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Philip Goulder and Nomonde Bengu

Non-progression in children is via a similar mechanism to natural SIV hosts

Without antiretroviral therapy (ART) most children progress rapidly to AIDS and 60% have died within 2 years. However a subset of 5-10% of children remain entirely healthy, maintaining normal-for-age CD4 counts despite persistent high viral loads. This phenotype is very similar to that observed in the non-human primate natural hosts of SIV (simian immunodeficiency virus) infection, such as sooty mangabeys and African green monkeys, whose normal, healthy life-spans are associated with normal CD4 counts and low immune activation despite persistent high viral loads. The fact that a proportion of the mothers of paediatric ‘non-progressors’ share the same phenotype suggests either a shared genetic mechanism and/or viral factors are involved. We have shown that HLA does not play a significant part in this phenotype, and diminished viral replicative capacity is also not the mechanism (Adland et al PLoS Path 2015). The strategy adopted by HIV-infected children to avoid disease in HIV infection is therefore entirely different from that observed in ‘elite controller’ adults, where HLA-mediated control of viral replication drives the virus down to undetectable levels.

We have shown that a fundamental mechanism by which these children remain healthy despite ongoing high viral replication is related to a low expression of CCR5 on the long-lived central memory CD4 T-cell subset (Muenchhoff et al, Science Translational Medicine, 2016). This means that, in contrast to pathogenic HIV and SIV infection, but in common with non-pathogenic SIV infection observed in the sooty mangabeys, most viral infection arises in the short-lived effector memory cells. Studies are ongoing to further define the underlying mechanism by which low immune activation is maintained in these children despite persistent high viraemia.


High frequency of highly potent, broadly neutralising antibody responses in children

A second feature we observed among these children is the highly potent, broadly neutralising  antibody responses that are generated. Recently (Roider et al, Front Imm 2018) we showed that Tfh cells, as in adults, correlate with neutralisation breadth, but are more abundant in children than adults, both in blood and lymphoid tissue germinal centres. In addition, HIV-specific Tfh cells are more abundant in lymphoid tissue and secrete the signature cytokine IL-21, which in adults they do not. We also observed increased Tfh regulation by more abundant regulatory follicular T-cells and HIV-specific CXCR5+ CD8 T-cells in paediatric compared to adult lymphoid tissue. These findings suggest that the optimal timing for next generation vaccine strategies designed to induce high-frequency, potent bnAbs to prevent HIV infection in adults would be in childhood.


 Non-progressors and Paediatric Elite Controllers:

HIV-infected children normally progress very rapidly to disease without ART, and those that maintain normal-for-age CD4 counts typical have high viral loads (~30,000c/ml). However a very small number of ART-naïve children maintain normal CD4 counts and undetectable viraemia (<50c/ml) and are termed paediatric elite controllers (EC). We have identified a small number of these and estimate that they arise 10-20-fold less often than adult EC (Vieira et al AIDS 2018). We believe the mechanisms underlying paediatric EC are very different from those mediating adult EC, and that defining these may be of relevance to understanding the mechanisms of post-treatment control (functional cure/remission) in paediatric infection.


Further studies of these groups of HIV-infected children are ongoing, in particular to define the mechanisms by which the immune response can be regulated in paediatric infection despite high viraemia; how these regulatory mechanisms alter through childhood into adolescence and adulthood; the impact these mechanisms might have on cure/remission potential; and the mechanisms by which immune control of viral replication can be achieved in childhood infection.