Towards Understanding and Identification of Human Viral Co-Infections

Abstract

Viral co-infections, in which a host is infected with multiple viruses simultaneously, are common in the human population. Human viral co-infections can lead to complex interactions between the viruses and the host immune system, affecting the clinical outcome and posing challenges for treatment. Understanding the types, mechanisms, impacts, and identification methods of human viral co-infections is crucial for the prevention and control of viral diseases. In this review, we first introduce the significance of studying human viral co-infections and summarize the current research progress and gaps in this field. We then classify human viral co-infections into four types based on the pathogenic properties and species of the viruses involved. Next, we discuss the molecular mechanisms of viral co-infections, focusing on virus-virus interactions, host immune responses, and clinical manifestations. We also summarize the experimental and computational methods for the identification of viral co-infections, emphasizing the latest advances in high-throughput sequencing and bioinformatics approaches. Finally, we highlight the challenges and future directions in human viral co-infection research, aiming to provide new insights and strategies for the prevention, control, diagnosis, and treatment of viral diseases. This review provides a comprehensive overview of the current knowledge and future perspectives on human viral co-infections and underscores the need for interdisciplinary collaboration to address this complex and important topic.

Keywords: clinical symptoms; experimental and computational identification; host immune response; human viral co-infections; viral interactions.

Figure 1

Types of human viral co-infection. (A) Co-infections with different variants of the same virus. (B) Co-infections with multiple conditionally pathogenic viruses. (C) Co-infections with pathogenic viruses and conditionally pathogenic viruses. (D). Co-infections with multiple pathogenic viruses. (Created with BioRender.com (accessed on 2 April 2024)).

Figure 2

Molecular and clinical impacts of human viral co-infection. (A) Virus–virus interactions. Interactions between co-infected viruses include competition, cooperation, and gene exchange. Competition and synergy can manifest as the inhibition and enhancement of viral genome replication. Gene exchange, which involves recombination or reassortment, is one of the major ways in which viruses evolve. The mechanism of viral recombination is relatively complex, and a common and widely accepted approach is “copy choice” recombination. During the process of viral replication, the polymerase moves from one template chain to another while remaining bound to the nascent chain, resulting in offspring viruses with chimeric genomes. The offspring chimeric virus may have stronger biological characteristics, including stronger virulence, causing more severe clinical symptoms, a stronger transmission ability, the outbreak of pandemics in populations, and even cross-species transmission. (B) Host immune responses. (C) Clinical manifestations of disease. (Created with BioRender.com (accessed on 2 April 2024)).

Figure 3

Experimental detection methods for viral co-infections. (A) PCR test. (B) Immunological assay. (C) Virus culture. (Created with BioRender.com (accessed on 17 April 2024)).

Figure 4

Computational identification methods for viral co-infections. (A) Genome sequencing. (B) Cov2Coinfect algorithm. The input data (both NGS sequencing data and lineage-defined feature mutation list) are sent for a hypergeometric distribution test to obtain candidate lineages. Then, the confirmed lineage composition is identified from the candidate lineages based on the genomic characteristics of the co-infection samples. When a patient is infected by one specific SARS-CoV-2 lineage, most of the feature mutations of the lineage are detected at the same frequency. When a patient is co-infected by two SARS-CoV-2 lineages, the feature mutations of the same lineage have similar frequencies; the sum of the average frequencies of the feature mutations unique to the two lineages is close to 100% and the frequency of the feature mutations shared by two lineages is close to 100%. When two co-infected lineages recombine in vivo, the feature mutations of the two co-infected lineages can be detected at a frequency of about 100% before and after the recombination breakpoint in the recombinant virus. Therefore, when two co-infected lineages recombine in a patient, changes in the frequency of the feature mutations of the two lineages before and after the recombination breakpoint can be observed (one increases, one decreases, and the sum remains at nearly 100%). (Created with BioRender.com (accessed on 2 April 2024)).