There are currently an estimated 33.2 million people living with human immunodeficiency virus (HIV) worldwide. For these individuals, long-term use of combination antiretroviral therapy (cART) is not feasible for a variety of reasons including major adverse complications, multi-drug resistance, poor adherence, and high cost. Hence, development of novel therapeutic strategies that can reduce the life-long dependency on cART is highly desired. In order to develop effective therapeutic strategies such as a therapeutic vaccine, we need to have a greater understanding of the immune correlates of viral control in chronic HIV infection. In this thesis, we used treatment interruption (TI) as a tool to test the efficacy of several therapeutic approaches and immune parameters for their association with effective control of viral replication. / In Chapter 2 we showed that cART intensification and Remune vaccination resulted in reduced viral load (VL) plateau during sequential TIs. Although HIV-specific immune responses measured by interferon-gamma (IFN-gamma) enzyme-linked immunospot assay (ELISPOT) increased in the same time frame, neither their breadth nor magnitude correlated with the decrease in VL plateau. In Chapter 3 the effect of ALVAC-vCP1425 plus Remune vaccination on HIV proteome-wide HIV-specific responses was monitored using a dual color IFN-gamma/interleukin-2 (IL-2) ELISPOT assay. We observed an increase in the magnitude of HIV-specific IFN-gamma/IL-2 responses, as well as in the breadth of Gag-specific IFN-gamma responses in the vaccinated groups compared to placebo groups. A shift towards an increased contribution of Gag-specific responses to total HIV-specific vaccine induced immune response was associated with longer delay to viral rebound during TI. In Chapters 4 and 5, we examined baseline pre-TI immune parameters and their association with viral rebound and CD4 count change during TI in HIV-infected individuals in the chronic phase of infection experiencing virologic failure before TI (Chapter 4) or with different levels of VL control while on therapy prior to TI (Chapter 5). We saw that chronic antigen stimulation from persistent viremia as well as co-infections such as with cytomegalovirus are associated with T-cell senescence, which may result in less favourable clinical outcomes during TI. / Consequently, results from this thesis contribute to further understanding of immune correlates of viral control in chronic HIV infection. New therapeutic vaccines and interventions should induce polyfunctional HIV-specific immune responses, broad Gag-specific immune responses, as well as reducing chronic antigen stimulation to prevent irreversible T-cell exhaustion. Taken together, these insights could potentially lead to the development of novel treatment interventions that could effectively control viral replication off cART.

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Estudo observacional em uma coorte 148 indivíduos infectados pelo HIV-1, em uso de terapia anti-retroviral, avaliando padrões de resposta imunológica, clínica e virológica em um período de 251 semanas, estratificados em três grupos de resposta virológica: Avirêmicos, Virêmicos e Virêmicos Atenuados. Este estudo observou melhor progressão clínica e imunológica foi observada no grupo Avirêmico, porém um significante ganho de linfócitos TCD4 (p < 0.013) e menor número de casos com evolução para Aids (p < 0.001) foi observado grupo Virêmico Atenuado comparado ao grupo Virêmico. / Observacional study in cohort of 148 HIV-1 infected patients under highly active antiretroviral therapy, analysed by different patterns of immunological reconstitution, clinical outcome and viral suppression in 251 weeks of follow up, estratified in Aviremic, Viremic and Virec Attenuated groups. This study observed better clinical and immunological response in Aviremic group, but Viremic Attenuated group shows a significant TCD4+ cells gain (p < 0.013) and less number of cases progressing to AIDS (p < 0.001) compared to Viremic group.

Estudo observacional em uma coorte 148 indivíduos infectados pelo HIV-1, em uso de terapia anti-retroviral, avaliando padrões de resposta imunológica, clínica e virológica em um período de 251 semanas, estratificados em três grupos de resposta virológica: Avirêmicos, Virêmicos e Virêmicos Atenuados. Este estudo observou melhor progressão clínica e imunológica foi observada no grupo Avirêmico, porém um significante ganho de linfócitos TCD4 (p < 0.013) e menor número de casos com evolução para Aids (p < 0.001) foi observado grupo Virêmico Atenuado comparado ao grupo Virêmico. / Observacional study in cohort of 148 HIV-1 infected patients under highly active antiretroviral therapy, analysed by different patterns of immunological reconstitution, clinical outcome and viral suppression in 251 weeks of follow up, estratified in Aviremic, Viremic and Virec Attenuated groups. This study observed better clinical and immunological response in Aviremic group, but Viremic Attenuated group shows a significant TCD4+ cells gain (p < 0.013) and less number of cases progressing to AIDS (p < 0.001) compared to Viremic group.