Viral Vector Expressing Tat As Immunomodulatory Molecule Represent A New Vaccine Strategy Against HSV Infection

Herpes simplex viruses type 1 and 2 (HSV1 and HSV2) are common infectious agents in both the industrialized and developing countries causing asymptomatic or symptomatic recurrent infections, and very severe diseases and death in newborns and immunocompromised patients. Current HSV treatment involves the use of antiviral medications, which can halt the symptomatic diseases but cannot avoid the asymptomatic shedding and, consequently, the spreading of the viruses among people. Therefore, prevention of HSV infections has been an area of intense research especially for the development of preventative and therapeutic anti-HSV vaccines. Nevertheless, this goal has not been achieved yet. One of the key points in developing anti-HSV vaccines is the identification and use of strategies promoting the emergence of Th1-type immune responses, not only, against dominant epitopes but also against subdominant epitopes that are crucial to control the virus. Since, it has been shown that HIV1 Tat protein possesses several immunomodulatory activities and increases CTL recognition directed to subdominant epitopes of heterologous antigens, a recombinant attenuated replication-competent HSV1 vector containing the tat gene (HSV1-Tat) was generated and assayed as a novel vaccine candidate in murine models. We have demonstrated that immunization with this attenuated replication-competent HSV-Tat vector confers protection in 100% of mice challenged intravaginally with a lethal dose of wild-type HSV1. The expression of Tat by the recombinant virus is able to increase and broad Th1-like and CTL responses against immunodominant and subdominant HSV-derived T cell epitopes and to elicite detectable IgG responses. In contrast, a control attenuated HSV1 recombinant vector without Tat (HSV1-LacZ) induces lower T cell responses, directed only against the immunodominant epitopes, in absence of measurable antibody responses and does not protect mice from challenge with wild-type HSV1. Therefore, our data suggest that recombinant HSV1 vectors expressing Tat may be further investigated as vaccine candidates against HSV1 infection to prevent and/or contain virus infection and dissemination