Project Title

Characterisation of Kaposi’s sarcoma-associated herpes virus (KSHV)-driven pathologies and disease outcome in Human immunodeficiency virus (HIV)-infected patients

Project Objectives

Aim 1: Characterise clinical outcome of HIV/KSHV co-infected patients with elevated KSHV VL in the context of suspected but microbiologically unconfirmed TB as well as without suspected TB. Aim 2: Assess EPHA2 sequence variations associated with KSHV susceptibility, lytic reactivation and mortality. Aim 3: Determine the spectrum of KSHV subtypes among patients displaying high KSHV VL

Results & Outcomes

Host Organisation

EDCTP Project Call

Senior Fellowship (SF)

Study Design

Cross sectional study

Project Summary

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 (ART). 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 and/or specific KSHV subtypes to disease outcome in HIV-infected patients is unknown. We have demonstrated that elevated blood KSHV VL was a strong predictor of death (odds ratio 6.5) in hospitalised 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 HIV-infected patients. The emergence of Covid-19 in South Africa in early 2020 posed additional unknown risks to HIV/KSHV co-infected patients, and we showed that detectable blood KSHV VL was associated with death in hospitalised South African Covid-19 patients (odds ratio 3.2). While the design of this study could not distinguish if disease synergy existed between Covid-19 and KSHV nor if either viral infection was indeed fuelling the other, these data pointed to a potential contribution of KSHV infection to Covid-19 outcome, or SARS-CoV-2 infection to KSHV reactivation, particularly in the South African context of high disease burden, that warranted further investigation. We therefore proposed in this project to comprehensively characterise the contribution of KSHV lytic reactivation, host receptor EPHA2 alterations and KSHV genetic diversity to clinical outcome. We were making use of both stored and newly recruited patients’ samples from carefully designed and well-characterised clinical HIV-infected cohorts that were followed for up to 2 years to ascertain vital status and disease outcome. While patient cohort 1 (pre-Covid-19, suspected but microbiologically unconfirmed TB) had been recruited already, patient cohort 2 (no suspected TB, high SARS-CoV-2 exposure, CD4 count <350 cells/μL) was newly recruited over the course of approximately 3 years. In the first year of this project, we set up the necessary infrastructure and logistics to conduct the proposed research, which included recruiting a post-doctoral fellow and a Research Nurse and ethics approval from the relevant authorities. We also setup several Covid-19-related research tools in the laboratory to respond to the unprecedented viral outbreak that also led to changes in the design of this research study. In year 2, a PhD student joined the project, and we completed the recruitment of 50% of patient cohort 2, determined KSHV and SARS-CoV-2 serology, KSHV VL and various clinical parameters. All KSHV seropositive patients (with or without previous SARS-CoV-2 infection) were enrolled for follow-up to determine whether KSHV lytic reactivation (potentially triggered by SARS-CoV-2) played yet unrecognised roles for morbidity and mortality in high HIV settings. A MSc student was recruited to the project in year 3, who determined the genetic variability of KSHV in selected patient samples. Patient recruitment and follow-up was completed by the end of year 4, while the focus of year 5 was on the completion of data analysis. Based on this unique cohort, we designed and published various sub-studies where we 1.) observed reactivation of KSHV by SARS-CoV-2 after exposure to multiple infection waves in Covid-19 unvaccinated patients; 2.) linked SARS-CoV-2 infection to uncontrolled HIV viral load in Covid-19 unvaccinated patients; and 3.) identified an association of previous exposure to common coronaviruses and protection against Covid-19. This patient cohort therefore provides a rich source for both KSHV- and Covid-19-related research in non-hospitalised, low-income, densely populated communities with a high prevalence of HIV and high exposure to SARS-CoV-2. Our studies 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. Moreover, this project had strong translational applications, contributed to building an interdisciplinary network, and assisted the applicant together with three junior African scientists to become an established research group in the field of clinical HIV/KSHV co-infection (in the context of Covid-19) with the ability to attract sustained research funding. https://publications.edctp.org/international-partnerships-against-infectious-diseases/georgia-schafer

Sites

Current Organisation

ICGEB Cape Town

Current Job Title

Group Leader "Virology - Emerging Viruses"

Biography

Publications