strikingly, the overall CD8 T-cell population developed a similar phenotype following CMV infection, which persisted for at least 12 months. In contrast, primary infection was accompanied by up-regulation of markers of activation (CD45R0 and HLA-D) on both CMV-specific cells and the overall CD8 T-cell population and division (Ki-67) of specific cells, but neither pattern persisted. At 12 months of age, the CD8 T-cell population of CMV-infected infants was more differentiated than that of uninfected infants. Although the subpopulation of CMV-specific cells remained constant, the CMV peptide-specific gamma interferon response was lower in younger infants and increased with age. As the CD8 T-cell phenotype induced by CMV is indicative of immune dysfunction in the elderly, the existence of a similar phenotype in large numbers of Gambian infants raises the question of whether CMV induces a similarly deleterious effect.

Seasonal variation in respiratory syncytial virus epidemics in the Gambia, West Africa.

Respiratory syncytial virus outbreaks tend to occur seasonally and are a major cause of childhood morbidity. In The Gambia a regular pattern of outbreaks during six consecutive annual seasons was disrupted by 2 years of irregular outbreaks, followed by another 2 years of regular seasonal outbreaks. Improved understanding of the transmission dynamics of respiratory syncytial virus is essential to design and test effective interventions.

An epidemiological study of RSV infection in the Gambia.

OBJECTIVE: To describe the epidemiology of respiratory syncytial virus (RSV) infection in a developing country. METHODS: The work was carried out in three hospitals for primary cases and in the community for secondary cases in the western region of the Gambia, West Africa. RSV infection was diagnosed by immunofluorescence of nasopharyngeal aspirate samples in children younger than two years admitted to hospital with acute lower respiratory infection (ALRI). Routine records of all children with ALRI were analysed, and the incidence rates of ALRI, severe RSV-associated respiratory illness and hypoxaemic RSV infections were compared. A community-based study was undertaken to identify secondary cases and to obtain information about spread of the virus. FINDINGS: 4799 children with ALRI who were younger than two years and lived in the study area were admitted to the study hospitals: 421 had severe RSV-associated respiratory illness; 55 of these were hypoxaemic. Between 1994 and 1996, the observed incidence rate for ALRI in 100 children younger than one year living close to hospital was 9.6 cases per year; for severe RSV-associated respiratory illness 0.83; and for hypoxaemic RSV-associated respiratory illness 0.089. The proportion of all ALRI admissions due to RSV was 19%. Overall, 41% of children younger than five years in compounds in which cases lived and 42% in control compounds had evidence of RSV infection during the surveillance period. CONCLUSION: RSV is an important cause of ALRI leading to hospital admission in the Gambia. Morbidity is considerable and efforts at prevention are worthwhile.

Influence of Mycobacterium bovis bacillus Calmette-Guérin on antibody and cytokine responses to human neonatal vaccination.

The immaturity of the immune system increases the susceptibility of young infants to infectious diseases and prevents the induction of protective immune responses by vaccines. We previously reported that Mycobacterium bovis bacillus Calmette-Guérin (BCG) vaccination induces a potent Th1 response to mycobacterial Ags in newborns. In this study, we evaluated the influence of BCG on the response to unrelated vaccines given in early life. Newborns were randomly allocated to one of three study groups receiving BCG at birth, when infants received their first dose of hepatitis B and oral polio vaccines; at 2 mo of age, when infants received their first dose of diphtheria and tetanus vaccines; or at 4.5 mo of age, when immune responses to vaccines were measured. Administration of BCG at the time of priming markedly increased the cellular and Ab responses to the hepatitis B vaccine, but had only a limited influence on the cytokine response to tetanus toxoid and no effect on the Ab responses to tetanus and diphtheria toxoids. Although BCG induced a potent Th1-type response to mycobacterial Ags, it promoted the production of both Th1- and Th2-type cytokines in response to unrelated vaccines. The effect of BCG was apparent at the systemic level, as it increased the Ab response to oral polio vaccine. These results demonstrate that BCG influences the immune response to unrelated Ags in early life, likely through its influence on the maturation of dendritic cells.