The emergence of resistant viral variants especially in high- progeny, low-fidelity RNA viruses such as HIV and HCV have resulted in the growing importance of resistance management in antiviral therapy. Also, viral latency in cellular comportments or tis- sues not reachable by antiviral drugs may lead to chronic infections and residual viremia even if the virus is present at undetectably low viral plasma loads.(26)
Three prominent strategies have been proposed for counteract- ing the emergence of viral drug resistance: first, drug combination therapies that increase the genetic barrier of the therapy against upcoming drug resistance by requiring the virus to develop escape mutations against two or more drugs with different mechanisms of action.(27) Second, methodologies of personalized medicine that afford insight in particularities of the viral and host genomes, re- spectively, in order to select drugs that maximize therapy success at any point in therapy.(28) Third, targeting host factors that are essential for viral infection or replication and may be associated with reduced emergence of resistance. The latter strategy will be discussed here in detail while the other two approaches, combina- tion therapies and personalized therapies, will be discussed at some greater detail in ChapterIV.
Advantages of drugs targeting host factors. Basic research on essen- tial host factors that are targeted by viral pathogens has lead to the development of several new compounds especially against highly diverse pathogens such as RNA viruses that rapidly acquire drug resistance. In contrast to therapeutic compounds that target viral factors and that may lose efficacy due to the emergence of resis- tance mutations in the viral genome, host factors are typically well conserved and can not be mutated by viral evolutionary processes. In addition, targeting host factors significantly increases the viable antiviral drug targets from about 10 proteins encoded in RNA-viral proteins to the larger number of virally accessed host factors, some of which may be relevant for other diseases and may thus have known inhibitors.
An especially interesting class of host proteins in this regard are bridge proteins, i.e., proteins that have a low number of binding partners but act as a common component for many host pathways. Such bridge proteins are selectively attacked by several classes of viruses and may therefore constitute factors essential for viral replication.(29) However, since these bridge proteins are also likely to be important factors for the host cell, their inhibition may cause unwanted side effects that may or may not surpass side effects of existing antivirals that target viral factors.
146 from basic research to clinical applications
(30)Bushman et al.(2009),König et al.
(2010,2008),Li et al.(2009b),Murali et al.
(2011)
(31)de Chassey et al.(2012a),Meyniel-
Schicklin et al.(2012)
(32)de Chassey et al.(2012b)
(33)Fätkenheuer et al.(2008)
(34)Garbelli et al.(2011),Geller et al.
(2007),Hopkins et al.(2010),Kumar et al.
(2011b)
(35)Chatterji et al.(2010),Delang et al.
(2011),Kwong et al.(2011)
(36)Dragic et al.(2000),Edinger et al.
(1997),Gorry and Ancuta(2011),Jones et al.(1998)
(37)Ogert et al.(2010),Pugach et al.(2007)
(38)Delobel et al.(2005),Regoes and
Bonhoeffer(2005)
(39)Fätkenheuer et al.(2008),Parra et al.
(2010)
(40)Fätkenheuer et al.(2008),Mosier(2009)
(41)Hung et al.(1999),Jensen and van ’t
Wout(2002),Schuitemaker et al.(2010),
Thielen et al.(2010)
The search for druggable host factors has identified several suitable targets with respect to HIV, HCV, and influenza infec- tion.(30)Interestingly, up to 20% of all experimentally identified viral host factors across experimental studies belong to a common set of human pathways, a fact that may firstly allow for the development of broad spectrum antivirals.(31) Only 10 of the more than 50 FDA- approved antiviral compounds target host factors and none of these compounds has been especially developed for broad efficacy;(32) however, some of the most successful FDA approved inhibitors such as the HIV antiviral Maraviroc exhibit favourable pharma- cokinetic and safety profiles, indicating that host factor targeting drugs are not necessarily paralleled by strong side effects.(33) In ad- dition, supplementary approaches for using host factors to increase therapeutic efficacy exist; as touched upon previously, at least two indirect acting antiviral compounds, interferon and ribavirin, in- crease the natural antiviral host response.
