Betaherpesvirus genetic variation and infection in HIV-1 exposed Zambian children

Abstract

The betaherpesviruses human cytomegalovirus (HCMV) and human herpesvirus 6 (HHV-6) are investigated here as pathogens in Zambia, an HIV -1 endemic region where there was little previous data. In particular we assess the effects of these viruses on 'maternally HIV-l exposed' infants: HIV-l negative infants of HI V-I positive mothers. HCMV and HHV-6 are serious causes of morbidity and mortality in HIV / AIDS and are linked with AIDS progression, so in this thesis they are investigated in both HIV -1 infected and uninfected Zambian children, along with maternally HIV exposed infants, an under studied and growing group in Southern Africa. The aim ofthis thesis is to employ qualitative and quantitative PCR assays to determine betaherpesvirus prevalence, loads and genotypes in three independent Zambian paediatric cohorts: Two retrospective cohorts (141 infants hospitalized with fever and 36 childhood HIV-1 positive respiratory mortalities), and also one prospective cohort (812 infants taking part in a population-based study designed to test the efficacy of a micronutrient fortified feed supplement to improve growth and health) in which relationships between betaherpesvirus infection, duration of breast feeding, infant growth and morbidity were investigated. Prevalence and loads were highest within the symptomatic cohorts, although lower levels of both viruses were also detected in sera from healthy infants taking part in the prospective study. High load HCMV infections were shown here to be significantly more prevalent in maternally HIV -1 exposed infants. Genotyping analysis focused of two hypervariable glycoproteins (gO and gN), which in HCMV have been shown to form seven linked genotypes. Here we identified a new genotype (gN4d) and demonstrated linkage with g05, demonstrating now eight gO/gN linkages. Analyses of this data and that generated in other countries show these linkages are globally maintained. Conversely for HHV -6, whilst HHV-6B is the predominant strain for childhood infections in the V.S, Europe and Japan, in Zambia HHV-6A was identified in 84% ofinfant infections, suggesting emergence elsewhere. The prevalence of active betaherpesvirus infections through detection of viral sera-DNA was 34-40% for HCMV and 8-13% for HHV-6, showing that primary infection with HCMV occurs much earlier in this region than in European and North American countries. Active HCMV infections were associated with inhibitory effects on growth and a trend for increased morbidity in HIV -1 exposed infants as measured by an increased rate of hospital referrals. HCMV seroprevalence was associated with anaemia and stunting, and breast feeding increased HCMV transmission, particularly in HIV -1 exposed infants. A micronutrient supplement with iron reduced anaemia. In summary, genotypes of HCMV and HHV-6 were identified and characterised in infant infections in this region, and analyses shows association with morbidity and growth delays for HCMV infected children, particularly with maternal HIV -1, a newly identified potential hazard for this population.