Final Activity Report Summary - THI-DOC (Doctorate training in Tuberculosis and HIV infections) Tuberculosis (TB) and HIV / AIDS cause more deaths than any other infectious disease, globally. Co-infections with Mycobacterium tuberculosis (MTB) and HIV lead to the accelerated death of the double-infected individuals. The mechanisms responsible for the frequent liaison between TB and HIV infections are not known.The MC-EST program entitled THI-DOC addressed the association between MTB and HIV explored at the level of host cell and of whole organism using a variety of experimental approaches.Eight PhD students (36 months) and 4 short-term fellows (6 months) conducted eight research projects dealing with various aspects of MTB and HIV infections.Project: Functional anatomy of antigen-specific T-cell responses in MTB and HIV infections (I. Magalhaes)Findings: CD8aa+ T-cells, thought to modulate T-cell activation, undergo expansion in TB infected and BCG vaccinated humans and rhesus macaques. The kinetics of this expansion suggests their participation in the establishment of relevant immune memory. The detection of antigen-specific CD8aa+ T-cells may be a marker of immunity valuable for rational vaccine design.Project: Mice with 'humanised' immune system as model for MTB and HIV infections (B. Carow / F. Heuts) Findings: Mouse model has been developed consisting of severly immunodeficient mouse strain reconstituted with human fetal blood, which gives rise to 'humanised' immune system. Such mice controlled mycobacterial infection which indicated functional maturity of the implanted human immune cells. This model will be of great value for studies of natural and vaccine-induced immunity to infection.Project: Immunogenicity and efficacy of HIV and tuberculosis vaccine candidates in a mouse model of HIV1/MuLV - MTB co-infection (L. Ignatowicz)Findings: Pre-existing chronic MTB infection severely impairs immune responses to HIV DNA vaccine given mucosally (intranasal vaccination). These results are important for the current and future HIV vaccine trials indicating that vaccination through mucosal route (nasal, vaginal, rectal, oral) might be ineffective if the vaccinees have chronic infection such as TB.Project: Functional polarisation of dendritic cells (DC) in co-infection with MTB and HIV; role of lipoarabinomannan (J. Mazurek)Findings: Two compounds of MTB, ManLAM and new glycolipid GlpX, exert divergent effects on DC: either stimulate (ManLAM) or inhibit (GlpX) immune responses to TB. MTB-infected macrophages affect DC in such way that they maintain the ability to transfer HIV to T-cells. These studies indicate that TB infection may facilitate HIV infection by involvement of DCs.Project: Development of novel imaging methods to study MTB and HIV infections and associated diseases (G. Petranyi) Findings: Automated microscopic system has been developed that allows to assess antiviral and antibacterial activity of compounds by measuring the degree of cytopathic effect (HIV) and bacterial death (MTB) in infected cell cultures. The method allows time-wise follow up of the compounds' effects and is important for simplification, and increased rapidity and throughput of novel compound screening.Project: The role of HLA class II alleles and HIV-1 phenotypes in infections with HIV-1 and MTB (S. Gaseitsiwe) Findings: Peptide microarray chips were developed which detect binding of MTB and HIV peptides to different HLA class II soluble alleles as well as antibody responses. Such chips will serve as important diagnostic tools valuable also for vaccine design.Project: IL-7 modulation of ligand-receptor pairs during HIV-1 infection (S. Sammicheli) Findings: High blood interleukin 7 observed in HIV infection may contribute to deregulation and dysfunction of NK cells that play important role in innate responses to infection. This observation must be taken into account when evaluating benefits of IL-7 in immune therapy for HIV.Project: Characteristics and function of B cell subpopulations during HIV-1 infection (L. Dang) Findings: There is an increase of CD27(-) B-cells in HIV infected patients and these cells produce somatically hypermutated non-specific antibodies. These data contribute to further understanding of abnormal B-cell activation in HIV.