Objective: Invasive aspergillosis is a dangerous and highly lethal opportunistic infection in immunosuppressed HIV-infected patients. Nothing is known about a putative cross-effect between fungal and viral infection. A deeper insight into pathogenic mechanisms is urgently needed for an adaptation of antiviral therapy in the case of invasive aspergillosis. Therefore we studied whether fungal metabolites influence HIV replication and thus contribute to a progression to AIDS. Methods: HeLa cells transfected with the HIV promoter, primary microglia, M8166 lymphocytes and THP-1 monocytes were pre-incubated with purified fungal metabolites followed by infection with HIV. Viral replication was analysed by quantification of promoter activity and by quantification of p24 in the culture supernatants. Toxicity and cell activation was controlled by measuring mitochondrial activity (MTS test). Results: Subtoxic concentrations of the fungal metabolites gliotoxin and citrinin, known to be produced by pathogenic Aspergillus species markedly stimulated the cellular activity. Furthermore the two compounds both strongly enhanced HIV infection of HeLa cells as shown by the increased numbers of infected cells and of generated syncytia. The viral load in the culture supernatants was amplified after pre-incubation with gliotoxin or citrinin compared to mock-treated control cells. A similar effect of gliotoxin was visible for the infection and the production of progenitor virus with T-cells, monocytes and primary microglia. Other fungal metabolites like patulin, fumitremorgin or verruculogen were proven to be ineffective and did not influence viral infection and replication. Conclusions: The fungal metabolites gliotoxin and citrinin boost and fuel the HIV infection of those cell types which represent viral targets in the patient, with a subsequent stimulation of progenitor virus production. Thus an opportunistic fungal infection of HIV-infected individuals should not only be treated with antimycotic drugs but also result in adaptation or initiation of antiviral therapy. Further knowledge in the pathogenic mechanisms of gliotoxin and citrinin might help to neutralize to metabolite-induced escalation of virus production and thereby inhibit disease progression in the patients.
Full conference title:
19th European Congress of Clinical Microbiology and Infectious Diseases
- ECCMID 19th (2009)