CARATTERIZZAZIONE VIROLOGICA E DETERMINAZIONE DELLA RISPOSTA NEUTRALIZZANTE IN PAZIENTI PEDIATRICI CON INFEZIONE DA HIV-1.

The study of HIV-1 phenotypic, genotypic and antigenic variability is fundamental to understand pathogenic processes but also for the development of immunogens for vaccines. Mother-to-child transmission of HIV-1 and disease progression of infected children are still a major problem at world-wide level. The aim of the thesis was to study the phenotypic and genotypic variation of R5 viruses, in mother-child pairs as well as to characterize the neutralizing response in seropositive children with different disease progression. We have investigated in detail the phenotype of the clonal viral population and in specific the capacity to infect in vitro target cells expressing CCR5/CXCR4 chimeric besides wild-type receptors. We showed that virus variation goes beyond the simple characterization of R5 and X4. Indeed, R5 virus populations were able to use multiple chimeric receptors and thus had an expanded phenotype, were highly heterogenous and variable throughout time. Viruses with expanded R5 phenotype were transmitted as much as those of narrow phenotype suggesting that no selective process occurs. The study of the autologous neutralization showed a low or no response before 6 months of age in the infected child followed by a continues formation of escape variants with time. Interestingly, children with slow progressing disease developed an increasing broadening neutralizing response against heterologous viruses while fast progressors did not. A further study of the specificity of the antibody response will be of utmost relevance for the development of immunogens able to elicit a broad neutralizing response.