Retasking of canonical antiviral factors into proviral effectors

Abstract

Under constant barrage by viruses, hosts have evolved a plethora of antiviral effectors and defense mechanisms. To survive, viruses must adapt to evade or subvert these defenses while still capturing cellular resources to fuel their replication cycles. Large-scale studies of the antiviral activities of cellular proteins and processes have shown that different viruses are controlled by distinct subsets of antiviral genes. The remaining antiviral genes are either ineffective in controlling infection, or in some cases, actually promote infection. In these cases, classically defined antiviral factors are retasked by viruses to enhance viral replication. This creates a more nuanced picture revealing the contextual nature of antiviral activity. The same protein can exert different effects on replication, depending on multiple factors, including the host, the target cells, and the specific virus infecting it. Here, we review numerous examples of viruses hijacking canonically antiviral proteins and retasking them for proviral purposes.

Figure 1:. Intrinsic immunity factors with antiviral and proviral functions.

Pre-expressed factors can serve to inhibit (left) or enhance (right) various stages of viral replication in both intra- and extracellular spaces. Cellular factors are identified with normal text and the steps during infection that are altered are highlighted with italics. The indicated viruses are used as examples, while extended details on mechanism and other viruses are described in the main text body. SARS-CoV-2 = SARS coronavirus 2. HIV = human immunodeficiency virus; HCV = hepatitis C virus.

Figure 2:. Innate immunity factors with antiviral and proviral functions.

Factors that become highly expressed in response to infection (e.g. IFN-stimulated genes [ISGs]) can either inhibit (left) or enhance (right) processes driving viral entry, replication, and egress. Cellular factors are identified with normal text and the steps during infection that are altered are highlighted with italics. The indicated viruses are used as examples, while extended details on mechanism and other viruses are described in the main text body. ATP = adenosine triphosphate; CTP = cytidine triphosphate; ddhCTP =3ʹ-deoxy-3′,4ʹ-didehydro-CTP; ISRE = IFN-stimulated response element; ORF44= Kaposi’s sarcoma-associated herpesvirus (KSHV) helicase; HIV = human immunodeficiency virus.

Figure 3:. Adaptive immunity factors with antiviral and proviral functions.

Molecules and cells involved in humoral and cell-mediated immunity can be used to inhibit (left) or enhance (right) viral entry and spread. Cellular factors are identified with normal text and the altered steps during infection are highlighted with italics. The indicated viruses are used as examples, while extended details on mechanism and other viruses are described in the main text body. Almost all viruses are subject to antigen presentation by MHC II, so a generic virus cartoon is used here. FcγR = Fcγ receptor; SAg = superantigen, Ab = antibody; MMTV = mouse mammary tumor virus.