Approximately 5 to 10% of individuals who get infected with Mycobacterium tuberculosis progress to clinical tuberculosis (TB), whereas the remaining individuals develop a latent infection with the organism. Another 5 to 10% of these latently infected individuals reactivate their infection and progress to clinical TB during subsequent years/decades. In either case, active infection with M. tuberculosis is identified only when progression to bacteriologically detectable disease occurs. Thus, clinical TB, whether noncavitary paucibacillary or cavitary multibacillary disease, represents the late stages of a chronic disease process.Our studies of humoral immune responses elicited by M. tuberculosis at different stages of infection and disease progression have shown that the profile of antigenic proteins expressed by the in vivo bacteria that elicit antibodies correlates with the stage of the infection (21-23, 35-37, 45). Thus, purified-protein derivative-positive (PPD ϩ ) healthy individuals have antibodies to only a small subset (4-6) of the Ͼ100 culture filtrate proteins (CFP) of M. tuberculosis. In contrast, patients with noncavitary paucibacillary TB have antibodies directed against ϳ10 to 12 additional CFP antigens (35). As the disease progresses to the development of cavitary lesions, besides the presence of antibodies to the above-mentioned antigens, antibodies to an additional ϳ10 to 12 antigens appear. These results provide evidence that as M. tuberculosis adapts to different in vivo environments, the profile of antigenic proteins that are expressed changes. Evidence for adaptation by M. tuberculosis to different environmental conditions by altering gene/protein expression has also come from several other labs (3,11,12,29,32,41,42,47,49).M. tuberculosis is a slowly growing organism, and it takes weeks to months for the infection to progress to primary clinical TB. The time that elapses between the initiation of reactivation of latent infection and the manifestation of clinical TB is not known. The goal of the current studies was to identify antigenic proteins that are expressed during the asymptomatic, subclinical stages of infection when the in vivo M. tuberculosis bacilli replicate actively but the infection has not progressed to clinically identifiable disease (incipient, subclinical TB). Insight into these antigenic proteins will aid understanding of the host-pathogen interactions that lead to the progression of infection to clinical disease, and modulation of these host-pathogen interactions could potentially alter the outcome of infection. Moreover, antigenic proteins expressed during subclinical stages of active infection would also be useful for devising diagnostic markers that can differentiate between truly latent TB that is unlikely to progress to clinical disease and incipient, subclinical TB.