This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Tuberculosis is the leading cause of death in AIDS patients worldwide, is one of the earliest opportunistic infections occurring in conjunction with HIV, and is an accelerant of the replication of HIV and subsequent deterioration of the immune system. Each year, one million children worldwide become newly infected with tuberculosis (TB) and 420,000 with HIV. Co-infection with Mtb and HIV, the """"""""cursed duet,"""""""" is an increasing global emergency. Although the use of highly active antiretroviral therapy during TB treatment in HIV-1/Mtb co-infected patients is associated with reduced mortality, it can also be in life threatening. A monkey model of HIV/Mtb co-infection is desperately needed so that cocktail treatments can be developed to fight both pathogens simultaneously. As vaccines for TB and AIDS are developed for adults, the infant monkey model also will become important for testing the efficacy and safety of these vaccines in infants (and in pregnant mothers who may transmit immunity to their infants passively). We have considerable experience with the infant rhesus model for AIDS and we also have considerable experience with the adult rhesus model of TB. We propose to establish and optimize a rhesus macaque newborn/infant model for TB infection to characterize the clinical, bacteriological, and immunological characteristics of disease progression. This work, which will be conducted in our ABSL-3 facility, is expected to provide sufficient data to establish a dose that is high enough to cause gradual development of TB disease, and not so high that the animals succumb too quickly to enable experimental interventions, particularly in co-infected animals. The overall goal is to establish a neonatal nonhuman primate tuberculosis model that mimics clinical, bacteriological, and immunological characteristics of newborn/infant disease. The goal of this pilot project is to establish and optimize a M. tuberculosis """"""""dose-response"""""""" infection in newborn and infant macaques to investigate the mechanisms of TB infection in the neonatal macaque model of pediatric AIDS. This information should enhance our basic understanding of disease progression and help to understand the immune responses in TB-infected newborns and infants.
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