The Investigator proposes to examine the contribution of host and pathogen genetic factors to disease progression from TB infection to active disease, and to assess the impact of HIV infection on this relationship. In Africa, TB is endemic and HIV is epidemic. Most Africans become infected with TB by the time they reach adulthood, but not all develop pulmonary disease: in the absence of HIV infection, the lifetime risk of developing TB disease is 5-10%, whereas the risk among HlV-infected individuals is 5-15% per year. TB disease may be influenced by several factors, including nature of exposure, HIV co-infection, virulence of the mycobacterium, and host immune response to exposure and infection with M.tb. Both pathogen virulence and host immune response are controlled by genetic factors. Variation in these genes may be responsible for differential risk of developing TB disease. The Investigator and her coworkers will test the following hypotheses: (1) variation in human leukocyte antigen (HLA) Class I and Class II genes influences the risk of developing active TB in Africa; with HIV infection, the relative contribution of HLA is reduced; (2) host genetic variation in other non-MHC proteins involved in the pathobiology of TB infection (e.g., mannose binding protein, NRAMP, TNF-alpha) influences risk of developing active TB; with HIV infection, these effects are less pronounced; (3) variation in strain of M.tb. among Africans with active TB differs among HIV+ individuals vs. HIV-individuals; M.tb. strains that appear less virulent among HIV- individuals are more prevalent among HIV+ individuals. To address these hypotheses the Investigator has developed strong local and international collaborations with teams in California, Uganda, and Zimbabwe. They will evaluate host and mycobacterial genetic variation among 125 participants in each of four groups from each African study site: TB+/HIV+, TB+/HIV-, TB-/HIV+, TB-/HIV-.
| Louie, Leslie G; Hartogensis, Wendy E; Jackman, Rachael P et al. (2004) Mycobacterium tuberculosis/HIV-1 coinfection and disease: role of human leukocyte antigen variation. J Infect Dis 189:1084-90 |
| Zijenah, Lynn S; Hartogensis, Wendy E; Katzenstein, David A et al. (2002) Association of high HIV-1 RNA levels and homozygosity at HLA class II DRB1 in adults coinfected with Mycobacterium tuberculosis in Harare, Zimbabwe. Hum Immunol 63:1026-32 |
