Within six months of starting antiretroviral therapy, up to 10% of people with advanced HIV die from secondary infections. The antibiotic azithromycin may reduce this mortality, but researchers do not fully understand how it works beyond killing bacteria. This project investigates azithromycin’s non-antimicrobial effects—specifically, whether it calms harmful immune activation and repairs the gut lining, both of which remain damaged even after HIV is suppressed by drugs. The work piggybacks on an existing 8,000-patient trial in sub-Saharan Africa. By analysing blood and rectal swabs from 200 participants before, during, and after azithromycin treatment, the researcher will measure changes in inflammation, immune cell types, gut bacterial metabolites, and epithelial barrier integrity. Lab experiments on human gut cells will test whether azithromycin directly strengthens tight junctions. If azithromycin’s immune-modulating and gut-healing properties are confirmed, the drug could be repurposed more broadly—not just for advanced HIV, but for other conditions driven by chronic inflammation and leaky gut. The findings could also guide the design of non-antibiotic macrolides that treat immune dysregulation without contributing to antimicrobial resistance. This is mechanistic, not immediately applied, but it addresses a concrete clinical problem: the high early death rate in advanced HIV.
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Within six months of starting antiretroviral therapy (ART), up to 10% of individuals with advanced HIV will die from secondary infections. Interventions to reduce this mortality are urgently required. The Bill and Melinda Gates Foundation-funded “Reducing Mortality in Adults with Advanced HIV Disease” (REVIVE) placebo-controlled, randomised trial will determine the efficacy of azithromycin in reducing mortality in adults (n=8000) starting or restarting ART with CD4 counts<100 cells/mm3. REVIVE is evaluating azithromycin daily for 4 weeks, alongside ART. Azithromycin is hypothesised to improve survival, in part, through antimicrobial activity against serious bacterial infections, and this is already being investigated within REVIVE. Azithromycin has documented immunomodulatory and epithelial barrier-promoting properties, although these are not well characterised. This proposal aims to define the non-antimicrobial effects of azithromycin in advanced HIV within the REVIVE trial. Clinical trials investigating the efficacy of azithromycin as an anti-inflammatory therapy did not examine underlying mechanisms. Observational and in vitro studies have described azithromycin-induced downregulation of inflammation, by modulating immune pathways. However, there is limited knowledge on how these mechanisms may impact HIV-associated immune dysregulation. Moreover, no clinical studies have evaluated azithromycin’s effect on gut barrier integrity. I will leverage the design of the REVIVE trial to address these knowledge gaps. This study hypothesises that the non-antimicrobial mechanisms of action of azithromycin may favourably modulate HIV-associated immune dysfunction and chronic gut injury that remain despite ART. This proposal presents a unique opportunity to conduct mechanistic studies with rigorous comparisons of azithromycin-induced changes relative to a placebo-controlled group. The proposed work will capitalise on the existing infrastructure of this recently initiated, fully funded clinical trial to conduct this important research. I will systematically investigate azithromycin-induced changes in immune activation and inflammation (aim 1), innate and adaptive immunity (aim 2), gut bacterial metabolites, and epithelial barrier function (aim 3). To achieve this, laboratory assays will be conducted on blood and rectal swabs from n=200 REVIVE participants collected at enrolment (pre-azithromycin), 4 weeks (end of azithromycin treatment), and at 6 months. Additionally, the direct effect of azithromycin on tight junctions and epithelial integrity will be examined in a human colorectal epithelial cell line (Caco-2; aim 4). The proposed study will use cutting-edge techniques including multiparameter flow cytometry, confocal microscopy, transcriptomics, and bacterial metabolomics. This study will significantly advance our understanding of the mechanisms of action of azithromycin, which may have broader applicability beyond HIV. A comprehensive understanding of its broader mechanisms is vital to inform its future use in different patient populations and direct the design of non-antibiotic macrolides to treat immune dysregulation. Knowledge that contributes to the reduction of morbidity and mortality in vulnerable populations would significantly contribute to the development of sub-Saharan countries, by reducing the pressure on their economies and public health systems. UKRI funding will also enable me to lead this project and to develop and refine the skills required to become an independent research leader in the field of infectious disease immunology.
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