Mycobacterium bovis Bacille Calmette-Guérin Enhances Pathogenicity of Simian Immunodeficiency Virus Infection and Accelerates Progression to AIDS in Macaques: A Role of Persistent T cell Activation in AIDS Pathogenesis

Abstract

It has recently been proposed that Mycobacterium tuberculosis may enhance the pathogenicity of HIV infections and accelerate the course of HIV disease. This hypothesis has been tested in the present study using a simian immunodeficiency virus of macaques (SIVmac)/Mycobacterium bovis bacille Calmette-Guérin (BCG)-coinfected macaque model. Naive and chronically SIVmac-infected monkeys were evaluated. Following BCG inoculation, the SIVmac-infected monkeys exhibited the dominant responses of TCR-β complementarity-determining region 3-restricted T cell subpopulations. This BCG-driven T cell activation correlated with a marked increase in viral loads in SIVmac-infected monkeys. Moreover, the prolonged T cell activation coincided with the enhanced decline of CD4+ PBL counts and the accelerated progression to clinical AIDS in the coinfected monkeys, suggesting that Mycobacterium-driven T cell activation may be the mechanism underlying the enhanced pathogenicity of AIDS virus infection in the coinfected individuals. Within 2 to 7 mo after BCG coinfection, all chronically SIVmac-infected monkeys died from SIV-induced AIDS including tuberculosis-like disease. Surprisingly, the naive monkeys manifested a T cell activation-related toxic shock syndrome and a profound depletion of CD4+ lymphocytes 2 wk after simultaneous SIVmac/BCG inoculation. These naive animals died 2 mo after SIVmac/BCG inoculation, with the evidence of the persistent SIV p27 antigenemia and SIVmac-induced disease. In contrast, the normal monkeys not infected with SIVmac survived BCG infection; the control SIVmac-infected animals showed a natural course of chronic SIV infection. Thus, results from this SIV/BCG coinfection model strongly support the hypothesis that active coinfection with HIV and Mycobacterium can impact remarkably on the AIDS virus-induced disease.