The manifestation of HIV-1 infection is different in children and adults. Most of the
children who acquire HIV perinatally progress to disease within the first two years of
life, while adults can remain asymptomatic for up to ten years. However, a small
minority group of children can control the virus for years in the absence of
antiretroviral therapy. We characterized CD8+ T cell responses critical for the
containment of HIV infection in a cohort of infants HIV infected from birth using IFN-
γ ELISPOT, multicolour flow cytometry and viral sequencing of the Gag protein. We
investigated whether the age at the time of infection, specificity and functionality of the
generated responses, genetic make up and the maternal immune responses to HIV,
influenced disease progression in the child.
We found that the majority of in-utero infected infants mounted CD8+ T cell responses
from the first days of life. In contrast to chronically infected children or adults, the
specificity of the initial response in acutely infected infants was directed towards Env
and Rev proteins and CD4+ T cell responses were minimal during the first 6 months of
life. Slow progression to disease was associated with possession of one of the
protective HLA-B alleles by either the mother or the child (P=0.007) and targeting of
Gag epitopes presented by the protective HLA-B alleles. Mothers who expressed
protective alleles but whose children did not possess these alleles, transmitted less fit
viruses that benefited their children. Furthermore, slow progressor children had more
polyfunctional CD8+ T cell responses in early infection when compared to rapid
progressors (P=0.05). The ability of infants to induce CD8+ T cell responses early in
life is encouraging for vaccine interventions. The differences in the specificity of the
initial responses between adults and children, insufficient priming of these responses as
a result of minimal CD4+ T cell help during infancy and possession of non-protective
HLA alleles shared between mother and child, may explain the rapid disease
progression generally noted in most infants. However, slow progression to disease in
the minority group of children may be attributed to functional capacity of the CD8+ T
cells generated by the child, mediation by protective HLA alleles, acquisition of low
fitness viruses from the mother or de novo attenuation of the virus by the child’s own
immune responses. / Thesis (Ph.D.)-University of KwaZulu-Natal, Durban, 2011.
| Identifer | oai:union.ndltd.org:netd.ac.za/oai:union.ndltd.org:ukzn/oai:http://researchspace.ukzn.ac.za:10413/5853 |
| Date | January 2011 |
| Creators | Thobakgale, Christina Fanesa. |
| Contributors | Kiepiela, Photini., Ndung'u, Thumbi., Goulder, Philip. |
| Source Sets | South African National ETD Portal |
| Language | en_ZA |
| Detected Language | English |
| Type | Thesis |
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