A HIV-Tat/C4-binding protein chimera encoded by a DNA vaccine is highly immunogenic and contains acute EcoHIV infection in mice

Abstract

DNA vaccines are cost-effective to manufacture on a global scale and Tat-based DNA vaccines have yielded protective outcomes in preclinical and clinical models of human immunodeficiency virus (HIV), highlighting the potential of such vaccines. However, Tat-based DNA vaccines have been poorly immunogenic, and despite the administration of multiple doses and/or the addition of adjuvants, these vaccines are not in general use. In this study, we improved Tat immunogenicity by fusing it with the oligomerisation domain of a chimeric C4-binding protein (C4b-p), termed IMX313, resulting in Tat heptamerisation and linked Tat to the leader sequence of tissue plasminogen activator (TPA) to ensure that the bulk of heptamerised Tat is secreted. Mice vaccinated with secreted Tat fused to IMX313 (pVAX-sTat-IMX313) developed higher titres of Tat-specific serum IgG, mucosal sIgA and cell-mediated immune (CMI) responses, and showed superior control of EcoHIV infection, a surrogate murine HIV challenge model, compared with animals vaccinated with other test vaccines. Given the crucial contribution of Tat to HIV-1 pathogenesis and the precedent of Tat-based DNA vaccines in conferring some level of protection in animal models, we believe that the virologic control demonstrated with this novel multimerised Tat vaccine highlights the promise of this vaccine candidate for humans.

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

“…The reason for this unexpected result remains unclear. However, sIgA was not detected in any animals vaccinated 3X pVAX-Gag-Tat at any time point; this was not surprising as we have previously shown that a minimum of 5 doses is required for a Tat DNA vaccine to elicit detectable mucosal sIgA25.…”

“…4A), additional markers which appear to correlate with control of HIV in humans1133 and SIV in animals3443. Although we did not assess functionality of the Tat-specific antibodies in terms of anti-Tat neutralization, a previous study conducted in our laboratory indicated that intradermal vaccination with pVAX-sTat-IMX313, one of the vaccines used in the regimens of this study, elicited antibodies with Tat neutralization activity that correlated with control of EcoHIV25. Surprisingly, Tat-specific sIgA was detected in CVL samples from rHRV-DNA vaccinated animals only after the DNA boost (Fig.…”

“…We previously showed that vaccination of mice with 3 doses of pVAX-Gag-PRF elicited broad, poly-functional Gag-specific CMI able to control EcoHIV after challenge24, and that vaccination with pVAX-sTat-IMX313 elicited high titre anti-Tat responses that also controlled EcoHIV infection post challenge25. Moreover, Tat shows adjuvant activities and the ability to broaden CTL responses without affecting Th2 responses when included together Gag- or Env-based HIV vaccines2627.…”

“…Plasmids encoding HIV Gag and perforin (PRF) (pVAX-Gag-PRF) or HIV Tat fused to the oligomerisation domain of the C4b-p (pVAX-sTat-IMX313) have been described recently2425. Briefly, the HIV gag and PRF genes were inserted downstream of the CMV and SV40 promoters, respectively, to generate pVAX-Gag-PRF24.…”

“…Briefly, the HIV gag and PRF genes were inserted downstream of the CMV and SV40 promoters, respectively, to generate pVAX-Gag-PRF24. To generate pVAX-sTat-IMX313, the human tissue plasminogen activator leader sequence and the oligomerisation domain of C4b-p (IMX313) were introduced at the N- and C-termini respectively of the HIV tat gene25.…”