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Tuberculosis (TB), caused by Mycobacterium tuberculosis ( M.tb ), is the leading cause of death among HIV positive patients. The precise mechanisms by which HIV impairs host resistance to a subsequent M.tb infection are unknown. We modeled this co-infection in Mauritian cynomolgus macaques (MCM) using SIV as an HIV surrogate. We infected seven MCM with SIVmac239 intrarectally and six months later co-infected them via bronchoscope with ~10 CFU M.tb . Another eight MCM were infected with M.tb alone. TB progression was monitored by clinical parameters, by culturing bacilli in gastric and bronchoalveolar lavages, and by serial 18 F-FDG PET/CT imaging. The eight MCM infected with M.tb alone displayed dichotomous susceptibility to TB, with four animals reaching humane endpoint within 13 weeks and four animals surviving >19 weeks post M.tb infection. In stark contrast, all seven SIV+ animals exhibited rapidly progressive TB following co-infection and all reached humane endpoint by 13 weeks. Serial PET/CT imaging confirmed dichotomous outcomes in MCM infected with M.tb alone and marked susceptibility to TB in all SIV+ MCM. Notably, imaging revealed a significant increase in TB granulomas between four and eight weeks post M.tb infection in SIV+, but not in SIV-naive MCM and implies that SIV impairs the ability of animals to contain M.tb dissemination. At necropsy, animals with pre-existing SIV infection had more extrapulmonary TB disease, more overall pathology, and increased bacterial loads than animals infected with M.tb alone. We thus developed a tractable MCM model in which to study SIV- M.tb co-infection and demonstrate that pre-existing SIV dramatically diminishes the ability to control M.tb co-infection. Author summary Mycobacterium tuberculosis ( M.tb ) is the etiologic agent of tuberculosis (TB) and infects a tremendous number of individuals. TB causes millions of deaths each year and is the leading cause of death in human immunodeficiency virus (HIV)-positive individuals. Currently, the mechanisms by which pre-existing HIV infection increases susceptibility to subsequent M.tb infection and predisposes an individual to TB disease are poorly understood. We developed a simian immunodeficiency virus (SIV) - M.tb co-infection model in Mauritian cynomolgus macaques (MCM) to investigate how SIV impairs the immune response to a subsequent M.tb infection. We show that naive MCM display variable resistance to TB while all SIV-infected MCM failed to control M.tb infection. Using quantitative measures of disease and serial PET/CT imaging, we show that SIV+ co-infected animals uniformly exhibit rapid TB progression, more tuberculosis disease dissemination, and increased mortality. This coinfection model will facilitate studies, provide unique insights into the defects underlying TB susceptibility in HIV+ individuals and will help us develop approaches to overcome these defects.

Rhesus macaques were studied to directly address the potential for plasmid-deficient Chlamydia trachomatis to serve as a live attenuated vaccine in the genital tract. Five repeated cervical inoculations of rhesus macaques with wild-type serovar D strain D/UW-3/Cx or a plasmid-deficient derivative of this strain, CTD153, resulted in infections with similar kinetics and induced comparable levels of protective immunity. After all animals received five challenges with D/UW-3/Cx, levels of inflammation observed grossly and histologically were similar between the groups. Animals in both groups developed evidence of oviduct dilatation; however, reduced oviduct dilatation was observed for "controllers," i.e., animals without detectable chlamydial DNA in the fimbriae at weeks 5 and 12. Grouping animals into "ascenders" and "controllers" revealed that elevated early T cell responses were associated with protection, whereas higher antibody responses were associated with ascension. Protected animals shared common major histocompatibility complex (MHC) alleles. Overall, genetic differences of individual animals, rather than the presence or absence of the chlamydial plasmid in the primary infecting strain, appeared to play a role in determining the outcome of infection.

The NF-κB/Rel family of transcription factors plays pivotal roles in multiple biologic processes, including innate and adaptive immunity and regulation of cell proliferation and death processes. In many human malignancies, NF-κB is often dysregulated leading to its constitutive activation. The two most well-known NF-κB activation mechanisms, canonical and noncanonical, which are mediated by degradation or processing of NF-κB inhibitor proteins by 26S proteasomes, are often implicated in its constitutive activation. Less well-studied NF-κB activation mechanisms also exist, and one of them is referred to as the “proteasome inhibitor resistant” (PIR) pathway, which was originally described as the principle mechanism behind constitutive NF-κB activation in certain murine B lymphoma cell lines as well as the human multiple myeloma (MM) cell line RPMI8226. Here we report that constitutive NF-κB activity in ten out of fourteen primary MM patient samples is refractory to inhibition by high doses of a proteasome inhibitor, bortezomib (Velcade/PS341). Moreover, when MM cells were co-cultured with patient-derived bone marrow stromal cells (BMSCs), microenvironment components critical for MM growth and survival, further increases in NF-κB activity were observed that were also resistant to bortezomib. Similarly, constitutive PIR NF-κB activity observed in RPMI8226 cells was augmented by the presence of BMSCs, resulting in increased NF-κB-dependent transcription and resistance to bortezomib-induced apoptosis. Thus, we propose that the PIR mechanism of NF-κB regulation is likely relevant to the often devastating biology of multiple myeloma.