Host-Directed Antiviral Therapy

Abstract

Antiviral drugs have traditionally been developed by directly targeting essential viral components. However, this strategy often fails due to the rapid generation of drug-resistant viruses. Recent genome-wide approaches, such as those employing small interfering RNA (siRNA) or clustered regularly interspaced short palindromic repeats (CRISPR) or those using small molecule chemical inhibitors targeting the cellular "kinome," have been used successfully to identify cellular factors that can support virus replication. Since some of these cellular factors are critical for virus replication, but are dispensable for the host, they can serve as novel targets for antiviral drug development. In addition, potentiation of immune responses, regulation of cytokine storms, and modulation of epigenetic changes upon virus infections are also feasible approaches to control infections. Because it is less likely that viruses will mutate to replace missing cellular functions, the chance of generating drug-resistant mutants with host-targeted inhibitor approaches is minimized. However, drug resistance against some host-directed agents can, in fact, occur under certain circumstances, such as long-term selection pressure of a host-directed antiviral agent that can allow the virus the opportunity to adapt to use an alternate host factor or to alter its affinity toward the target that confers resistance. This review describes novel approaches for antiviral drug development with a focus on host-directed therapies and the potential mechanisms that may account for the acquisition of antiviral drug resistance against host-directed agents.

Keywords: antiviral agents; drug resistance; epigenetic regulation; host factors; precision medicine.

FIG 1

Novel strategies of antiviral drug development. (A) In order to effectively replicate inside cells, virus is highly dependent on certain cellular factors, some of which are dispensable for cells and therefore may serve as targets for antiviral drug development. (B) Epigenetic changes such as DNA methylation and histone acetylation have also been shown to regulate viral replication/transcription/translation; thereby, inhibitors targeting the enzymes responsible for these epigenetic modifications (DNA methyltransferase, histone methyltransferase, histone acetylase, histone deacetylase) may serve as viable targets for antiviral drug development.

FIG 2

Regulation of host antiviral responses. An antiviral immune response can be boosted by several possible means. (A) Monoclonal antibodies. Blocking CD69 by using anti-CD69 monoclonal antibodies increases leukocytic numbers in the secondary lymphoid organs during infection and improves the capacity to clear viral infection. (B) PRR agonists. Agonists targeting PRRs are another possible strategy to potentiate the innate immune response for enhanced virus clearance. (C) Modulation of counterinflammatory mechanisms. Counterinflammatory mechanisms such as the Tim-3/Galectin-9 interaction and the PD-1/PDL-1 axis prevent collateral tissue damage caused by an excessive immune response. Thus, antiviral immunity can be augmented by blocking these counterinflammatory mechanisms. (D) Manipulating Treg responses. Treg are the suppressor cells that act to limit an excessive immune response. FTY720 expands and potentiates Treg function, which in turn ameliorates virus-induced immunopathology. On the other hand, inhibiting Treg (adefovir dipivoxil) enhances antiviral effector responses. (E) Cytokine therapy. Administration of proinflammatory cytokines and alternatively a blockade of immunosuppressive cytokines may serve to enhance antiviral immune responses.

FIG 3

Potential mechanisms underlying acquisition of resistance against host-directed antiviral agents. Three possible mechanisms that may be associated with acquisition of resistance against host-directed antiviral agents have been hypothesized. (A) Switch to use alternate host factor. Long-term restricted availability of a critical cellular factor may induce the virus to use an alternate host factor to become resistant. (B) Increased affinity to substrates. If viruses are cultured long term in the presence of restricted availability of a particular host factor, they may increase their efficiency to optimally replicate under a limiting amount of the targeted host protein.