Paediatric HIV infection: correlates of protective immunity and global perspectives in prevention and management

Abstract

The impact of the HIV epidemic on child health globally is beginning to be appreciated. With the burden of new infections falling on young women, there is a skyrocketing number of AIDS orphans, and a rapidly increasing number of children infected via mother-to-child-transmission (MTCT). An estimated 600,000 new paediatric infections occur each year, of which some 1500/day (> 90%) occur in sub-Saharan Africa. But whereas children account for only 4% of those currently living with HIV infection, 20% of AIDS deaths have been in children. This reflects the rapid progression to disease in paediatric HIV infection. Whereas a dramatic reduction in viraemia follows acute adult infection, corresponding to the appearance of a vigorous anti-HIV cytotoxic T lymphocyte response, virtually no impact of the immune response is observed in acute paediatric infection following MTCT. Two specific challenges for the paediatric immune response are: (i) infection occurs before the immune system itself is fully developed; and (ii) the viruses transmitted by MTCT have already evaded an immune system sharing close genetic relatedness to that of the child. Accumulating evidence indicates that the immune system is potentially capable of effective control of HIV infection, and that events occurring in acute infection critically determine the ultimate outcome. Technological advances that have transformed the study of T-cell immunity now enable the developing immune system in childhood to be better understood. Via novel immunotherapeutic approaches described, it may be possible to modulate the infant's immune response to reach effective and durable suppression of HIV, as can be achieved by the rare long-term non-progressors of HIV infection. The feasibility of adopting these approaches globally are as yet untested. Finally, the striking disparity between the burden of paediatric HIV infection and access to the necessary infrastructure and therapeutic options required for its optimal management is addressed in a comparison between three sites of paediatric HIV care: Durban, South Africa; London, UK; and Boston, USA.

Correlates of Delayed Disease Progression in HIV-1-Infected Kenyan Children

“…Early studies of perinatally infected children in developed countries before the era of highly active antiretroviral therapy (HAART) 3 indicated that a subset of children (ϳ25%) progressed very rapidly to AIDS (within 1 year). The median time to AIDS for the remaining 75% was ϳ7 years (2). However, a minority of HIV-1-infected infants remain clinically asymptomatic beyond childhood and into adolescence.…”

“…More specifically, infection with nef/long terminal repeat-deleted HIV-1 resulted in slower disease progression among recipients from the Sydney Blood Bank Cohort (3). Differences in MHC class Irestricted HIV-1-specific CD8 ϩ T cell responses variably impact on disease progression (2). These include maintenance of large expansions of oligoclonal or monoclonal memory CD8 ϩ T cells targeted toward multiple conserved HIV-1 epitopes in a significant proportion of long-term survivors (LTSs).…”

“…The relative contribution of individual host genetic factors to delayed disease progression in Africans has not been examined in detail, but a study of Kenyan sex workers showed that the protective polymorphisms in CCR5 and SDF-1␣ were rare (12) and that the CCR2-V64I mutation accounted for a significant proportion of long-term nonprogressors (LTNPs). Biological determinants contributing to accelerated disease progression in infants and children may include relative immunological immaturity, thymic HIV-1-mediated destruction at a time of active thymopoiesis, and HLA class I sharing between mother and infant (2). There have been no previous studies investigating possible links between clinical outcome and immunological features in pediatric LTSs from Africa.…”

Functional state of CD4+ and CD8+ T lymphocytes and their role in the slow progression of HIV infection in pediatric patients

“…Curiosamente, todas essas respostas efetoras se perderam completamente em ambos os grupos de pacientes quando suas CMSPs foram cultivadas na presença do antí-geno viral (Env). Essa falta de resposta pode ser explicada pelo efeito inibidor das proteínas virais e/ou pela perda de clones específicos contra o HIV durante a progressão da infecção 24,25 , ou pelo fato de que a infecção viral afetou as linhagens de células T no timo e destruiu a capacidade de produção de clones anti-HIV, como descrito [11][12][13] . Esse achado experimental requer maiores investigações para identificar os mecanismos moleculares responsáveis por essa falta de resposta por parte das crianças infectadas pelo HIV frente ao antígeno viral (Env).…”

“…Em crianças, devemos considerar vários fatores: a relativa imaturidade imunológica, a destruição do timo mediada pelo HIV-1 em um momento de timopoiese ativa, e o compartilhamento de antígenos leucocitários humanos de classe I entre a mãe e o bebê [11][12][13] . Poucos estudos investigaram o estado funcional dos linfócitos T CD4+ e CD8+ em PRs e PLs 11 com o objetivo de estabelecer relações entre evolução clínica e aspectos imunológicos.…”