Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), infects one third of the worlds population. Tuberculosis is a deadly disease that kills more young people than any other infectious disease. Fortunately, most people mount immune responses that contain the infection and they maintain the infection in a subclinical state referred to as latency with only a 10% lifetime risk of experiencing reactivation. A broad number of host factors are responsible for maintenance of latency. Host immune cells, including macrophages and lymphocytes, form nodular structures called granulomas that wall off bacteria and effectively prevent dissemination. A number of other factors, including cytokines and chemokines, are required to coordinate cellular activities maintain the granuloma integrity. Infection with human immunodeficiency virus (HIV) is the most significant risk factor for development of active or reactivation TB. HIV infected individuals with latent TB have dramatically increased odds of reactivation, with a 10% annual (versus 10% lifetime) risk of experiencing reactivated TB. Additionally, infection with M. tuberculosis results in increased HIV replication. Thus, individuals who are coinfected experience a series of negative events, most of which remain poorly understood, that greatly increase morbidity and mortality. While M. tuberculosis infection can be treated with drugs, the rise of multidrug resistance in areas of the world with high incidence of HIV is a matter of great concern. We have developed a nonhuman primate model using cynomolgus macaques that accurately describes the pathology of latent TB in humans. We will use the cynomolgus macaques to coinfected with TB and simian immunodeficiency virus (SIV), an HIV-like virus, to explore the hypothesis that reactivation of latent TB can be predicted by changes in immune status including lymphocyte numbers and cytokine expression. Our purpose is to understand why HIV-related changes in immune status cause reactivated TB, even in the early stages of infection, and to clarify why coinfection dramatically enhances pathogenicity of HIV and M. tuberculosis infection. We anticipate the results of these studies will also uncover clinically relevant immune markers that may hearld reactivated TB and provide useful diagnostic tools for clinicans treating HIV- infected individuals.
