Abstract
Herpes Simplex Virus type-1 (HSV-1) and type-2 (HSV-2) establish life-long infections and cause significant orofacial and genital infections in humans. HSV-1 is the leading cause of infectious blindness in the western world. Currently, there are no available vaccines to protect against herpes simplex infections. Recently, we showed that a single intramuscular immunization with an HSV-1(F) mutant virus lacking expression of the viral glycoprotein K (gK), which prevents the virus from entering into distal axons of ganglionic neurons, conferred significant protection against either virulent HSV-1(McKrae) or HSV-2(G) intravaginal challenge in mice. Specifically, 90% of the mice were protected against HSV-1(McKrae) challenge, while 70% of the mice were protected against HSV-2(G) challenge. We constructed the recombinant virus VC2 that contains specific mutations in gK and the membrane protein UL20 preventing virus entry into axonal compartments of neurons, while allowing efficient replication in cell culture, unlike the gK-null virus, which has a major defect in virus replication and spread. Intramuscular injection of mice with 107 VC2 plaque forming units did not cause any significant clinical disease in mice. A single intramuscular immunization with the VC2 virus protected 100% of mice against lethal intravaginal challenge with either HSV-1(McKrae) or HSV-2(G) viruses. Importantly, vaccination with VC2 produced robust cross protective humoral and cellular immunity that fully protected vaccinated mice against lethal disease. Quantitative PCR did not detect any viral DNA in ganglionic tissues of vaccinated mice, while unvaccinated mice contained high levels of viral DNA. The VC2 virus may serve as an efficient vaccine against both HSV-1 and HSV-2 infections, as well as a safe vector for the production of vaccines against other viral and bacterial pathogens.
Highlights
Genital herpes has a very high global prevalence and disease burden
The VC2 recombinant virus was constructed utilizing the twostep double-Red recombination protocol implemented on the cloned Herpes Simplex Virus type-1 (HSV-1)(F) genome [55] in a bacterial artificial chromosome (BAC) plasmid [56], as we have described previously [57,58], and detailed in the Materials and Methods section
The VC2 virus contains the gKD31-68 deletion (37 aa; glycoprotein K (gK) aa 31–68) in the amino terminus of gK that prevents the virus from entering into ganglionic neurons after infection via the ocular route [55], as well as a deletion of the amino-terminal 19 amino acids of the UL20 virus (Fig. 1A)
Summary
Genital herpes has a very high global prevalence and disease burden. Recent seroprevalence studies for the years 2005–2010 indicate that 1 out of 2 adults in the United States ages 14–49 years old are latently infected with herpes simplex type-1 (HSV1) [1]. A successful vaccination strategy against HSV-2 infection is predicted to have a dramatic global impact on HIV spread, prevention of genital clinical disease and neonatal infections [14,15,16]. Tissue specific CD4+ and CD8+ T cells are crucial for controlling HSV infections and clearing the virus after initial infection. These T cell responses are important in containing the virus in a latent state in ganglionic or dorsal neurons, as well as for controlling the virus after reactivation from latency [18,19,20,21,22,23,24]. Humoral responses have been implicated in playing an important role in controlling HSV infectivity, spread, and the rate of reactivation from latency [25,26,27]
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