Lead: Tuberculosis remains a public-health problem, especially in the context of HIV. This study aims to analyse differences in genetic population structure and correlates between genetic Mycobacterium tuberculosis strain variation and disease manifestation in HIV co-infected compared to HIV-negative tuberculosis patients.Summary: Tuberculosis (TB), caused by the bacterium Mycobacterium tuberculosis, remains a major public-health problem worldwide, especially in the context of the HIV epidemic and the spread of drug-resistant TB. The disease manifestation of human infection with Mtb is extremely variable, ranging from lifelong asymptomatic infection to active lung disease and life-threatening meningitis. Human immunodeficiency virus infection (HIV) substantially increases the lifetime risk of active TB. Traditionally, host and environmental factors have been invoked to explain this variability, but there is growing evidence that bacterial factors could also be involved. M. tuberculosis has a global phylogeographic population structure consisting of six main phylogenetic lineages which are associated with specific, sympatric human populations; however it has been observed that allopatric lineages (e.g. European patient with an East-Asian strain) were more likely to spread in immunodeficient populations. The overall goal of this study is to analyse differences in the genetic population structure of M. tuberculosis and the associations between the genetic M. tuberculosis strain variation and disease manifestations in HIV co-infected compared to HIV-negative TB patients. We also intend to analyse genetic mutations conferring resistance to first-line anti-TB drugs, and to analyse the relationship between resistance mutations, genetic strain background and bacterial fitness. The results will shed a light on the impact of genetic strain variation on the disease manifestation and differences between populations infected and not infected with HIV. This is the first study describing the genetic diversity of M. tuberculosis in Switzerland and it is also the first time that novel genotyping techniques will be applied to M. tuberculosis in an epidemiological study. This study will provide the basis for a larger future project in sub-Saharan Africa where people disproportionally suffer from TB, within the framework of a network of HIV treatment programmes. This TB research initiative builds upon a research network of complementary expertise in epidemiology, bacterial population genetics, and clinical aspects in TB and HIV, and is embedded in the established Swiss HIV Cohort Study.