Immunization with a DNA Vaccine Cocktail Protects Mice Lacking CD4 Cells against an Aerogenic Infection withMycobacterium tuberculosis

Abstract

Tuberculosis (TB) is the most common opportunistic disease and a potentially fatal complication among immunocompromised individuals infected with human immunodeficiency virus (HIV). Effective vaccination against TB in persons with HIV has been considered unlikely because of the central role that CD4 cells play in controlling tuberculous infections. Here we show that the vaccination of CD8^−/−mice with a TB DNA vaccine cocktail did not significantly enhance protective responses to aMycobacterium tuberculosisinfection. In contrast, immunization with a DNA vaccine cocktail or with the current TB vaccine,Mycobacterium bovisBCG, induced considerable antituberculosis protective immunity in immune-deficient mice lacking CD4 cells. In vaccinated CD4^−/−animals, substantially reduced bacterial burdens in organs and much improved lung pathology were seen 1 month after an aerogenicM. tuberculosischallenge. Importantly, the postchallenge mean times to death of vaccinated CD4^−/−mice were significantly extended (mean with DNA cocktail, 172 ± 7 days; mean with BCG, 156 ± 22 days) compared to that of naïve CD4^−/−mice (33 ± 6 days). Furthermore, the treatment of DNA-vaccinated CD4^−/−mice with an anti-CD8 or anti-gamma interferon (IFN-γ) antibody significantly reduced the effect of immunization, and neither IFN-γ^−/−nor tumor necrosis factor receptor-deficient mice were protected by DNA immunization; therefore, the primary vaccine-induced protective mechanism in these immune-deficient mice likely involves the secretion of cytokines from activated CD8 cells. The substantial CD8-mediated protective immunity that was generated in the absence of CD4 cells suggests that it may be possible to develop effective TB vaccines for use in HIV-infected populations.