Impact of HIV co-infection on Mycobacterium tuberculosis evolution and antibiotic resistance development

The association between HIV and multidrug-resistant TB (MDR-TB) remains unclear. We have sequenced about 300 Mtb genomes from two large and ongoing TB outbreaks in Argentina. The HIV status of all the patient isolates is known (about 60% HIV+). So far we have published three papers where we confirm that WGS is efficient and sensitive for predicting drug resistance. We also find that most resistance mutations evolved surprisingly early in the oubtreaks, namely in the mid-70s, well before the HIV epidemic reached South America. By means of phylogenetic methods and mathematical modelling we have also assessed directly the impact of HIV co-infection on Mtb evolution within the outbreak.

Tuberculosis (TB) remains a major global disease, with 8.8 million estimated cases in 2010. TB caused by multidrug-resistant strains of Mycobacterium tuberculosis is estimated to 650,000 cases annually, resulting in 150,000 deaths. The toll of TB in south ern Africa is significantly exacerbated by increasing rates of drug resistance and extremely high rates of HIV co-infection in certain regions. There is a strong association between HIV infection and MDR-TB outbreaks, yet it is unclear whether MDR-TB is disproportionally associated with HIV infection within outbreaks. This might indicate that MDR-TB evolves more easily in HIV-infected individuals, often with no significant loss of transmissibility. This project builds on the hypothesis that HIV co-infec tion is affecting Mycobacterium tuberculosis evolution and antibiotic resistance development. In collaboration with the Kwazulu-Natal Provincial Department of Health and the UCL Genetics Institute, we will utilize two complementary approaches to investiga te this hypothesis. A genomic approach will encompass whole-genome sequencing of all clinical TB isolates isolated from patients at two OPDs in Kwa-Zulu Natal, an area with extreme rates of HIV-TB co-infection, and mapping of all known and putative resi stance conferring mutations and compensatory mutations. An in-vitro approach will encompass drug susceptibility testing of the isolates and competition/fitness assays. The project aims to investigate whether drug resistance develops more often in M. tuber culosis strains infecting HIV positive compared to HIV negative patients, whether HIV positive individuals are more prone to infection by drug resistant TB strains and to what degree various mutations causing mono-, poly- and multi- resistance affect TB s train fitness. The project aims to significantly improve our understanding of the current HIV-TB epidemic in Southern Africa, which will prove crucial for devising improved anti-TB treatment schemes.