Limitations of host factor antivirals. Although host factor target- ing medicines have been shown to be effective in many different settings,(34)they may not be the golden bullet either. While viruses cannot directly prevent antivirals from binding to host factors, adaption of viral binding interfaces by mutation and selection may result in differential usage of host factors and consequent loss of drug efficacy. This is exemplified by recent results concerning HCV that have demonstrated how alternative use of host factors may result in resistance to the cyclophilin inhibitor SCY-635.(35)
Similarly, HIV-1 is also able to circumvent drugged host fac- tors: immunodeficiency viruses employ host chemokine receptors such as as CXCR4 or CCR5 as cofactors for viral entry that are tar- geted by drugs in highly active antiretroviral therapy (HAART).(36) Treatment with these drugs may result in mutations of viral glyco- proteins that are associated with a shift in viral coreceptor usage or by viral adaption to the inhibitor bound coreceptor, both of which result in drug resistance.(37)
While this switch in coreceptor usage may partly reflect the normal evolution of HIV-1,(38)and the reported levels of drug resis- tance are comparably low and affect only a minority of patients,(39) HIV resistance to host factor drugs is still considered an important contributing factor to therapy failure.(40) As a result, determination of viral host tropism profiles based on sequencing has significant clinical consequences and is commonly used to inform therapy decisions.(41)
an introduction to antivirals 147
(42)Fox(2007),Huthoff and Towers(2008),
Miller et al.(2008)
(43)Chen and Dimitrov(2012),Hu and
Robinson(2010),Zeller and Kumar(2011)
(44)Fox(2007),Holt et al.(2010),Huthoff
and Towers(2008),Lim and Murphy
(2011),Miller et al.(2008),Reeves et al.
(2005)
(45)Amara et al.(2001),Bacon et al.(2009),
Chen and Dimitrov(2012),Ivacik et al.
(2011)
(46)Lingappa et al.(2012),Rider et al.
(2011)
Future antivirals. Based on the successes of broadly acting drugs, the drug-induced activation of host enzymes associated with the innate immune systems such as APOBEC, TRIM, and toll-like re- ceptors (TLRs) are considered to be an interesting approach to broadly and indirectly acting antivirals.(42) Also, novel compounds that do not target host factors but represent orthogonal approaches to attacking viral factors are under active development. These ap- proaches include broadly acting antibodies and RNAi technologies whose therapeutic potential against HCV, HBV, HIV, and highly ag- gressive viruses such as Marburg virus and Ebola virus is currently explored.(43)
Current antiviral therapy is mainly aimed at lowering viral load in order to limit symptoms of the disease and facilitate immune clearance. In addition, low viral loads implicitly reduce the abun- dance and thus the diversity of the viral infections, thus reducing the viral adaptability to future interventions such as antiviral ther- apy. As will be discussed in more detail in ChapterIV, combination therapy is successful in increasing the overall genetic barrier of the treatment especially if the drugs employed have orthogonal modes of action and, as a consequence, feature differing pathways to re- sistance. However, ongoing low-level replication, mutation, and selection within highly adaptive viral species will commonly result in development of multi-drug resistant variants and thus therapy failure.
If antiviral compounds currently under development are a sign of things to come, then the antiviral drugs of the next two decades may increasingly focus on host factors instead of on viral factors as drug targets. While the control of side effects of these drugs re- mains an important goal, the potential for repurposing existing drugs that already target host factors, the promise of reduced drug resistance, and the potential of host factor targeting drugs to act as broad-spectrum antivirals makes the development of these com- pounds attractive endeavours.(44)
In addition, and in accordance with general trends in the phar- maceutical industry, the importance of biologicals such as anti- bodies, RNAi, vaccines, and synthetic interferons is also likely to increase.(45) Although significantly more expensive to produce than small molecule inhibitors and facing additional pharmacokinetic constrains, biologicals often have proven effectiveness in the host as confirmed by basic research, have high specificity towards one or multiple closely related pathways, and have important competitive advantages such as being harder to reproduce as generics. Exam- ples for this development are early-stage broad-spectrum antivirals that employ biologicals to emulate intracellular apoptotic control circuits or inhibit viral maturation by blocking capsid assembly on a broad range of viruses.(46)
(1)Aloy and Russell(2002),Gingras and
Raught(2012),Gonzalez and Kann(2012)
(2)Ideker and Sharan(2008),Kann(2007)
(3)Eisenberg et al.(2000)