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Sex Differences in Antiretroviral Therapy Initiation in Pediatric HIV Infection
The incidence and severity of infections in childhood is typically greater in males. The basis for these observed sex differences is not well understood, and potentially may facilitate novel approaches to reducing disease from a range of conditions. We here investigated sex differences in HIV-infected children in relation to antiretroviral therapy (ART) initiation and post-treatment outcome. In a South African cohort of 2,101 HIV-infected children, we observed that absolute CD4+ count and CD4% were significantly higher in ART-naĂŻve female, compared to age-matched male, HIV-infected children. Absolute CD4 count and CD4% were also significantly higher in HIV-uninfected female versus male neonates. We next showed that significantly more male than female children were initiated on ART (47% female); and children not meeting criteria to start ART by >5yrs were more frequently female (59%; p<0.001). Among ART-treated children, immune reconstitution of CD4 T-cells was more rapid and more complete in female children, even after adjustment for pre-ART absolute CD4 count or CD4% (p=0.011, p=0.030, respectively). However, while ART was initiated as a result of meeting CD4 criteria less often in females (45%), ART initiation as a result of clinical disease in children whose CD4 counts were above treatment thresholds occurred more often in females (57%, p<0.001). The main sex difference in morbidity observed in children initiating ART above CD4 thresholds, above that of TB disease, was as a result of wasting and stunting observed in females with above-threshold CD4 counts (p=0.002). These findings suggest the possibility that optimal treatment of HIV-infected children might incorporate differential CD4 treatment thresholds for ART initiation according to sex
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-naĂŻve, 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
Cohort characteristics.
<p>Cohort characteristics.</p
Individuals making CD8+ T cell responses against CMV IE-2 epitope HLA-B*44:03-NW8.
<p>(A) Representative FACS plot of a Durban cohort subject 202-30-0064 (expressing HLA-B*44:03/B*58:01) to HLA-B*44:03-restricted NW8 tetramer. (B) FACS plot of subject R048 (HLA-A*29:02, -A*6802, -B*15:03, -B*44:03, -C*02:10, -C07:01) with NW8 tetramer and HLA-mismatched tetramer. (C) FACS plot of a TVC subject R112 (HLA-A*23:01, -A*3002, -B*18:01, -B*18:01, -C*02:02, -C07:04) to HLA-B*44:03-restricted NW8 tetramer, as B*44:03-negative control. The FACS plots show tetramer-specific cells expressed as the percentage of live CD3+ CD8+ T-cells. (D) Percentage of live CD3+ CD8+ tetramer-specific T-cells in individuals expressing HLA-B*44:03 measured using the B*44:03-NW8 tetramer.</p
HLA associations with the remaining 15-mer OLP’s in CMV pp65, IE-1 and IE-2 that were targeted by ≥4% of the study cohort.
<p>HLA associations with the remaining 15-mer OLP’s in CMV pp65, IE-1 and IE-2 that were targeted by ≥4% of the study cohort.</p
Immunodominant CMV-specific CD8+ T-cell responses within pp65, IE-1 and IE-2 measured by IFN-g ELISpot assay for CMV+ subjects.
<p>(A) Percentage responders to each protein-covering peptide pool. (B) Percentage responders among 152 CMV+ individuals to pp65 15mer overlapping peptides that were targeted by >4% of the study population. (C) Percentage responders among 95 CMV+ individuals to IE-1 15mer overlapping peptides that were targeted by >3% of the study population. (D) Percentage responders among 92 CMV+ individuals to IE-2 15mer overlapping peptides that were targeted by >3% of the study population.</p
Phenotypic frequencies of closely related HLA I molecules and their impact on CMV specific CD8+ T-cell hierarchies.
<p>(A) The phenotypic frequency of some of the HLA class I molecules in A2 superfamily in white populations [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0189612#pone.0189612.ref028" target="_blank">28</a>] and our African cohort. (B) The percentage of subjects with HLA alleles A*02:01 (n = 23), A*02:02 (n = 10) and A*02:05 (n = 16), responding to epitope (NLVPMVATV) in pp65-123/124 peptide and predicted epitope (FVFPTKDV) in pp65-46/47 peptide. (C) The phenotypic frequency of the HLA class I molecules in B07 superfamily in white populations [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0189612#pone.0189612.ref028" target="_blank">28</a>] and our African cohort. (D) The percentage of subjects with B*07:02 (n = 21), B*35:01 (n = 10), B*39:10 (n = 6), B*42:01 (n = 26) and B*81:01(n = 12) alleles in our African cohort responding to predicted epitopes in pp65, GPISGHVL (OLP-4), RPHERNGFTVL (OLP-66/67) and TPRVTGGGAM (OLP-104/105). The percentage of subjects in our African cohort responding to predicted epitope in IE-1, TMYGGISLL (OLP-212/213) with HLA-B*07:02 (n = 11), B*35:01 (n = 6) B*39:10 (n = 5), B*42:01 (n = 19) and B*81:01(n = 1) alleles.</p
HLA associations with the most targeted 15-mer OLP’s in CMV pp65, IE-1 and IE-2.
<p>HLA associations with the most targeted 15-mer OLP’s in CMV pp65, IE-1 and IE-2.</p
Validation of novel CD8+ T-cell epitopes in CMV using HLA-Class I tetramers.
<p>(A) Flow cytometry plot of CD8+ T-cell responses from a Durban cohort subject SK-251 (HLA-A*02:05, -A*30:01, -B*42:01, -B*58:01, -C*07:01, -C*017:01) to HLA-A*30:01-restricted IE-2-342/343 epitope-KK9 and an HLA-mismatched tetramer stain as a control. (B) Flow cytometry plot from a Durban cohort subject SK-331 (HLA-A*30:01, -A*66:01, -B*42:01, -B*58:02, -C*06:02, -C*017:01) to B*42:01-restricted pp65-66/67 epitope RL11 and an HLA-mismatched tetramer stain as a control. The plots show gated live CD3+ T-cells; the number shown above each gate is the percentage of live CD3+ CD8+ cells that are tetramer-specific.</p