Attenuated Phenotype and Immunogenic Characteristics of a Mutated Herpes Simplex Virus 1 Strain in the Rhesus Macaque

Abstract

Herpes simplex virus type 1(HSV-1) presents a conundrum to public health worldwide because of its specific pathogenicity and clinical features. Some experimental vaccines, such as the recombinant viral glycoproteins, exhibit the viral immunogenicity of a host-specific immune response, but none of these has achieved a valid epidemiological protective efficacy in the human population. In the present study, we constructed an attenuated HSV-1 strain M3 through the partial deletion of UL7, UL41, and the latency-associated transcript (LAT) using the CRISPR/Cas9 system. The mutant strain exhibited lowered infectivity and virulence in macaques. Neutralization testing and ELISpot detection of the specific T-cell responses confirmed the specific immunity induced by M3 immunization and this immunity defended against the challenges of the wild-type strain and restricted the entry of the wild-type strain into the trigeminal ganglion. These results in rhesus macaques demonstrated the potential of the attenuated vaccine for the prevention of HSV-1 in humans.

Reducing Viral Inhibition of Host Cellular Apoptosis Strengthens the Immunogenicity and Protective Efficacy of an Attenuated HSV-1 Strain

“…In these works, the UL7 gene was identified as being related to viral genomic transcriptional regulation, and its modification led to an attenuated viral phenotype (Xu et al 2016). Furthermore, the UL41 and LAT genes were also modified in the UL7-mutated strain, and the associated phenotype was identified in cell culture, mice, or macaques; compared with the WT strain, the mutant strain (M3) containing modified UL7, UL41 and LAT genes showed reduced proliferation in cell culture and asymptomatic infection in mice or macaques (Xu et al 2017b;Fan et al 2018). However, a study of M3 indicated that fewer copies of viral genomic DNA were detected in the trigeminal ganglion of infected animals by qPCR, and M3infected mice were even found to be capable of defending against WT challenge with an asymptomatic outcome.…”

“…The experiment not only discerned that proteins encoded by the UL7 gene are capable of regulating viral genome transcription but also provided an attenuated strain with mutated UL7, UL41 (encoding the Vhs protein), and LAT genes (Xu et al 2016). This mutant M3 virus showed an attenuated phenotype in mice and rhesus macaques, with asymptomatic infection in the animals and a lower viral load in various organs, especially in the nervous system (Xu et al 2017a;Fan et al 2018). Importantly, the infected animals were observed to show protection against wildtype challenge (Xu et al 2017b).…”

Traditional Chinese Medicine as a Potential Source for HSV-1 Therapy by Acting on Virus or the Susceptibility of Host

“…Since no suitable drug is available for the treatment of latent HSV-1 infection in clinics yet, searching for strategies based on the prevention of transmission, suppression of reactivation, and viral shedding together with inhibition of epithelial damage is an effective measure to get out of the predicament of drug research and development against HSV-1. Moreover, some mutated HSV-1 strains produced by the CRISPR/Cas9 system could be potential vaccines in full swing for the prevention of HSV-1 in humans [ 91 , 92 ].…”

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“…This could be the most viable option of closing the gap of immunity. The bottleneck is to develop a technology for easily targeting multiple components, and fortunately, the Cas gene editing tools provide a fresh air in the vaccine field 134. CRISPR/Cas has enabled the possibility of quick diagnosis of multiple pathogens 135.…”

“…The bottleneck is to develop a technology for easily targeting multiple components, and fortunately, the Cas gene editing tools provide a fresh air in the vaccine field. 134 CRISPR/Cas has enabled the possibility of quick diagnosis of multiple pathogens. 135 We may soon see more effective vaccines or preventive weapons being developed with improved CRISPR-Cas technology.…”