Abstract
Herpes simplex virus type 2 (HSV-2) is currently the leading cause of Genital Ulcer Disease (GUD) both globally and within South Africa. HSV-2 infections are most often treated with acyclovir (ACV), a guanosine nucleoside analogue that requires phosphorylation by virus-encoded thymidine kinase (TK). Resistance to ACV is mainly due to mutations in the viral UL23 gene that codes for TK. ACV was added as part of the first-line syndromic management treatment algorithm for GUD in South Africa in late 2008. In order to assess the prevalence of TK-associated ACV resistance among HSV-2 virions detected in genital ulcer specimens, pre- and post-introduction of ACV, we amplified and fully sequenced the UL23 gene of 254 HSV-2 positive specimens obtained from participants in GUD aetiological surveys conducted between 2007 and 2011 in Johannesburg, South Africa. We identified 63 nucleotide mutations in the UL23 genes analysed, that resulted in 30 silent mutations and 32 amino acid changes. A large proportion (41%) of these amino acid changes were due to previously described natural polymorphisms that occur in both sensitive and resistant HSV strains. In addition, we identified 19 unknown amino acid changes in 30 samples that have not been described before. All mutations detected were outside the recognised TK conserved domains where ACV resistance mutations typically occur. No frameshift mutations or mutations causing stop codons were identified in those UL23 genes analysed. Importantly, no evidence was found of known ACV resistance mutations in HSV-2 following the addition of ACV as first-line therapy for GUD.
Highlights
Herpes simplex virus type 2 (HSV-2) is the leading cause of genital ulcer disease (GUD) in sub-Saharan Africa where, in the general adult population, anti-HSV-2 IgG seroprevalence may range from 30 to 80% in women and from 10 to 50% in men [1]
In this paper we described some of the known polymorphism mutations as well as novel mutations identified in the UL23 gene of HSV-2 from HSV-2 positive ulcer swabs collected as part of the NMS programme
Due to the number of mutations that have been described in the UL23 genes of HSV isolates, it is sometimes difficult to differentiate between natural polymorphism and resistance mutations, especially when no previous isolate from the same individual was available for comparison after ACV therapy
Summary
Herpes simplex virus type 2 (HSV-2) is the leading cause of genital ulcer disease (GUD) in sub-Saharan Africa where, in the general adult population, anti-HSV-2 IgG seroprevalence may range from 30 to 80% in women and from 10 to 50% in men [1]. After primary infection and replication, HSV-2 establishes latency in the sensory nerve ganglia, from where it can re-activate later in life [2]. HSV-2 infections are usually self-limited but can cause major complications in immunocompromised individuals [3]. ACV, an inactive prodrug, is phosphorylated to its monophosphate form by virusencoded thymidine kinase (TK) and twice phosphorylated by cellular thymidilate kinases, resulting in the active triphosphate ACV form. Active ACV is a competitive inhibitor of viral DNA polymerase, competing with the natural nucleotide, deoxyguanosine triphosphate (dGTP), resulting in the cessation of viral replication by means of chain termination [5]
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