Virology-The next fifty years

Abstract

Virology has made enormous advances in the last 50 years but has never faced such scrutiny as it does today. Herein, we outline some of the major advances made in virology during this period, particularly in light of the COVID-19 pandemic, and suggest some areas that may be of research importance in the next 50 years. We focus on several linked themes: cataloging the genomic and phenotypic diversity of the virosphere; understanding disease emergence; future directions in viral disease therapies, vaccines, and interventions; host-virus interactions; the role of viruses in chronic diseases; and viruses as tools for cell biology. We highlight the challenges that virology will face moving forward-not just the scientific and technical but also the social and political. Although there are inherent limitations in trying to outline the virology of the future, we hope this article will help inspire the next generation of virologists.

Keywords: cancer; chronic disease; co-infection; therapies; vaccines; virology; virosphere.

Figure 1.. The scale of the RNA virosphere.

The inner (unrooted) phylogeny depicts the current large-scale classification of RNA viruses, with the five major phyla marked on the outer rim. Some individual families and orders of RNA viruses are also indicated. Note that because of the enormous genetic distances involved and inherent alignment uncertainties, this phylogeny should not be considered an accurate representation of evolutionary history. The hypothetical outer limit of virus detection using current computational methods based on primary sequence similarity only (e.g., from metagenomics) is marked by the dashed yellow circle. The analysis of patterns of protein structural conservation may extend the detectable virosphere to the outer dashed circle. Beyond that, viruses may be undetectable using any sequence-based approach. Phylogeny adapted from Charon et al. (2022), with branch lengths scaled to the number of amino acid substitutions per site (scale bar of 0.8 amino acid substitutions/site).

Figure 2.. Competition between related and unrelated viruses in humans.

(A) Circulation of influenza viruses since 1918. The H1N1 subtype of influenza A virus was present in the human population from 1918 to 1957. In 1957, a different influenza A virus subtype, H2N2, caused a pandemic and outcompeted H1N1 within a short time period, leading to its elimination from the human population. In 1968, another influenza A subtype, H3N2, caused a pandemic leading to the elimination of H2N2. The H1N1 subtype returned in 1977 and circulated until 2009 when a novel swine-origin H1N1 virus caused a pandemic and eliminated seasonal H1N1. The competition between these viruses was likely due to increased serological cross-reactivity leading to elimination of the older, likely less fit virus. Of note, H1N1 and H3N2 are serologically distinct (i.e., the HA and NA come from different phylogenetic groups) which likely allows their co-circulation. Influenza B viruses evolved from an ancestral lineage into the B/Victoria/2/87-like lineage in the mid-1970s and the B/Yamagata/16/88-like lineage in the mid-to late 1980s. The Yamagata lineage was eliminated in 2020 likely due to non-pharmaceutical interventions imposed during the SARS-CoV-2 pandemic. (B) Data (% positive tests per day) from New York City, USA, suggesting competition between unrelated viruses. In the late autumn of 2021 an increase of H3N2 activity was detected. However, at approximately the same time, the early Omicron variant BA.1 of SARS-CoV-2 started to cause a massive wave of infections in New York City, during which time H3N2 activity seemed suppressed. With the decline of Omicron BA.1, influenza H3N2 virus activity started to rise again. Courtesy of the Mount Sinai Pathogen Surveillance Program.

Figure 3.. Patterns of virus infection and disease outcomes.

Upon infection of a permissive host, virus replication will result in the production of viral progeny for spread to other cells/tissues within the host and to secondary hosts (yellow box). The outcome of infection (acute infection and clearance versus persistence) and the associated disease outcomes are in large part determined by the balance between the nature and strength of the immune response, the modulation of host response by virus-encoded factors and, in some cases, the emergence of escape variants. Replication products first stimulate innate and then adaptive immune responses (1, arrow), viral replication products in turn inhibit or manipulate host responses (2, bar) as immune responses attempt to limit infection (3, bar). Other infections (e.g., viral, bacterial, fungal, protozoan, etc.) impact infection and responses to infection in ways that are still poorly understood. The interplay between the infecting virus and the host will often result in clearance of the virus. While clearance will typically result in complete resolution and recovery, in rare cases, immune responses or other host biology altered by the infection may not fully resolve and can result in chronic disease, with chronic inflammation or autoimmunity as an underlying cause. However, some viruses (e.g., herpesviruses, HIV, hepatitis B and C viruses, papillomaviruses, and polyomaviruses) are capable of evading host defences and are not cleared, establishing a persistent or latent infections. In either case, a dynamic and metastable state is reached within the host. Viral persistence may result in chronic or episodic disease, driven by sustained immune response and inflammation, or immune exhaustion and the inability to control replication. Alternatively, persistent viruses may result in an inapparent, asymptomatic infection in a healthy immune competent host.

Figure 4.. Emerging concepts for viral vaccines.

(A) Currently used vaccines often induce strain-specific immunity. However, many RNA viruses like influenza virus and SARS-CoV-2 are antigenically unstable and undergo antigenic evolution (i.e., “drift”). In addition, vaccines that can broadly target related but antigenically distinct viruses are needed for pandemic preparedness. (B) Broadly protective or universal vaccines that refocus immune responses on conserved antigens shard by variants or related viruses would enhance protection from drifting viruses and pandemic preparedness. (C) Most vaccines against respiratory viruses are injected and induce systemic immunity that protects well from symptomatic and severe disease. However, these vaccines do not effectively induce immunity in the upper respiratory tract. (D) To avoid (breakthrough) infections and transmission within the population, vaccines that induce strong immune responses in the upper respiratory tract are needed. Vaccination via mucosal routes (intranasal, oral etc.) may provide this type of protection. In general, mucosal immunity is currently understudied but has become a focus for future exploration.

Figure 5.. Products of virology.

In addition to understanding the basic biology of viral infection and disease, the science of virology has been the driver for the discoveries that underpinned the broad-scale development of vaccines and antiviral therapies, as well tools for the treatment of cancer and genetic disorders. Of equal importance, viruses have been major tools for foundational discovery in molecular and cell biology, defining the basic mechanisms of DNA replication and transcription to oncogenesis. While this figure is not comprehensive, it conveys the scope of how the study of viruses has impacted science and health. RT, reverse transcriptase.