Abstract
Infections with mycobacteria, including Mycobacterium tuberculosis (Mtb) and Mycobacterium bovis (M. bovis) BCG, are a leading cause of morbidity and mortality for HIV-infected persons. In contrast to HIV, nonpathogenic SIV infections of sooty mangabeys are characterized by a lack of clinical disease including an absence of opportunistic infections. The goal of this study was to identify innate immune responses to M. bovis BCG maintained during nonpathogenic lentiviral infections through a comparison of functional responses during pathogenic HIV or nonpathogenic SIV infections. Monocytes were evaluated for their ability to express key anti-mycobacterial cytokines TNF-α and IL-12 following a six-hour ex vivo BCG exposure. While HIV-infection was associated with a decreased percentage of IL-12-producing monocytes, nonpathogenic SIV-infection was associated with an increased percentage of monocytes producing both cytokines. Gene expression analysis of PBMC following ex vivo BCG exposure identified differential expression of NK cell-related genes and several cytokines, including IFN-γ and IL-23, between HIV-infected and control subjects. In contrast, SIV-infected and uninfected-control mangabeys exhibited no significant differences in gene expression after BCG exposure. Finally, differential gene expression patterns were identified between species, with mangabeys exhibiting lower IL-6 and higher IL-17 in response to BCG when compared to humans. Overall, this comparison of immune responses to M. bovis BCG identified unique immune signatures (involving cytokines IL-12, TNF-α, IL-23, IL-17, and IL-6) that are altered during HIV, but maintained or increased during nonpathogenic SIV infections. These unique cytokine and transcriptome signatures provide insight into the differential immune responses to Mycobacteria during pathogenic HIV-infection that may be associated with an increased incidence of mycobacterial co-infections.
Highlights
M. bovis Bacillus Calmette-Guérin (BCG), a live-attenuated vaccine against M. tuberculosis (Mtb), is administered to infants in settings with a high prevalence of tuberculosis
Nonhuman primate species serve as models of mycobacterial infection, in which a synergistic disease outcome has been shown when BCG is combined with pathogenic simian immunodeficiency virus (SIV) infection in Rhesus macaques [5, 6], successfully modeling the immunopathology observed during HIV/Mtb coinfection of humans
Alterations in monocyte functional responses to mycobacteria have been observed in HIV-infected persons [30,31,32], and this likely contributes to the increased susceptibility to mycobacterial diseases
Summary
M. bovis Bacillus Calmette-Guérin (BCG), a live-attenuated vaccine against M. tuberculosis (Mtb), is administered to infants in settings with a high prevalence of tuberculosis. The BCG vaccine is generally safe and efficacious in preventing mortality caused by Mtb in immunocompetent infants and small children [1, 2]. It presents unique challenges in the context of HIV infection as HIV-infected infants have a dramatically increased risk of disseminated BCG disease following vaccination. The absence of clinical disease in natural host species, such as sooty mangabeys, has been attributed to a co-evolution with their species-specific viruses that has occurred over at least the last 30,000 years [7] This prolonged virus-host interaction contrasts the relatively recent introduction of HIV and pathogenic SIV into humans and macaques, respectively. One important immunologic difference between nonpathogenic and pathogenic SIV/HIV infections is the presence of the chronic phase systemic immune activation during pathogenic infections that impacts functionality of numerous immune cell subsets, including innate cells [8,9,10]
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