Similarities and dissimilarities in immune responses and metabolism in SARS-CoV-2 and HIV-1 infections

Clinical Trials & Research

Among the various viral diseases, two of the most prevalent viruses that have affected millions of lives are severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and human immunodeficiency virus-1 (HIV-1). The current coronavirus disease 2019 (COVID-19), caused by SARS-CoV-2, has infected more than 319 million individuals and claimed more than 5.52 million lives worldwide. According to a current report of the Joint United Nations Programme on HIV/AIDS (UNAIDS), more than 38 million people are living with HIV-1 (PLWH), and over 36 million AIDS-related deaths have occurred since the beginning of the AIDS epidemic.

Study: A single-cell atlas reveals shared and distinct immune responses and metabolism during SARS-CoV-2 and HIV-1 infections. Image Credit: Design_Cells / Shutterstock

SARS-CoV-2 and HIV-1

Studies have shown that both SARS-CoV-2 and HIV-1 are RNA viruses and have higher mutation rates than DNA viruses. Although both the viruses have been characterized as highly virulent, the manner of disease progression differs considerably. For example, in the case of SARS-CoV-2, the mortality and morbidity can be observed within a few days of infection, whereas for HIV-1 infection, it takes months or years. Also, in SARS-CoV-2 infection, neutralizing antibodies are generated rapidly post-infection, but with PLWH, antibodies take many years to develop.

Scientists have reported that PLWH with compromised immune systems makes them susceptible to SARS-CoV-2 infection. Additionally, this group has exhibited suboptimal responses to SARS-CoV-2 vaccination. Hence, complete immune profiling of SARS-CoV-2 and HIV-1 infections would elucidate the mechanism of disease progression, which could guide researchers in the discovery of novel therapeutics.

Many COVID-19 patients with severe infection produce high levels of inflammatory cytokines and chemokines, such as IL-6, IL-10, TNF-α, IFN-γ, and IP-10. Similarly, these cytokines are also released during acute HIV-1 infection and can persist if left untreated. Different types of immune cells drive inflammatory responses during viral infection.

The distribution and cell type-specific functions of different immune cells, such as T cells, B cells, macrophages, natural killer cells, dendritic cells, monocytes, differ across various infections, stages of disease progressions, and conditions.

Single-cell RNA Sequencing Method

Single-cell RNA sequencing (scRNA-seq) has been extensively used to understand the heterogeneity within immune cell subsets. This sequencing method provides highly accurate annotation of individual cells. It has become a powerful tool for elucidating complex cell-cell interactions and understanding the subpopulation dynamics with single-cell resolution. 

Scientists have indicated that not much evidence is available regarding immune cell populations during HIV-1 and COVID-19 infections at the single-cell level. Although several scRNA-seq atlases have been developed on COVID-19, they substantially differ in terms of granularity and markers used for annotation. Not many HIV-1 scRNA-seq profiling studies are available that are comparable to COVID-19 infection.

A New Study

A new study, posted to the bioRxiv* preprint server, has developed a single-cell atlas that presents the shared and distinct immune responses and metabolism following SARS-CoV-2 and HIV-1 infections.

The researchers from the University of Chicago and Northwestern University utilized single-cell transcriptomics to systematically compare scRNA-seq data of 115,272 single Peripheral Blood Mononuclear Cells (PBMCs) obtained from seven COVID-19, nine HIV-1, and three healthy patients. Thereby, they produced a high-quality unified cellular atlas of the immune landscape by combining the advantages of all three methods to annotate scRNA-seq data that include molecular-profile-correlation-based label transfer, manual annotation, and deep-learning-based classification.

The newly developed atlas enabled scientists to compare the phenotypic features and regulatory pathways of principal immune cells. They reported common signatures of inflammation, i.e., IFN-I and cytokine-mediated signaling, as well as errored mitochondrial function in both COVID-19 and HIV-1. However, the difference between COVID-19 and HIV-1 was found in terms of antibody diversity, cell signaling, IFN-I signaling, and metabolic function. For instance, cytokine response by IL-2, IL-4, and IL-20 signaling was found to be more prominent in COVID-19 patients compared to HIV-1 patients that displayed high levels of NF-kB signaling.

Researchers identified 27 different cell types that include five B cell subsets, two dendritic cell subsets, four monocyte subsets, seven CD4+ T cell subsets, eight CD8+ T cell subsets, and one natural killer cell subset, post COVID-19 and HIV-1 infections. However, the types and frequencies of cellular communications among immune cells differed significantly between COVID-19 and HIV-1 patients. The authors reported the development of inhibitory interactions mediated by CTLA4 and HAVCR2 that were distinctive to COVID-19 patients. In line with previous reports, a robust humoral immune response was found in both COVID-19 and HIV-1 patients. Additionally, IFN-I signaling has been reported to be closely linked with both HIV-1 and COVID-19 infection, which promotes essential cellular functions such as cell signaling, motility, and cytokine secretion. The authors reported a decrease in mitochondrial oxidative phosphorylation (OXPHOS) and ribosome biogenesis in response to both SARS-CoV-2 and HIV-1 infection.


The current study has offered a vital resource to understand the pathophysiological differences between COVID-19 and HIV-1. It revealed that the HIV-1 antibody repertoire was much less diverse compared to the COVID-19 antibody repertoire. One of the advantages of repertoire mapping is that it helps researchers locate high-frequency and overlapping combinations in sequences, which could inspire antibody-based therapeutics to treat comorbid patients. The authors are optimistic that this study will help develop novel molecular targets for treating these diseases.

*Important Notice

bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

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