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 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

Early structural and functional changes of the vasculature in HIV-infected children: impact of disease and antiretroviral therapy

Background - Premature cardiovascular disease is increasingly recognized in HIV-infected patients, but the mechanisms involved are unclear. The purpose of this study was to determine the impact of HIV infection and antiretroviral therapy (ART) on markers of early vascular disease in children. Methods and Results - We studied 83 HIV-infected children (56 had taken ART, of whom 31 received a regimen containing protease inhibitors [PIs]; 27 were never treated) and a control group of 59 healthy children. Carotid intima-media thickness (IMT) and brachial artery flow-mediated dilatation (FMD) were measured. IMT was significantly greater in HIV-infected children compared with the control subjects (P<0.001). Among the HIV-infected children, age and treatment were significantly associated with increased IMT. Children exposed to PIs had greater IMT compared with both non-PI-treated children and untreated children (P=0.02). FMD was also significantly reduced in the HIV-infected children compared with control subjects (P=0.02). Pairwise comparisons of different treatment exposure groups revealed that FMD was impaired by a mean of 3.6% (95% CI, 1.8 to 5.3; P<0.001) for children exposed to PIs compared with untreated children and by a mean of 1.8% (95% CI, 0.01 to 3.5; P=0.05) compared with non-PI-treated children. HIV-infected children had lipid abnormalities, but they did not account for the observed differences in either FMD or IMT. Conclusions - HIV infection in childhood is associated with adverse structural and functional vascular changes that are most pronounced in children exposed to PI therapy. Longitudinal studies are required to differentiate the relative impact of HIV disease and ART and to assess the potential for prevention. © 2005 American Heart Association, Inc

Strong sex bias in elite control of paediatric HIV infection

Reports of posttreatment control following antiretroviral therapy (ART) have prompted the question of how common immune control of HIV infection is in the absence of ART. In contrast to adult infection, where elite controllers have been very well characterized and constitute approximately 0.5% of infections, very few data exist to address this question in paediatric infection.Methods:We describe 11 ART-naive elite controllers from 10 cohorts of HIV-infected children being followed in South Africa, Brazil, Thailand, and Europe.Results:All but one of the elite controllers (91%) are females. The median age at which control of viraemia was achieved was 6.5 years. Five of these 11 (46%) children lost control of viraemia at a median age of 12.9 years. Children who maintained control of viraemia had significantly higher absolute CD4 cell counts in the period of elite control than those who lost viraemic control. On the basis of data available from these cohorts, the prevalence of elite controllers in paediatric infection is estimated to be 5-10-fold lower than in adults.Conclusion:Although conclusions are limited by the study design, these data suggest that, whilst paediatric elite control can be achieved, compared with adult elite controllers, this occurs rarely, and takes some years after infection to achieve. Also, loss of immune control arises in a high proportion of children and often relatively rapidly. These findings are consistent with the more potent antiviral immune responses observed in adults and in females

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

Ajuts: Wellcome Trust (WT104748MA, PJRG), South African DST/NRF Research Chairs Initiative, Victor Daitz Foundation, International Early Career Scientist Award i Miguel Servet Contract (MS09/00279)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-progressio

Gag-specific CD8+ T-cell responses and autologous viral sequences in a rapid progressing child, P1.

<p>A. Viral load and CD4% changes, CTL assays and viral sequencing timepoints. Closed red squares: viral load. Closed green squares: CD4%. Horizontal dotted lie: threshold for ART initiation (confirmed CD4<20%). Black closed circle: timepoint of maternal viral sequencing. Dbd: days before delivery. sdNVP: single dose nevirapine, given during labour and on the first day of life to the infant. D182: age of child at ART initiation. B. Gag-specific intracellular interferon-gamma staining assay undertaken when P1 was 10 days of age. C. Interferon-gamma elispot responses to Gag-33 and Gag-34 (two of 66 overlapping 18mers spanning the Gag protein), and on day 41 to the HLA-B*58:01-retricted Gag epitope TSTLQEQIAW contained within overlapping peptides Gag-33/4; and Gag-specific IFN-γ ICS data, showing responses to 66 pooled overlapping Gag peptides. D. Maternal viral sequence 31 days before delivery and autologous viral sequence in P1 showing lack of escape in all time points analyzed from day 1 to day 207, 25 days after ART initiation.</p

Rapid progression and lack of CTL escape in 4 additional rapid progressor expressing protective HLA-B*57/58:01/81:01.

<p>A-D. Clinical data for subjects P2-P5 (as for P1 in <a href="http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1004954#ppat.1004954.g007" target="_blank">Fig 7A</a>). E. In child P5, elispot IFN-γ responses to 17–18mer Gag peptides Gag-40 (from day 4 of life) and Gag-25 (from day 79 of life) and Gag ICS responses to the pool of 66 Gag overlapping peptides. F. In child P5, recognition in IFN-γ elispot assays of autologous TL9 variants TP<u>S</u>DLNTML (Q182S) and TPS<u>E</u>LNTML (D183E), compared to recognition of wildtype TL9. PBMC were tested at day 79 and day 141, with the pattern; data are shown from PBMC at day 141.</p

Relative contribution of HLA-B alleles in VRC in mothers and children.

<p>A. VRC in mothers expressing protective HLA alleles (n = 16) and not (n = 30); and in children expressing protective HLA alleles (n = 22) and not (n = 54). B. VRC in mothers expressing disease-susceptible HLA alleles (n = 9) and not (n = 37); and in children expressing disease-susceptible alleles (n = 14) and not (n = 62). C. VRC in the child according to expression of protective HLA alleles in mother or child (+/+ n = 8;-/+ n = 8; +/- n = 9;-/- n = 18). D. VRC in the child according to expression of disease-susceptible alleles in the mother and/or child (+/+ n = 7;-/+ n = 7; +/- n = 6;-/- n = 23).</p

Impact of protective and disease-susceptible HLA alleles on disease progression in adults in children.

<p>A. The frequency of ART-naïve adults and children stratified according to CD4 count and disease progression (see <a href="http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1004954#sec002" target="_blank">Methods</a>) expressing one or more of the protective HLA alleles HLA-B*57/58:01/81:01. Adult study numbers: absolute CD4<200/mm³, n = 204; CD4 350–749/mm³, n = 553; CD4≥750/mm³ n = 77. Children study numbers: Rapid Progressors, n = 98; CD4 350–749/mm³, n = 102; CD4≥750/mm³, n = 161. B. As in panel A, but the frequency of subjects expressing one or more of the disease-susceptible HLA alleles HLA-B*18:01/45:01/58:02. C. Viral load in ART-naïve adults (total, n = 1,211) according to the presence of protective HLA alleles and/or disease-susceptible alleles. ** represents p<0.001, *** represents p<0.0001. Not shown on the figure are significant differences between viral loads in the disease-susceptible group and each of the other groups (in each case p<0.0001). D. As in panel C, but in ART-naïve children (total n = 256, age ≥5yrs).</p