An Attenuated Herpes Simplex Virus Type 1 (HSV1) Encoding the HIV-1 Tat Protein Protects Mice from a Deadly Mucosal HSV1 Challenge

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.

The HIV-1 Tat protein affects human CD4+ T-cell programing and activation, and favors the differentiation of naïve CD4+ T cells

“…In addition, Tat increased the expansion and differentiation of naïve CD4 þ T cells activated in NPC. These findings, together with the observations made in CD8 þ T cells [15,16,28], confirm that Tat plays an important role in the hyperactivation of the T-cell compartment, a phenomenon characterizing the progression to AIDS and possibly the residual disease observed in successfully ART-treated individuals [29,30].…”

Mucosal vaccination with a live recombinant rhinovirus followed by intradermal DNA administration elicits potent and protective HIV-specific immune responses

“…To further support our hypothesis, Gavioli et al demonstrated previously that including Tat in a multi-antigenic vaccine enhanced the magnitude and broadened Gag- and Env-specific T cell responses without affecting the quality of the Th2 responses27. Furthermore, the inclusion of Tat in a candidate vaccine against Herpes Simplex Virus type 1 (HSV-1) enhanced the induction of broad, high magnitude effector memory HSV-1 specific CD 8 T cell responses49 that completely protected mice after a lethal intravaginal challenge with wild type HSV-14950 HSV-1. Collectively, this evidence supports the inclusion of Tat as a component of a multi antigenic vaccine and implies that the rHRV-DNA vaccination regimen reported here, that contains Tat and Gag as immunogens, will most likely be highly immunogenic.…”

HPV-Specific Systemic Antibody Responses and Memory B Cells are Independently Maintained up to 6 Years and in a Vaccine-Specific Manner Following Immunization with Cervarix and Gardasil in Adolescent and Young Adult Women in Vaccination Programs in Italy

“…at 37 • C [33]. The optical density at 620 nm was determined with "Sunrise optical reader" (Tecan) and then analyzed as previously described [34,35]. For each type-specific VLP, the cut-off values were determined by analyzing the plasma of 24 unvaccinated healthy donors at 1:100 dilution as the mean OD (±3 SD): 0.374 for HPV-16; 0.346 for HPV-18; 0.388 for HPV-6; and, 0.346 for HPV-11.…”