title: Viral Evolution and Cytotoxic T Cell Restricted Selection in Acute Infant HIV-1 Infection.
abstract: Antiretroviral therapy-naive HIV-1 infected infants experience poor viral containment and rapid disease progression compared to adults. Viral factors (e.g. transmitted cytotoxic T- lymphocyte (CTL) escape mutations) or infant factors (e.g. reduced CTL functional capacity) may explain this observation. We assessed CTL functionality by analysing selection in CTL-targeted HIV-1 epitopes following perinatal infection. HIV-1 gag, pol and nef sequences were generated from a historical repository of longitudinal specimens from 19 vertically infected infants. Evolutionary rate and selection were estimated for each gene and in CTL-restricted and non-restricted epitopes. Evolutionary rate was higher in nef and gag vs. pol, and lower in infants with non-severe immunosuppression vs. severe immunosuppression across gag and nef. Selection pressure was stronger in infants with non-severe immunosuppression vs. severe immunosuppression across gag. The analysis also showed that infants with non-severe immunosuppression had stronger selection in CTL-restricted vs. non-restricted epitopes in gag and nef. Evidence of stronger CTL selection was absent in infants with severe immunosuppression. These data indicate that infant CTLs can exert selection pressure on gag and nef epitopes in early infection and that stronger selection across CTL epitopes is associated with favourable clinical outcomes. These results have implications for the development of paediatric HIV-1 vaccines.
authors.affiliation: Nuffield Department of Clinical Medicine, University of Oxford, Oxford, United Kingdom.|KEMRI-Wellcome Trust Research Program, Centre for Geographical Medicine Research, Kilifi, Kenya.
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Garcia-Knight
authors.affiliation: Department of Global Health, University of Washington, Seattle, Washington, United States of America.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Slyker
authors.affiliation: Department of Paediatrics and Child Health, University of Nairobi, Nairobi, Kenya.|Department of Medicine, University of Washington, Seattle, Washington, United States of America.
authors.forename: Barbara Lohman
authors.initials: BL
authors.lastname: Payne
authors.affiliation: Department of Medicine, University of California San Diego, San Diego, California, United States of America.
authors.forename: Sergei L Kosakovsky
authors.initials: SL
authors.lastname: Pond
authors.affiliation: Section of Paediatrics, Department of Medicine, Wright Fleming Institute, Imperial College London, London, United Kingdom.
authors.forename: Thushan I
authors.initials: TI
authors.lastname: de Silva
authors.affiliation: Department of Global Health, University of Washington, Seattle, Washington, United States of America.|Kenyan Medical Research Institute, Nairobi, Kenya.
authors.forename: Bhavna
authors.initials: B
authors.lastname: Chohan
authors.affiliation: Kenyan Medical Research Institute, Nairobi, Kenya.
authors.forename: Brian
authors.initials: B
authors.lastname: Khasimwa
authors.affiliation: Department of Paediatrics and Child Health, University of Nairobi, Nairobi, Kenya.
authors.forename: Dorothy
authors.initials: D
authors.lastname: Mbori-Ngacha
authors.affiliation: Department of Global Health, University of Washington, Seattle, Washington, United States of America.|Department of Medicine, University of Washington, Seattle, Washington, United States of America.|Department of Epidemiology, University of Washington, Seattle, Washington, United States of America.|Department of Pediatrics, University of Washington, Seattle, Washington, United States of America.
authors.forename: Grace
authors.initials: G
authors.lastname: John-Stewart
authors.affiliation: Nuffield Department of Clinical Medicine, University of Oxford, Oxford, United Kingdom.
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Rowland-Jones
authors.affiliation: Nuffield Department of Clinical Medicine, University of Oxford, Oxford, United Kingdom.|Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, Stockholm, Sweden.
authors.forename: Joakim
authors.initials: J
authors.lastname: Esbjörnsson
mesh_terms: D002675:Child, Preschool; D018450:Disease Progression; D019143:Evolution, Molecular; D005260:Female; D015750:Genes, gag; D015751:Genes, pol; D015658:HIV Infections / Q000235:genetics*; D015497:HIV-1 / Q000235:genetics*; D006801:Humans; D007223:Infant; D013602:T-Lymphocytes, Cytotoxic / Q000821:virology*; D054311:nef Gene Products, Human Immunodeficiency Virus
chemical_list: D054311:nef Gene Products, Human Immunodeficiency Virus