Outcome of Immunization of Cynomolgus Monkeys with Recombinant Semliki Forest Virus Encoding Human Immunodeficiency Virus Type 1 Envelope Protein and Challenge with a High Dose of SHIV-4 Virus

Abstract

Infection of macaques with chimeric simian-human immunodeficiency viruses (SHIVs) allows evaluation of HIV-1 envelope vaccines. SHIV-4 is based on SIVmac239 but carries the env, tat, and rev genes of HIV-1IIIB. In this study we used Semliki Forest virus (SFV) RNA vectors to express the envelope protein gp160 of HIV-1IIIB in cynomolgus macaques. Monkeys were immunized four times with recombinant suicide SFV. Whereas two of four monkeys showed T cell-proliferative responses, only one monkey had demonstrable levels of antibodies to HIV-1 gp41 and gp120 as shown by enzyme-linked immunosorbent assay (ELISA) and Western blot. The vaccinated monkeys and four control animals were challenged with 10,000 MID100 (100% minimum infectious doses) of cell-free monkey cell-grown SHIV-4 virus. As demonstrated by virus isolation, all macaques became infected after challenge. All vaccinated monkeys showed an HIV-1-specific anamnestic T cell-proliferative response. Three of four vaccines had developed HIV-1-Env-specific antibodies 2 weeks after challenge whereas none of the four controls showed any detectable immune response at this time point. Furthermore, three of four vaccinated monkeys had no demonstrable viral antigenemia and low viral load as opposed to one of the four naive control animals.

Immunization strategy against cervical cancer involving an alphavirus vector expressing high levels of a stable fusion protein of human papillomavirus 16 E6 and E7

“…40 Several murine and primate studies have demonstrated the efficacy as well as the biosafety of the SFV vector system. 5,15,17,32,[41][42][43] Thus far the SFV vector system has not been evaluated in humans. With respect to the potential oncogenicity of E6 and E7, it should be noted that cellular transformation requires the constitutive expression of both proteins.…”

Genetic immunization against cervical carcinoma: induction of cytotoxic T lymphocyte activity with a recombinant alphavirus vector expressing human papillomavirus type 16 E6 and E7

“…This promising result, combined with studies showing the high efficacy of the SFV system for priming the immune system of mice as well as primates, 29,35,36 and the recent development of the extremely safe two-helper system 37 provide the essential steps towards the design of an effective immunization strategy for the treatment and prophylaxis of HPV-induced cervical carcinoma. …”

Replication-defective recombinant Semliki Forest virus encoding GM-CSF as a vector system for rapid and facile generation of autologous human tumor cell vaccines

“…25 In primates it has been shown that SFV vectors encoding envelope glycoproteins of simian immunodeficiency virus (SIV) could protect monkeys against a lethal SIV challenge 26 and that human immunodeficiency virus-1 (HIV-1) envelope vaccines (based on SFV) induced B and T cell responses and modified challenge-virus replication. 27 The SFV expression system is based on the availability of an infectious clone of the virus. RNA transcripts produced in vitro from this clone (plasmid pSP6-SFV4, containing a cDNA copy of the full-length viral genome), direct virus replication when introduced into cells by, for example, electroporation.…”