Questions to be answered (5-10 yrs)
Essential background data
Current Specific Objectives per Question.
Achievements – sharing our success in grants and papers
- How does HIV infection impact the immune competence of the lung and the vascular compartments and how can this knowledge translate into strategies to reduce susceptibility to, and improve the management of lower respiratory tractinfections (LRTIs) as well as cardiovascular/cerebrovascular disease (CVD/CBD) in HIV-infected individuals in sub-Saharan Africa?
- What is the effect of persistent HIV-infection in the lung during potent antiretroviral therapy (ART) and how can this be mitigated?
- HIV-infected individuals have increased risk of LRTIs and CVD/CBD compared to HIV-uninfected populations. This suggests strongly that HIV alters the immune competence of the lung and vascular compartments but current understanding of immune mechanisms underlying the increased risk is incomplete. HIV-infected adults with LRTIs and CVD/CBD constitute a considerable burden on national healthcare services in sub-Saharan Africa (SSA), even in the era of antiretroviral therapy (ART). While current ART is highly effective at suppressing viral replication in circulating CD4+ T cells and clearing the virus from plasma, it does not entirely eliminate HIV from the human host. We have recently shown that HIV persists in human alveolar macrophages (AMs) in the lung in individuals on ART with undetectable plasma viraemia, suggesting that the lung represents an under-appreciated HIV reservoir.
- a) Elucidation of cellular mechanisms that control LRTIs such as Mycobacterium tuberculosis in HIV-infected and uninfected AMs in the lung; b) Identification of specific HIV-mediated defects in immune competence of the lung that favour progression of LRTIs; c) Characterisation of chronic lung disease in perinatally HIV-infected adolescents; d) Investigation of immunological correlates of influenza viral clearance that predict severity and duration of influenza illness in HIV-infected Malawian adults; e) Characterisation of mechanisms responsible for chronic systemic immune activation and vascular inflammation in HIV-infected adults in SSA..
- a) Characterisation of mechanisms for HIV persistence in human AMs; b) Investigation of the role of HIV- and ART-mediated chronic immune activation in cardiovascular disease in HIV-infected adults in SSA.
- Selected publications: Mwandumba et al., J Immunol 2004; Russell et al., Nat Rev Immunol 2009; Jambo et al., Mucosal Immunol 2014, Jambo et al., Am J Respir Crit Care Med 2014, Sloan et al., Clin Infect Dis 2015, Mzinza et al., Tuberculosis 2015, Sloan et al., Int J Tuberc Lung Dis 2015; Longwe et al., PLoS One 2015; Longwe et al., BMC Immunol 2015; Iwajomo et al., J Infect 2015; Rylance et al., PLoS One 2015.