Annulling a dangerous liaison: vaccination strategies against AIDS and tuberculosis

Abstract

Human immunodeficiency virus (HIV) and Mycobacterium tuberculosis annually cause 3 million and 2 million deaths, respectively. Last year, 600,000 individuals, doubly infected with HIV and M. tuberculosis, died. Since World War I, approximately 150 million people have succumbed to these two infections--more total deaths than in all wars in the last 2,000 years. Although the perceived threats of new infections such as SARS, new variant Creutzfeldt-Jakob disease and anthrax are real, these outbreaks have caused less than 1,000 deaths globally, a death toll AIDS and tuberculosis exact every 2 h. In 2003, 40 million people were infected with HIV, 2 billion with M. tuberculosis, and 15 million with both. Last year, 5 million and 50 million were newly infected with HIV or M. tuberculosis, respectively, with 2 million new double infections. Better control measures are urgently needed.

Figure 1. Different outcomes of M. tuberculosis infection and underlying immune mechanisms.

M. tuberculosis enters the host within inhaled droplets. Three outcomes are possible. (i) Immediate eradication of M. tuberculosis by the pulmonary immune system. This alternative is rare to absent. (ii) Infection transforms into tuberculosis. This frequently occurs in immunodeficient individuals, with the notable example of HIV infection increasing the risk of developing tuberculosis 800-fold. (iii) Infection does not transform into disease because M. tuberculosis is contained inside granulomas. In the diseased individual, M. tuberculosis is no longer contained because caseation of the lesion results in dissemination and transmission of M. tuberculosis. After inhalation, M. tuberculosis is engulfed by alveolar macrophages and DCs. In draining lymph nodes, these cells present mycobacterial antigens to different T cell populations. Antigen presentation probably involves cross-priming, allowing transfer of mycobacterial antigens from infected macrophages to dendritic cells. Antigen-specific CD4⁺ T cells, CD8⁺ T cells, γδT cells and CD1-restricted T cells participate in protection. Most importantly, macrophages are activated by IFN-γ and TNF-α. In addition, T cells may kill mycobacteria present in macrophages by means of perforin and granulysin.

Figure 2. Differential antigen requirements of pre- and postexposure vaccines.

(a,b) A pre-exposure vaccine should comprise the set of antigens that are rapidly secreted early after infection, but would be ineffective in latent infection because its antigenic composition does not match the dormancy-induced antigenic repertoire. (c) A postexposure vaccine composed of dormancy-induced proteins should match the antigenic repertoire of dormant M. tuberculosis. (d) Ideally, a combination of both types of antigens would protect against both early childhood tuberculosis and adult reactivation tuberculosis because the antigenic repertoire would reflect the different stages of infection. Red line, nonvaccinated; blue line, vaccinated.

Figure 3. Absolute numbers of cases of active tuberculosis (TB) (2002) and estimated absolute numbers of people living with HIV (2004) and distribution of major HIV subtypes around the world.

The HIV-1 subtypes A–H and the HIV-2 subtypes N and O are shown. Sequence differences between the subtypes mean that different subtype vaccines will be needed for different parts of the world.

Figure 4

The major components of the immune response can be stimulated by different types of vaccine.