Paediatric non-progression following grandmother-to-child HIV transmission.
BACKGROUND
In contrast to adult HIV infection, where slow disease progression is strongly linked to immune control of HIV mediated by protective HLA class I molecules such as HLA-B*81:01, the mechanisms by which a minority of HIV-infected children maintain normal-for-age CD4 counts and remain clinically healthy appear to be HLA class I-independent and are largely unknown. To better understand these mechanisms, we here studied a HIV-infected South African female, who remained a non-progressor throughout childhood.


RESULTS
Phylogenetic analysis of viral sequences in the HIV-infected family members, together with the history of grand-maternal breast-feeding, indicated that, unusually, the non-progressor child had been infected via grandmother-to-child transmission. Although HLA-B*81:01 was expressed by both grandmother and grand-daughter, autologous virus in each subject encoded an escape mutation L188F within the immunodominant HLA-B*81:01-restricted Gag-specific epitope TL9 (TPQDLNTML, Gag 180-188). Since the transmitted virus can influence paediatric and adult HIV disease progression, we investigated the impact of the L188F mutant on replicative capacity. When this variant was introduced into three distinct HIV clones in vitro, viral replicative capacity was abrogated altogether. However, a virus constructed using the gag sequence of the non-progressor child replicated as efficiently as wildtype virus.


CONCLUSIONS
These findings suggest alternative sequences of events: the transmission of the uncompensated low fitness L188F to both children, potentially contributing to slow progression in both, consistent with previous studies indicating that disease progression in children can be influenced by the replicative capacity of the transmitted virus; or the transmission of fully compensated virus, and slow progression here principally the result of HLA-independent host-specific factors, yet to be defined.
Department of Paediatrics, University of Oxford, Peter Medawar Building for Pathogen Research, South Parks Road, Oxford, OX1 3SY, UK.
M-H
MH
Tsai
Department of Paediatrics, University of Oxford, Peter Medawar Building for Pathogen Research, South Parks Road, Oxford, OX1 3SY, UK.
M
M
Muenchhoff
Department of Paediatrics, University of Oxford, Peter Medawar Building for Pathogen Research, South Parks Road, Oxford, OX1 3SY, UK.
E
E
Adland
Department of Paediatrics, University of Oxford, Peter Medawar Building for Pathogen Research, South Parks Road, Oxford, OX1 3SY, UK.
A
A
Carlqvist
Department of Paediatrics, University of Oxford, Peter Medawar Building for Pathogen Research, South Parks Road, Oxford, OX1 3SY, UK.
J
J
Roider
Cardiff University School of Medicine, Heath Park, Cardiff, UK.
D K
DK
Cole
Cardiff University School of Medicine, Heath Park, Cardiff, UK.
A K
AK
Sewell
Microsoft Research, eScience Group, Los Angeles, CA, USA.
J
J
Carlson
HIV Pathogenesis Program, Doris Duke Medical Research Institute, University of KwaZulu-Natal, Durban, South Africa.|Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Cambridge, MA, USA.|Max Planck Institute for Infection Biology, Berlin, Germany.
T
T
Ndung'u
Department of Paediatrics, University of Oxford, Peter Medawar Building for Pathogen Research, South Parks Road, Oxford, OX1 3SY, UK. philip.goulder@paediatrics.ox.ac.uk.|HIV Pathogenesis Program, Doris Duke Medical Research Institute, University of KwaZulu-Natal, Durban, South Africa. philip.goulder@paediatrics.ox.ac.uk.
P J R
PJ
Goulder
D000328:Adult; D001942:Breast Feeding; D018791:CD4 Lymphocyte Count; D002648:Child; D018450:Disease Progression; D005260:Female; D000066502:Grandparents; D015658:HIV Infections / Q000635:transmission* / Q000821:virology*; D020276:HIV Long-Term Survivors; D015497:HIV-1 / Q000235:genetics / Q000302:isolation & purification / Q000502:physiology*; D015235:HLA-B Antigens / Q000276:immunology; D006801:Humans; D018445:Infectious Disease Transmission, Vertical; D009154:Mutation; D010802:Phylogeny; D013019:South Africa; D014779:Virus Replication
D015235:HLA-B Antigens
CT; Grandmother-to-child transmission; HIV; HLA-B*81:01; Paediatric non-progressor; Viral replicative capacity