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Project Topic
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Acquired immunodeficiency syndrome (AIDS)-related deaths have declined from an estimated 1.9 million in 2005 to 1.0 million in 2016, due to global scale-up of antiretroviral therapy. Of those, 730,000 occurred in Sub-Saharan Africa (SSA), where tuberculosis (TB) is the leading cause of mortality among human immunodeficiency virus (HIV)-infected individuals, accounting for a third of all AIDS-related deaths. The exceptionally high burden of suspected TB in SSA causes misdiagnosis or delayed diagnosis of diseases mimicking TB, such as several pathologies associated with Kaposi’s sarcoma-associated herpes virus (KSHV), a gamma-herpesvirus with a particularly high seroprevalence in SSA. Besides being the etiological agent of Kaposi’s sarcoma (KS), the commonest AIDS-related malignancy worldwide, KSHV also causes primary effusion lymphoma (PEL), multicentric Castleman disease (MCD) and KSHV inflammatory cytokine syndrome (KICS), the two latter conditions being characterised by elevated viral load (VL), cytokine dysregulation and high mortality. Despite the high seroprevalence in SSA, the contribution of dysregulated KSHV lytic replication, host KSHV receptor variations and/or specific KSHV subtypes to disease outcome in HIV-infected patients is unknown. We recently demonstrated elevated blood KSHV VL was a strong predictor of death (odds ratio 6.5) in hospitalized South African HIV-infected patients with culture-negative TB. Further, we identified variants in the KSHV entry receptor, EPHA2, to be associated with susceptibility to infection and/or KS development in South African HIVinfected patients. Given these findings, we propose to comprehensively characterise the contribution of KSHV lytic reactivation, host receptor EPHA2 alterations and KSHV genetic diversity to clinical outcome. We will use both stored and newly recruited patients’ samples from carefully designed and well-characterised clinical HIV-infected cohorts that were/will be followed for 12-16 weeks to ascertain vital status. We propose to: 1. Characterise clinical outcome of HIV/KSHV co-infected patients with elevated KSHV VL in the context of suspected but microbiologically unconfirmed TB (cohort 1) as well as without suspected TB but low CD4 count (<350 cells/μl) (cohort 2) 2. Assess EPHA2 sequence variations associated with KSHV susceptibility, lytic reactivation and mortality 3. Determine the spectrum of KSHV subtypes among patients displaying high KSHV VL We hypothesise that KSHV lytic reactivation plays yet unrecognised roles for morbidity and mortality in high HIV settings. Thus, these studies will provide novel unprecedented insights into KSHV-associated pathologies and will facilitate the development of novel diagnostic and surveillance tools leading to the evaluation of therapeutic strategies. This project will contribute to building clinical research capacity of three junior African scientists and the applicant, who will gain greater experience in project leadership, management and mentorship, and who will become a more effective trainer and scientist. The work proposed herein has strong translational applications, will contribute to building an interdisciplinary network, and will eventually assist the applicant to become an established researcher in the field of clinical HIV/KSHV co-infection with the ability to attract sustained research funding, and continue training young scientists.
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