While a quarter of the world carries the burden of tuberculosis, emerging data suggests that those coinfected with HIV are at an elevated risk of reactivating the disease. However, the specific immunological perturbations that lead to loss of Tb control are poorly understood. One critical risk factor associated with HIV coinfection is the depletion of CD4 T cells, which has been linked to increased Mycobacterium tuberculosis (Mtb) uptake into macrophages and diminished granuloma integrity. However, even with the restoration of CD4 T cells with HAART, Mtb/HIV co-infected individuals continue to exhibit a higher risk of Mtb reactivation. However, CD4+ T cell loss/perturbations may also contribute to loss of Mtb containment through indirect mechanisms such as the loss of the requisite help to B cells required for the production of highly functional antibodies. Along these lines, mounting data point to an enrichment of anti-microbial antibody responses among latently infected individuals, able to contain bacterial growth in vitro and even control bacteria in vivo when transferred to mice prior to challenge. Thus, given our emerging appreciation for a role for antibodies in Mtb-control/killing, here we propose to use a systems serology profiling approach, to begin to define the specificities and functions of antibodies that contribute to longitudinal control of Mtb in both HIV uninfected and infected populations. Moreover, linked to B cell cloning, Fc-engineering, and in vitro/in vivo models, we also seek to divorce humoral biomarkers of Mtb control from mechanistic roles of antibodies in preventing progression to TB. Collectively, these data will provide novel insights into the potential humoral profiles that if harnessed via vaccination or through therapeutics may lead to enhanced control of Mtb.