An HLA-I signature favouring KIR-educated Natural Killer cells mediates immune control of HIV in children and contrasts with the HLA-B-restricted CD8+T-cell-mediated immune control in adults

Natural Killer (NK) cells contribute to HIV control in adults, but HLA-B-mediated T-cell activity has a more substantial impact on disease outcome. However, the HLA-B molecules influencing immune control in adults have less impact on paediatric infection. To investigate the contribution NK cells make to immune control, we studied >300 children living with HIV followed over two decades in South Africa. In children, HLA-B alleles associated with adult protection or disease-susceptibility did not have significant effects, whereas Bw4 (p = 0.003) and low HLA-A expression (p = 0.002) alleles were strongly associated with immunological and viral control. In a comparator adult cohort, Bw4 and HLA-A expression contributions to HIV disease outcome were dwarfed by those of protective and disease-susceptible HLA-B molecules. We next investigated the immunophenotype and effector functions of NK cells in a subset of these children using flow cytometry. Slow progression and better plasma viraemic control were also associated with high frequencies of less terminally differentiated NKG2A+NKp46+CD56dim NK cells strongly responsive to cytokine stimulation and linked with the immunogenetic signature identified. Future studies are indicated to determine whether this signature associated with immune control in early life directly facilitates functional cure in children

Gauge and Scheme Dependence of Mixing Matrix Renormalization

We revisit the issue of mixing matrix renormalization in theories that include Dirac or Majorana fermions. We show how a gauge-variant on-shell renormalized mixing matrix can be related to a manifestly gauge-independent one within a generalized ${\bar {\rm MS}}$ scheme of renormalization. This scheme-dependent relation is a consequence of the fact that in any scheme of renormalization, the gauge-dependent part of the mixing-matrix counterterm is ultra-violet safe and has a pure dispersive form. Employing the unitarity properties of the theory, we can successfully utilize the afore-mentioned scheme-dependent relation to preserve basic global or local symmetries of the bare Lagrangian through the entire process of renormalization. As an immediate application of our study, we derive the gauge-independent renormalization-group equations of mixing matrices in a minimal extension of the Standard Model with isosinglet neutrinos.Comment: 31 pages, LaTeX, uses axodraw.st

Strong sex bias in elite control of paediatric HIV infection

Background: 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.</p

An HLA-I signature favouring KIR-educated natural killer cells mediates immune control of HIV in children and contrasts with the HLA-B-restricted CD8+T-cell-mediated immune control in adults

Natural Killer (NK) cells contribute to HIV control in adults, but HLA-B-mediated T-cell activity has a more substantial impact on disease outcome. However, the HLA-B molecules influencing immune control in adults have less impact on paediatric infection. To investigate the contribution NK cells make to immune control, we studied >300 children living with HIV followed over two decades in South Africa. In children, HLA-B alleles associated with adult protection or disease-susceptibility did not have significant effects, whereas Bw4 (p = 0.003) and low HLA-A expression (p = 0.002) alleles were strongly associated with immunological and viral control. In a comparator adult cohort, Bw4 and HLA-A expression contributions to HIV disease outcome were dwarfed by those of protective and disease-susceptible HLA-B molecules. We next investigated the immunophenotype and effector functions of NK cells in a subset of these children using flow cytometry. Slow progression and better plasma viraemic control were also associated with high frequencies of less terminally differentiated NKG2A+NKp46+CD56dim NK cells strongly responsive to cytokine stimulation and linked with the immunogenetic signature identified. Future studies are indicated to determine whether this signature associated with immune control in early life directly facilitates functional cure in children

Strong sex bias in elite control of paediatric HIV infection

Background: Reports of post-treatment 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 (EC) have been very well characterized and comprise approximately 0.5% of infections, very few data exist to address this question in paediatric infection. Methods: We describe 11 ART-naïve EC from 10 cohorts of HIV-infected children being followed in South Africa, Brazil, Thailand, and Europe, and describe their key clinical features. Results: All but one EC (91%) are female. The median age at which control of viraemia was achieved was 6.5yrs. Five of these 11 (46%) children lost control of viraemia at a median age 12.9yrs. Children who maintained control of viraemia had significantly higher absolute CD4 counts in the period of EC than those who lost viraemic control. Based on the data available from cross-sectional cohorts, the prevalence of EC in paediatric infection is estimated to be 5-10-fold lower than in adults. Conclusion: These data indicate that, whilst paediatric elite control can be achieved, compared to adult EC 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