While COVID-19 has challenged healthcare systems worldwide, its impact on individuals with pre-existing conditions like HIV has sparked particular concern. People living with HIV are often at a higher risk for various infections, raising critical questions about their resilience against SARS-CoV-2. This concern stems from the complex interplay between their compromised immune systems and the intrinsically aggressive nature of COVID-19, especially in unvaccinated individuals,making the exploration of this intersection a public health priority.

As the world grapples with the ongoing challenges of the COVID-19 pandemic, a recent study published in the journal iScience, led by Prof. Giulia Marchetti from the University of Milan, delves into the exacerbated risks faced by people living with HIV (PLWH) who contract COVID-19. This research uncovers how SARS-CoV-2 RNAemia, skewed T cell responses, and inflammation amplify the severity of COVID-19 in this vulnerable population.

Prof. Marchetti explains the severity of the immune dysfunction: “PLWH displayed a significantly higher RNAemia than HIV-negative individuals, indicating a greater replication and potentially systemic dissemination of the virus in PLWH.” She adds, “We found a clear separation between PLWH and HIV-negative individuals based on principal component analysis of plasma cytokines, suggesting an exacerbated inflammatory response to SARS-CoV-2 in PLWH.” These insights provide a deeper understanding of the unique challenges faced by PLWH during the COVID-19 pandemic.

The study employed a cross-sectional design, recruiting both unvaccinated PLWH and age/sex-matched HIV-negative individuals. Methods such as flow cytometry, ELISA, and cytometric bead array were used to analyze SARS-CoV-2–specific T-cell and humoral responses as well as a panel of plasma cytokines. This approach provided a detailed view of how the immune system of unvaccinated PLWH uniquely responds to SARS-CoV-2 infection.

Despite relatively preserved humoral immunity, PLWH exhibited fewer and less polyfunctional SARS-CoV-2-specific T cells, pointing to a compromised adaptive immune response to the virus. The peculiar cytokine profile in PLWH was marked by elevated levels of granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-4 (IL-4), and tumor necrosis factor-alpha (TNF-α), with reduced levels of interleukin-2 (IL-2) and IL-9. These findings indicate a more severe cytokine storm in PLWH, correlating with more severe respiratory insufficiency.

To further contextualize the importance of this study, it is essential to consider the broader implications for public health policies and clinical practices. The findings underscore the necessity for proactive health measures tailored specifically for PLWH during pandemic conditions. This includes not only the development of more effective therapeutic interventions but also enhanced screening and prevention strategies to manage potential outbreaks. Ensuring that these individuals receive vaccinations promptly and are monitored closely for COVID-19 symptoms could significantly reduce hospitalization rates and improve outcomes. Integrating these preventive measures with existing HIV care programs could provide a dual benefit, reinforcing the health infrastructure needed to protect this high-risk population during ongoing and future health crises.

These profound implications, as highlighted by Prof. Giulia Marchetti and her team, underscore the urgent need for tailored clinical strategies to effectively manage SARS-CoV-2 infection in PLWH. Prof. Marchetti suggests that enhanced surveillance and possibly early therapeutic strategies are crucial to mitigate the severe impacts observed in this vulnerable population.

Journal Reference

Augello, Matteo; Bono, Valeria; Rovito, Roberta; et al. “Association between SARS-CoV-2 RNAemia, skewed T cell responses, inflammation, and severity in hospitalized COVID-19 people living with HIV.” iScience, January 19, 2024. DOI: https://doi.org/10.1016/j.isci.2023.108673

About The Authors

Giulia Marchetti received her MD in 1995, she completed Residency in Infectious Diseases in 2000 (Milan), and took her PhD in HIV/AIDS in 2003 (Milan). 

She was visiting fellow at the RIVM (Bilthoven, the Netherlands), Rush University (Chicago, US) and the NIH (Bethesda, US) between 1996 and 2002. She is currently Full Professor at the University of Milan – Department of Health Sciences at San Paolo Hospital where she runs a Laboratory focused on studies on HIV pathogenesis and immune reconstitution, and – most recently- SARS-COV-2-related disease. 

She is now Head of the Clinic of Infectious Diseases at San Paolo Hospital, Milan. 

Dr. Marchetti has been involved in studies of HIV pathogenesis, therapies and HIV-related co-morbidities since 1996, and has authored or co-authored more than 180 original peer-reviewed publications in this field. In particular, her major research fields are the immunopathogenesis of HIV infection with a particular focus on the interconnection between HIV-related inflammation and damage to the gastrointestinal system. Most recently, she has started a new research topic on the immunopathogenesis of COVID-19 with a particular focus on the pathogenetic determinants of severe versus mild disease. She is the PI of several competitive grants from the Italian Ministry of Health, Regione Lombardia, Fondazione Cariplo, Horizon for studies on the immunopathogenesis of HIV and – most recently – of SARS-COV-2. 

Her work has been presented at national and international conferences, and she has participated and invited lecturer to both national and international conferences.

Matteo Augello, M.D. is an Infectious Diseases and Tropical Medicine Specialist at the Clinic of Infectious Diseases and Tropical Medicine, San Paolo Hospital in Milan, Italy. He is currently Ph.D. Student at the Department of Health Sciences, University of Milan. His major interest lies in the immune responses to viral infections (mainly HIV) and vaccines. During the COVID-19 pandemic he was involved in projects aiming to characterize immune responses to SARS-CoV-2 natural infection and vaccination in people living with HIV.

I am Roberta Rovito, postDoc in the Laboratory of Professor Giulia Marchetti, University of Milan, Clinic of Infectious Diseases, San Paolo Hospital. 

My educational and professional background has been shaped by the desire to understand the dynamics through which pathogens bypass host defenses and the host adopts strategies to counter the infection. An aspect that in the last years of the COVID-19 pandemic has proved to be of fundamental importance.

Therefore, after the Master Degree in Medical Biotechnology, in particular in the Molecular Virology laboratory of Turin University, I had the opportunity to carry out my PhD in a European Marie Curie Framework aimed at training the Next Generation Vaccinologists. I did the PhD in the Department of Medical Microbiology of Leiden University Medical Center, The Netherlands, working on the immunopathogenesis of congenital Cytomegalovirus infection. 

After the PhD, I started a postdoc in the Laboratory of Professor Giulia Marchetti, University of Milan, Clinic of Infectious Diseases, San Paolo Hospital. My work focuses on the immunopathogenesis of SARS-CoV-2 and HIV infection.

Camilla Tincati, M.D., PhD. I am specialized in Infectious Diseases with expertise in the management of HIV infection. My medical background has led me to explore the reasons by which HIV induces a wide range of immune abnormalities, which are linked to clinical progression (non-infectious comorbidities) in People Living with HIV (PLWH). 

My current research focuses on the role of the gastrointestinal tract in the pathogenesis of HIV infection; stemming from the observation that alterations of the mucosal structure, immunity and microbiome are key in accounting for disease progression, I am also studying their interplay in HPV-related dysplasia and cancer.

Valeria Bono, M.Sc, is a PhD candidate in the Translational Medicine course at the University of Milan. She has been working on antigen-specific T cellular and humoral responses in HIV-infected individuals with SARS-CoV-2 infection. Currently, her focus is on the study of inflammation, microbial translocation and gut barrier damage in primary and chronic HIV infection.