Abstract
Herpes simplex virus types 1 and 2 (HSV1 and HSV2) are common infectious agents in both industrialized and developing countries. They cause recurrent asymptomatic and/or symptomatic infections, and life-threatening diseases and death in newborns and immunocompromised patients. Current treatment for HSV relies on antiviral medications, which can halt the symptomatic diseases but cannot prevent the shedding that occurs in asymptomatic patients or, consequently, the spread of the viruses. Therefore, prevention rather than treatment of HSV infections has long been an area of intense research, but thus far effective anti-HSV vaccines still remain elusive. One of the key hurdles to overcome in anti-HSV vaccine development is the identification and effective use of strategies that promote the emergence of Th1-type immune responses against a wide range of epitopes involved in the control of viral replication. Since the HIV1 Tat protein has several immunomodulatory activities and increases CTL recognition of dominant and subdominant epitopes of heterologous antigens, we generated and assayed a recombinant attenuated replication-competent HSV1 vector containing the tat gene (HSV1-Tat). In this proof-of-concept study we show that immunization with this vector conferred protection in 100% of mice challenged intravaginally with a lethal dose of wild-type HSV1. We demonstrate that the presence of Tat within the recombinant virus increased and broadened Th1-like and CTL responses against HSV-derived T-cell epitopes and elicited in most immunized mice detectable IgG responses. In sharp contrast, a similarly attenuated HSV1 recombinant vector without Tat (HSV1-LacZ), induced low and different T cell responses, no measurable antibody responses and did not protect mice against the wild-type HSV1 challenge. These findings strongly suggest that recombinant HSV1 vectors expressing Tat merit further investigation for their potential to prevent and/or contain HSV1 infection and dissemination.
Highlights
Worldwide prevalence of the herpes simplex virus (HSV) infection remains high, making it a major public health concern
The HSV type 1 (HSV1)-LacZ virus was generated by homologous recombination between wild-type HSV1 and the pB41-lacZ plasmid containing the lacZ marker gene, under the control of the ICP0 immediate early promoter of HSV inserted in the UL41 gene of HSV1 [53,54]
Uninfected cells and cells infected with wild-type HSV1 and HSV1-LacZ viruses were used as negative controls, and the recombinant Tat protein was used as positive control
Summary
Worldwide prevalence of the herpes simplex virus (HSV) infection remains high, making it a major public health concern. Chiron and GlaxoSmithKline vaccine candidates based on recombinant HSV envelope glycoproteins have failed to show efficacy [21,22] This has prompted researchers to increase their efforts to define immune correlates of protection and new vaccination strategies able to induce protective immunity [8,19,20,23]. Previous in vitro (B, T and dendritic cells) and in vivo (mice, nonhuman primates and humans) evidence indicates that the Tat protein, in addition to being a safe and relevant HIV vaccine antigen, possesses several immunomodulatory features that could make it suitable for new vaccination strategies and therapeutic interventions aimed at modulating antigen-specific immune responses in various human diseases [36]. Tat possesses an intrinsic adjuvanticity, attributed to its dimerization capacity [42], increases the number of regulatory T-cells (Treg) [43], promotes the activation of virusspecific CTLs [44], and induces protective immunity against Leishmania major [45]
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