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

Abstract

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

Role of HIV-specific CD8+ T cells in pediatric HIV cure strategies after widespread early viral escape

“…This is well illustrated by the Gag-TL9 epitope studied here and previously ( Fig. 4 ; Wright et al, 2010 , 2012 ; Tsai et al, 2016 ), in which the T186S and T186M mutants dramatically decrease viral replicative capacity, whereas mutants such as Q182S have relatively little impact.…”

Impact of HLA-B*52:01-Driven Escape Mutations on Viral Replicative Capacity

“…In contrast to previous studies (11), in our hands the Gag-280 variants had a more substantial impact in the C clade backbones tested and did not lower VRC significantly in the B clade backbone. Also, as shown previously (25,26), the impact of a particular mutation is strikingly backbone dependent even when backbones of the same clade are compared. In the current study, for example, the V280A/K286R combination reduced VRC somewhat in the C clade consensus SK-254(M) backbone but abrogated replication altogether when it was introduced into the IC backbone.…”

“…The HLA-B*52:01-associated escape mutation in B clade infection involves substitution of Gag-280T, but in C clade virus the consensus amino acid at Gag-280 is valine. Based on data from previous studies (25,26), we hypothesized that the impact of particular escape mutants on viral replicative capacity might be highly clade specific. To test this hypothesis, we therefore carried out assays of viral replicative capacity (VRC) using a green fluorescent protein (GFP) reporter cell line to assess the impact of these HLA-B*52:01-restricted mutants on VRC in different backbones of p24 Gag.…”

Long-term Persistent Elite HIV-controllers: The Right Model of Functional Cure

“…In this sense, protective HLA-alleles are for sure to go on playing a major role, as it has been recently shown in a cohort of long term non progressor HIV-controllers enriched in this persistent elite HIV-controller phenotype ( Dominguez-Molina et al, 2017 ). However, like in the case report presented herein and other works, no association was found between spontaneous control and protective HLA alleles ( Tsai et al, 2016 ). Interestingly, other factors like certain KIR ligands, ADCC-mediated response, dendritic cell mechanisms ( Machmach et al, 2012 ) and others yet undefined are likely to be associated with persistent control of HIV-1 infection.…”