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Paediatric non-progression following grandmother-to-child HIV transmission

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ABSTRACT

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.

Conclusion: 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.

Electronic supplementary material: The online version of this article (doi:10.1186/s12977-016-0300-y) contains supplementary material, which is available to authorized users.

No MeSH data available.


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Grandmother-to-child transmission in a non-progressing child. a Viral load and absolute CD4 count in non-progressing, ART-naive child GD. b Family tree including HIV-infected family members GM (grand-mother), GD (grand-daughter), D2 (second daughter of GM) and uninfected mother of GD, D1. c Phylogenetic tree including GD, GM and D2, and 43 HIV-infected adults from the same locality in Durban, South Africa. d Frequency of the Gag variant L188F present in all three family members in chronically infected adults with C clade infection (data from Ref. [32])
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Fig1: Grandmother-to-child transmission in a non-progressing child. a Viral load and absolute CD4 count in non-progressing, ART-naive child GD. b Family tree including HIV-infected family members GM (grand-mother), GD (grand-daughter), D2 (second daughter of GM) and uninfected mother of GD, D1. c Phylogenetic tree including GD, GM and D2, and 43 HIV-infected adults from the same locality in Durban, South Africa. d Frequency of the Gag variant L188F present in all three family members in chronically infected adults with C clade infection (data from Ref. [32])

Mentions: We have previously defined ‘paediatric slow progressors’ as ART-naïve, HIV-infected children who have not progressed to meet clinical or CD4 count criteria for ART initiation [15]. The CD4 count criteria for ART initiation in children aged >5 years in South Africa until 2013 was an absolute CD4 count of ≤350 cells/ul [15]. Within a study cohort of paediatric slow progressors in Durban, South Africa, a female (‘GD’) was enrolled at age 9.1 years, with an absolute CD4 count of 830 cells/ul and viral load of 42,000 copies/ml (Fig. 1a). The mother (‘D1’) of GD, however, tested HIV-uninfected. It emerged that the HIV-infected grandmother (‘GM’) of GD had a second daughter (‘D2’) who was born 5 weeks after GD (Fig. 1b), and that GM had breast-fed both her daughter (D2) and her grand-daughter (GD). Phylogenetic analysis (Fig. 1c) of HIV Gag sequences obtained from GM, D2 and GD were consistent with mother-to-child transmission of HIV from GM to D2, and with grandmother-to-child transmission of HIV from GM to GD.Fig. 1


Paediatric non-progression following grandmother-to-child HIV transmission
Grandmother-to-child transmission in a non-progressing child. a Viral load and absolute CD4 count in non-progressing, ART-naive child GD. b Family tree including HIV-infected family members GM (grand-mother), GD (grand-daughter), D2 (second daughter of GM) and uninfected mother of GD, D1. c Phylogenetic tree including GD, GM and D2, and 43 HIV-infected adults from the same locality in Durban, South Africa. d Frequency of the Gag variant L188F present in all three family members in chronically infected adults with C clade infection (data from Ref. [32])
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC5016918&req=5

Fig1: Grandmother-to-child transmission in a non-progressing child. a Viral load and absolute CD4 count in non-progressing, ART-naive child GD. b Family tree including HIV-infected family members GM (grand-mother), GD (grand-daughter), D2 (second daughter of GM) and uninfected mother of GD, D1. c Phylogenetic tree including GD, GM and D2, and 43 HIV-infected adults from the same locality in Durban, South Africa. d Frequency of the Gag variant L188F present in all three family members in chronically infected adults with C clade infection (data from Ref. [32])
Mentions: We have previously defined ‘paediatric slow progressors’ as ART-naïve, HIV-infected children who have not progressed to meet clinical or CD4 count criteria for ART initiation [15]. The CD4 count criteria for ART initiation in children aged >5 years in South Africa until 2013 was an absolute CD4 count of ≤350 cells/ul [15]. Within a study cohort of paediatric slow progressors in Durban, South Africa, a female (‘GD’) was enrolled at age 9.1 years, with an absolute CD4 count of 830 cells/ul and viral load of 42,000 copies/ml (Fig. 1a). The mother (‘D1’) of GD, however, tested HIV-uninfected. It emerged that the HIV-infected grandmother (‘GM’) of GD had a second daughter (‘D2’) who was born 5 weeks after GD (Fig. 1b), and that GM had breast-fed both her daughter (D2) and her grand-daughter (GD). Phylogenetic analysis (Fig. 1c) of HIV Gag sequences obtained from GM, D2 and GD were consistent with mother-to-child transmission of HIV from GM to D2, and with grandmother-to-child transmission of HIV from GM to GD.Fig. 1

View Article: PubMed Central - PubMed

ABSTRACT

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.

Conclusion: 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.

Electronic supplementary material: The online version of this article (doi:10.1186/s12977-016-0300-y) contains supplementary material, which is available to authorized users.

No MeSH data available.


Related in: MedlinePlus