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

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.

Keywords: CT; Grandmother-to-child transmission; HIV; HLA-B*81:01; Paediatric non-progressor; Viral replicative capacity.

Fig. 1

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])

Fig. 2

Impact of variants within the HLA-B*81:01-TL9 epitope on viral replicative capacity (VRC). a–c Percentage GXR cells expressing GFP following infection with an MOI of 0.03 using virus variants shown. d–f Impact of viral variants studied on replication capacity compared to NL4-3 in three distinct viral backbones

Fig. 3

Structural modelling of the impact of escape mutations around the p24-Gag B81:01-TL9 epitope. a Overall structure of p24-Gag protein residues 133–283 demonstrating the position of the B*81:01-TL9 epitope (red cartoon) and the polymorphisms between the NL4-3 and SK-254 viruses (blue cartoon). The environment that is likely to be affected by mutations around the B*81:01-TL9 epitope, in helix 3, is highlighted in the black box. b Binding network (green and red sticks) around residue 188L (yellow sticks) in the NL4-3 virus, likely to be important for maintaining the protein fold between helix 3 and 4. c Modelling of the rare L188F mutation, shown to reduce viral replication capacity. This mutation could abrogate interactions between residue 188 with 184L, 198 M, 201L and 266I, possibly destabilizing the helix 3–helix 4 interface. d Binding network (green and red sticks) around residue 186T (yellow sticks) in the NL4-3 virus, likely to be important for maintaining the protein fold between helix 1 and 3. e Modelling of the T186S mutation (black arrow), shown to be detrimental to viral health. This mutation abrogates interactions between residue 186 with 152L and 147I/T (black circle), possibly destabilizing the helix 1–helix 3 interface. f Structural modeling of the T190I mutation (black arrow) that can rescue the T186S mutation, restoring viral replication capacity. Modelling suggests that new interactions can form between residue 190I and 152L (black circle), potentially restoring helix 1–helix 3 interface stability