VACCINES: VACCINE RELATED GENE TRANSFER RESEARCH 165. A Lentiviral HIV Vaccine Candidate Elicits Long-Term Humoral and Cellular HIV-Speci c Immunity and Minimal Neutralizing Activity

Recombinant viral vectors are considered one of the major means for induction of strong immune responses against recombinant antigens by genetic immunization. Recently developed viral-vectored HIV vaccine candidates, despite achieving high levels transgene expression and inducing high magnitude immune responses to HIV, have faced limitations related to anti-vector immunity. In contrast, lentiviral vectors (LV) have been shown to be less sensitive to antivector neutralizing activity, while displaying desirable characteristics such as transduction of non-dividing cells, including antigenpresenting cells, and long-term transgene expression. We have developed a VSV-G-pseudotyped HIV-based lentiviral vaccine candidate, VRX1023, carrying unmodi ed HIV Gag, Pol and Rev genes derived from the HIV-1 NL4-3 strain and which expression is driven by the wild-type HIV LTR. In mice, this vector was shown to induce signi cant mucosal and systemic cellular and humoral responses against HIV after sub-cutaneous injection. In the present study, we investigated the ability of this vector to confer durable HIV-speci c immunogenicity for a time period of up to 1 year in the murine model. HIV-speci c immunity was tested in splenocytes from immunized animals, at various timepoints over a 12 month period postimmunization, by IFN-g Elispot. Gag and Pol-specific T-cell responses, assessed after stimulation with overlapping HIV-peptides, were sustained in the range of 800 spot forming units/million cells on average for over a year with no diminution over time. Rev-speci c immunity, although detected at lower levels, was also sustained, for up to 6 months post-immunization. Gag p24-speci c IgG levels could be detected at remarkably consistent levels from 2 weeks to 12 months post-vector administration. LV-speci c humoral immunity, speci cally targeted towards the VSV-G pseudotyping protein, was detected at high level throughout the course of the study, but was found to have minimal neutralizing activity. LV was successfully repeatedly administered without any marked increase of anti-vector neutralizing activity. In summary, VRX1023 represents a highly attractive HIV vaccine candidate that combines long-term immunogenicity with the ability to elicit weak host neutralizing activity despite repeated immunizations. VRX1023, in addition to competing favorably with existing vectors for anti-HIV immune responses, demonstrates unique features likely to address some of the pitfalls of current vector-based HIV vaccine strategies.