Tuberculosis (TB) is a global pandemic which resulted in 5.8 million disease cases and approximately 1.5 million deaths worldwide in 2020. TB disease is the leading cause of death worldwide from a single infectious agent, Mycobacterium tuberculosis (M.tb). It is estimated that a one fourth of the world's population is latently infected with TB and of these 5-10% will go on to develop active TB in their lifetime. Human immunodeficiency virus (HIV) infection is the greatest risk factor for developing active TB, with people living with HIV (PLWH) up to 19 times more likely to develop active TB compared to HIV uninfected individuals. Epidemiological studies show that there is increased risk of developing active TB (either reactivation of latent TB or new M.tb infection) throughout the course HIV infection, with the highest risk observed within the first year of infection, even when CD4+ T cell counts are still high. Previous studies have demonstrated that M.tb-specific CD4+ T cell responses are depleted early after HIV infection, within 3-12 months. This early defect in M.tb-specific CD4+ T cells may explain the elevated risk of TB even within the first year of HIV infection, prior to substantial immunosuppression. Antiretroviral therapy (ART) is an important strategy in preventing TB in PLWH. Earlier studies done in sub-Saharan Africa show that ART is associated with a 70-90% reduction in TB risk and a 52% decrease in TB related mortality. Several studies have also shown the importance of early ART initiation for HIV pathogenesis and transmission. However, despite ART intervention studies in sub-Saharan Africa, as well as Europe and North America, show that in these regions rates of TB remain high in PLWH. These high TB rates are most likely linked to the incomplete restoration of TB immune responses during ART. Overall, this thesis focused on characterising M.tb-specific CD4+ T cell responses during the course of HIV infection, from the acute phase of infection to post ART initiation. In Chapter 3, we aimed to confirm and extend previous findings that show there is a rapid depletion of M.tb-specific CD4+ T cells soon after HIV infection. We examined the kinetics of M.tb-specific CD4+ T cell responses over the course of HIV infection in two cohorts, a cross sectional cohort (n=58) and a longitudinal cohort (n=17). Consistent with previous findings, our results showed that there is a significant decrease in the frequency of M.tb responders 3 months after HIV infection. However, not all participants experienced M.tb-specific CD4+ T cell loss after HIV infection, with half the cohort losing 50% or more of their responses and the other half maintaining their responses. In the group that maintained their M.tb responses after HIV infection, the majority had very little fluctuations in their responses during the acute and chronic phase of infection. When comparing the clinical characteristics and the function and phenotype of M.tb-specific CD4+ T cells between individuals who maintained their M.tb-specific response and those who don't, no significant differences were found. In Chapter 4, to investigate the impact of early ART on M.tb immunity, we characterised M.tb-specific CD4+ T cell responses in individuals who initiated ART at an early stage of HIV infection (median 7.5 months post infection, n=16) in comparison to those who started ART during the chronic phase of HIV infection (median 66 months post infection, n=22). In this study, we examined multiple parameters between the two groups including their clinical characteristics, as well as the magnitude, function and phenotype of their M.tb-specific CD4+ T cells. We show that 2 years after ART initiation (irrespective of its timing) induced a significant immune reconstitution, marked by an increase in CD4 T cell count and restoration of the C4/CD8 ratio, but had no significant impact on the magnitude, function or phenotype of M.tb-specific CD4+ T cells. In Chapter 5, we sought to characterise M.tb-specific T cell responses in a small (n=13) cohort of participants who developed active TB during the CAPRISA 002 study. We performed a descriptive study examining the magnitude and phenotype of M.tbspecific T cells longitudinally over the course of TB treatment: before TB treatment/diagnosis, during treatment and after successful treatment. Despite the limited number of participants in this sub-study, we showed that after TB treatment there was a decreasing trend of activated M.tb-specific CD4+ T cells coincident with an increase in IFN-+ IL-2+ dual functional cells. Overall, our data confirms previous findings that there is an early depletion of M.tbspecific CD4+ T cells within a year HIV infection. However, in our study we found that not all HIV infected individuals lose their M.tb-specific responses. Instead, there was a variation in M.tb-specific responses after HIV infection, with some individuals maintaining their responses and others completely losing them. Results of our study also showed there were no major differences between participants who initiated ART early and those who initiated later during chronic HIV infection. To our knowledge this is the first study which looks at the impact of ART timing on M.tb-specific immunity in PLWH. The study therefore provides further insight, for future research, into whether early ART preserves TB immunity and therefore reduce the early, elevated risk of TB in HIV infected individuals.