Immunologival Consequences of Mycobacterium tuberculosis and Human Immunodeficiency Virus coinfection in Ethiopia

Abstract

Coinfections with Mycobacterium tuberculosis (MTB) during HIV-infection are a major problem in African countries because they lead to a higher death rate. In this thesis we investigated the interaction and the immunological consequences of HIV/TB coinfection.

First we focussed on the burden of HIV-infection in TB patients and its impact on screening and diagnostic methods of MTB. (part I) We demonstrate a high rate of HIV-infection among suspected TB patients, although still a lot of coinfected cases might be missed due to lower sensitivity of the diagnostic tests, which increases the risk of transmission of TB in the community.To study the impact of HIV-infection on clinical read-outs of MTB infection further, we determined the in vivo tuberculin PPD skin test reactivity, positivity and conversion rate in adult HIV-infected and non-infected Ethiopians. We observed lower PPD skin test positivity rate among clinically diagnosed MTB-infected adults with and without HIV-infection in Ethiopia, which suggests the need for other sensitive methods to detect active TB cases, particularly among HIV positives.

To study the immunological consequences of HIV-MTB coinfection, we examined immune activation parameters and disease progression. (part II) We analysed the expression of chemokine receptors CCR5 and CXCR4 on CD4+ T-cells and plasma chemokine levels among TB patients with HIV co-infection during the first 2 months of anti-TB treatment. We showed that increased expression of CCR5 and CXCR4 on activated CD4+ T-cell population coupled with persistently elevated chemokines may provide a suitable condition for continuous replication of HIV associated with TB co-infection. To investigate immune activation, proliferation rate of T cell subsets was analyzed among HIV/TB (n=21), HIV (n=23), TB (n=20) and Healthy controls (n=20). A seven, three and twofold-increased rate of proliferation was observed on CD4+ T cells in HIV-TB (13.7%), HIV (6.6%) and TB (3.7%) infected individuals, respectively compared to healthy controls (1.9%). This implies that coinfected individuals experience even more activation of their immune system. Interestingly, analyses of HIV-infected individuals who were followed before and after development of clinical active tuberculosis disease, showed a sustained/increased level of immune activation level paralleling the level of plasma viral RNA level and a progressive loss of CD4+ T cells. Thus, unlike in Caucasians, sustained level of immune activation in African HIV/TB coinfected patients despite anti-TB treatment will lead to the absence of immune restoration and reduction in plasma viral RNA level. Furthermore we analysed the level of regulatory T cells and found that these were increased in chronically ill HIV/TB patients. The level of Tregs correlated positively with HIV viral load and immune activation markers, thereby suggesting that these Tregs are antigen-dependent.

Finally, we analysed disease progression and outcomes of HIV/TB coinfection. (part III) The slow CD4-decline in HIV-infected Ethiopians compared to their Caucasian counterparts was explained by lower immune activation levels in the Ethiopians. Survival rate analysis of HIV/TB coinfected individuals before and after implementation of antiretroviral therapy (ART) showed that although survival increased due to ART, however mortality is still higher in HIV-infected compared to HIV uninfected TB patients.