Discordant Impact of HLA on Viral Replicative Capacity and Disease Progression in Pediatric and Adult HIV Infection

Abstract

HLA class I polymorphism has a major influence on adult HIV disease progression. An important mechanism mediating this effect is the impact on viral replicative capacity (VRC) of the escape mutations selected in response to HLA-restricted CD8+ T-cell responses. Factors that contribute to slow progression in pediatric HIV infection are less well understood. We here investigate the relationship between VRC and disease progression in pediatric infection, and the effect of HLA on VRC and on disease outcome in adult and pediatric infection. Studying a South African cohort of >350 ART-naïve, HIV-infected children and their mothers, we first observed that pediatric disease progression is significantly correlated with VRC. As expected, VRCs in mother-child pairs were strongly correlated (p = 0.004). The impact of the protective HLA alleles, HLA-B*57, HLA-B*58:01 and HLA-B*81:01, resulted in significantly lower VRCs in adults (p<0.0001), but not in children. Similarly, in adults, but not in children, VRCs were significantly higher in subjects expressing the disease-susceptible alleles HLA-B*18:01/45:01/58:02 (p = 0.007). Irrespective of the subject, VRCs were strongly correlated with the number of Gag CD8+ T-cell escape mutants driven by HLA-B*57/58:01/81:01 present in each virus (p = 0.0002). In contrast to the impact of VRC common to progression in adults and children, the HLA effects on disease outcome, that are substantial in adults, are small and statistically insignificant in infected children. These data further highlight the important role that VRC plays both in adult and pediatric progression, and demonstrate that HLA-independent factors, yet to be fully defined, are predominantly responsible for pediatric non-progression.

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

“…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.…”

Immune activation and paediatric HIV-1 disease outcome

“…In the majority of cases, however, the virus ‘wins’ this contest, and the aggressive immune response adopted in adult infection does not succeed. In HIV-infected infants expressing these ‘protective’ HLA alleles, the same HIV-specific CD8+ T-cell responses may be generated against the virus, but owing to the factors relating to immune ontogeny described above, these responses usually have no impact on viral replication, or on disease outcome generally in paediatric infection (72) **. In the interest of minimizing immune activation, therefore, it may be a more successful strategy in paediatric infection to make no adaptive immune response against the virus.…”

“…Whilst it is clear that viruses with higher VRC tend to be favored in adult transmission (77)*, transmission of HIV across the placenta may involve distinct mechanisms. Strategies designed to prevent MTCT have tended to be most successful at blocking intra-partum and post-partum transmission, therefore increasing the proportion of transmissions that arise in utero (for example, see (78)), and it is notable that in the limited studies undertaken to date, VRC of the virus transmitted to the child (recipient) tends to be lower than in the infected mother (donor) (72, 79) – the opposite of that observed in adult transmission (77)*.…”

Paediatric HIV infection: the potential for cure

“…Non-progressing adult infection, in so-called ‘elite’ controllers [G] , is typically characterised by a strong HIV-specific CD8 + T-cell response restricted by ‘protective’ MHC class I molecules such as HLA-B*27 and HLA-B*57 [refs 3–5], such that high CD4 + T cell counts [G] are maintained as a consequence of successful suppression of viraemia beneath the levels of detection (normally <50 HIV RNA copies/ml). By contrast, non-progressing HIV-infected children (defined here as healthy, ART-naïve children aged >5yrs who maintain absolute CD4 counts in the normal range for age-matched uninfected children, ie above 750 cells/mm 3 [ref,6]), maintain normal CD4 + T cell counts despite median viral loads of ~30,000 copies/ml plasma 7 , and here the HLA-B alleles that strongly influence disease outcome in adult infection do not play a significant role 8 . It is important here to clarify the distinction between non-progressing adult and paediatric infection, defined above by the maintenance of normal CD4 counts in the absence of ART, and long-term survivors who typically have low CD4 counts and high immune activation 7 but may be asymptomatic, presenting late, and in the case of children are usually stunted 9,10 .…”