Discordant Impact of HLA on Viral Replicative Capacity and Disease Progression in Pediatric and Adult HIV Infection.
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 progre...
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| Main Authors: | , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2015-06-01
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| Series: | PLoS Pathogens |
| Online Access: | https://doi.org/10.1371/journal.ppat.1004954 |
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| author | Emily Adland Paolo Paioni Christina Thobakgale Leana Laker Luisa Mori Maximilian Muenchhoff Anna Csala Margaret Clapson Jacquie Flynn Vas Novelli Jacob Hurst Vanessa Naidoo Roger Shapiro Kuan-Hsiang Gary Huang John Frater Andrew Prendergast Julia G Prado Thumbi Ndung'u Bruce D Walker Mary Carrington Pieter Jooste Philip J R Goulder |
| author_facet | Emily Adland Paolo Paioni Christina Thobakgale Leana Laker Luisa Mori Maximilian Muenchhoff Anna Csala Margaret Clapson Jacquie Flynn Vas Novelli Jacob Hurst Vanessa Naidoo Roger Shapiro Kuan-Hsiang Gary Huang John Frater Andrew Prendergast Julia G Prado Thumbi Ndung'u Bruce D Walker Mary Carrington Pieter Jooste Philip J R Goulder |
| author_sort | Emily Adland |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-47befb569ead468d89d7765d7369e30d |
| institution | Kabale University |
| issn | 1553-7366 1553-7374 |
| language | English |
| publishDate | 2015-06-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Pathogens |
| spelling | doaj-art-47befb569ead468d89d7765d7369e30d2025-08-20T03:46:13ZengPublic Library of Science (PLoS)PLoS Pathogens1553-73661553-73742015-06-01116e100495410.1371/journal.ppat.1004954Discordant Impact of HLA on Viral Replicative Capacity and Disease Progression in Pediatric and Adult HIV Infection.Emily AdlandPaolo PaioniChristina ThobakgaleLeana LakerLuisa MoriMaximilian MuenchhoffAnna CsalaMargaret ClapsonJacquie FlynnVas NovelliJacob HurstVanessa NaidooRoger ShapiroKuan-Hsiang Gary HuangJohn FraterAndrew PrendergastJulia G PradoThumbi Ndung'uBruce D WalkerMary CarringtonPieter JoostePhilip J R GoulderHLA 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.https://doi.org/10.1371/journal.ppat.1004954 |
| spellingShingle | Emily Adland Paolo Paioni Christina Thobakgale Leana Laker Luisa Mori Maximilian Muenchhoff Anna Csala Margaret Clapson Jacquie Flynn Vas Novelli Jacob Hurst Vanessa Naidoo Roger Shapiro Kuan-Hsiang Gary Huang John Frater Andrew Prendergast Julia G Prado Thumbi Ndung'u Bruce D Walker Mary Carrington Pieter Jooste Philip J R Goulder Discordant Impact of HLA on Viral Replicative Capacity and Disease Progression in Pediatric and Adult HIV Infection. PLoS Pathogens |
| title | Discordant Impact of HLA on Viral Replicative Capacity and Disease Progression in Pediatric and Adult HIV Infection. |
| title_full | Discordant Impact of HLA on Viral Replicative Capacity and Disease Progression in Pediatric and Adult HIV Infection. |
| title_fullStr | Discordant Impact of HLA on Viral Replicative Capacity and Disease Progression in Pediatric and Adult HIV Infection. |
| title_full_unstemmed | Discordant Impact of HLA on Viral Replicative Capacity and Disease Progression in Pediatric and Adult HIV Infection. |
| title_short | Discordant Impact of HLA on Viral Replicative Capacity and Disease Progression in Pediatric and Adult HIV Infection. |
| title_sort | discordant impact of hla on viral replicative capacity and disease progression in pediatric and adult hiv infection |
| url | https://doi.org/10.1371/journal.ppat.1004954 |
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