Distribution and effects of amino acid changes in drug-resistant α and β herpesviruses DNA polymerase

Abstract

Emergence of drug-resistance to all FDA-approved antiherpesvirus agents is an increasing concern in immunocompromised patients. Herpesvirus DNA polymerase (DNApol) is currently the target of nucleos(t)ide analogue-based therapy. Mutations in DNApol that confer resistance arose in immunocompromised patients infected with herpes simplex virus 1 (HSV-1) and human cytomegalovirus (HCMV), and to lesser extent in herpes simplex virus 2 (HSV-2), varicella zoster virus (VZV) and human herpesvirus 6 (HHV-6). In this review, we present distinct drug-resistant mutational profiles of herpesvirus DNApol. The impact of specific DNApol amino acid changes on drug-resistance is discussed. The pattern of genetic variability related to drug-resistance differs among the herpesviruses. Two mutational profiles appeared: one favoring amino acid changes in the Palm and Finger domains of DNApol (in α-herpesviruses HSV-1, HSV-2 and VZV), and another with mutations preferentially in the 3′-5′ exonuclease domain (in β-herpesvirus HCMV and HHV-6). The mutational profile was also related to the class of compound to which drug-resistance emerged.

Selected nucleos(t)ide-based prescribed drugs and their multi-target activity

“…Brivudine (BVDU, 5-[2-bromovinyl]-2′-deoxyuridine), similar to idoxuridine, is a 5-substituted thymidine analogue approved as a drug for use against a wide range of herpesviruses. Brivudine is highly specific against HSV-1 and VZV; however, it does not show activity against HSV-2 (Topalis et al, 2016). This drug is widely available in Europe, except the United Kingdom, and many other countries, except the United States (De Clercq, 2004;Andrei et al, 2005).…”

The impact of interspecies recombination on human herpes simplex virus evolution and host immune recognition

“…This critical domain interacts with double-stranded DNA as it leaves the catalytic center of the enzyme. Though none of the 23 residues affected by the recombination event have been associated with drug resistance to date, 21.5% of drug-resistance (acyclovir, penciclovir, foscarnet, cidofovir) mutations identified in the HSV-1 DNA polymerase are in the thumb domain (Sauerbrei et al, 2016; Topalis et al, 2016).…”

“…Indeed, this process may be accelerating as rare genotypes, such as the NR genotypes at UL29 and UL30, are shuffled around the world by globalization. The potential for rapid creation of new genotypes through recombination at these loci is perhaps most concerning at the UL30 locus, as the region of the gene were HSV-1 sequence is commonly observed is also where about 20% of all described drug resistance mutations in UL30 are located (Sauerbrei et al, 2016; Topalis et al, 2016).…”

Guanine α-carboxy nucleoside phosphonate (G-α-CNP) shows a different inhibitory kinetic profile against the DNA polymerases of human immunodeficiency virus (HIV) and herpes viruses

“…The majority of these drugs are nucleoside analogues for which the virus-encoded DNA and RNA polymerases are the prime targets for the inhibition of virus replication. Indeed, a variety of nucleoside analogues efficiently inhibit the herpes DNA polymerases encoded by herpes simplex virus type 1 and type 2 (2), varicella zoster virus (VZV) (2, 3) and human cytomegalovirus (HCMV) (2, 4), the reverse transcriptase of retroviruses such as HIV-1 and HIV-2 (5), the DNA polymerase of hepatitis B virus (6), as well as the RNA polymerases specified by several RNA viruses such as respiratory syncytial virus (7), influenza viruses (8), and also flaviruses as exemplified by hepatitis C virus (9, 10). Such inhibitors need to be activated (phosphorylated) by virus-encoded kinases or by cellular nucleoside/nucleotide kinases to their 5′-triphosphate derivatives, or in case of the acyclic nucleoside phosphonates to their diphosphate derivatives before these nucleoside/nucleotide analogues can be recognized by the viral DNA or RNA polymerases (1–10).…”

“…Such inhibitors need to be activated (phosphorylated) by virus-encoded kinases or by cellular nucleoside/nucleotide kinases to their 5′-triphosphate derivatives, or in case of the acyclic nucleoside phosphonates to their diphosphate derivatives before these nucleoside/nucleotide analogues can be recognized by the viral DNA or RNA polymerases (1–10). The nucleoside analogues are often incorporated in the growing viral DNA or RNA chain, and function as chain terminators (2, 5). Instead, several non-nucleoside derivatives have also been discovered to act against viral polymerases, either at a non-substrate active site of the enzyme [such as the non-nucleoside RT inhibitor (NNRTI) interaction with HIV-1 RT] (11–13) or at the substrate-active site of the RT enzyme [such as the nucleotide-competing RT inhibitor (NcRTI) (i.e.…”