Project Title

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

EDCTP Project Call

Senior Fellowship (SF)

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

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. 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 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 HIV-infected patients. The emergence of Covid-19 in South Africa in early 2020 poses additional unknown risks to HIV/KSHV co-infected patients, and we recently 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 exists between Covid-19 and KSHV nor if either viral infection is indeed fueling the other, these data point 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 warrants further investigation. We therefore propose in this project to comprehensively characterise the contribution of KSHV lytic reactivation, host receptor EPHA2 alterations and KSHV genetic diversity to clinical outcome. We are making use of both stored and newly recruited patients’ samples from carefully designed and well-characterised clinical HIV-infected cohorts that were/will be 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) has been recruited already, patient cohort 2 (no suspected TB, high SARS-CoV-2 exposure, CD4 count <350 cells/μl) is proposed to be newly recruited over the course of approximately 3 years. In the first year of this project, we have set up the necessary infrastructure and logistics to conduct the proposed research, which included recruitment of a post-doctoral fellow and a Research Nurse and ethics approval from the relevant authorities. We have also set-up 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 have recruited 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) plays yet unrecognised roles for morbidity and mortality in high HIV settings. A MSc student was recruited to the project in year 3, who determined genetic variability of KSHV in selected patient samples. By the end of year 4 patient recruitment was completed, and the focus shifted to the follow-up aspects of the project. Based on this unique cohort, we designed and published various cross-sectional 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 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 has strong translational applications, will contribute to building an interdisciplinary network, and will eventually assist the applicant together with at least 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.

Host Organisation

Current Organisation

ICGEB Cape Town

Current Job Title

Group Leader "Virology - Emerging Viruses"

Biography

Publications