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102 HIV-1 Vpr Gene Suppresses Immune Responses in Vitro and in Vivo
K. Muthumani*1, D. Zhang1, S. Kudchodkar1, N. Dayes1, D. S. Hwang1, V. Ayyavoo2, and D. B. Weiner1
Univ. of Pennsylvania, Philadelphia, USA and 2Univ. of Pittsburgh, PA, USA
HIV-1 Vpr is a virion-associated gene product that profoundly affects T-cell proliferation, induces apoptosis, and can affect cytokine production in part through interfering with NF-kappaB-mediated transcription from host cells. Here we examined the effect of Vpr expression in an in vivo and in vitro model system on the induction of antigen-specific immune responses. Plasmid vpr covaccination significantly altered the immune response to codelivered plasmid antigen. Specifically, in the presence of Vpr, inflammation was markedly reduced compared with antigen alone. Vpr reduced antigen-specific CD8-mediated cytotoxic T-lymphocyte (CTL) activity and suppressed Th1 immune responses in vivo as evidenced by lower levels of IFN-gamma.
To further examine this property of Vpr we have created an engineered adenovirus H5.010CMV-VPR to deliver the vpr gene product to immune cells. The effect of this virus on the immune response was studied. After adenoviral infection, culture supernatants from infected PBMCs were analyzed for chemokine and cytokine production. A greater than 50% decreases in MIP-1alpha, and over 90% suppression of MIP-1beta and RANTES induction was observed in the Vpr-infected group. We also observed similar impressive suppression of the production of TNF-alpha and IFN-gamma. Furthermore, nonspecific stimulation of human PBMCs with PHA, Con-A, or SEB was inhibited by adenoviral delivery of Vpr. These studies illustrate that there was a particularly dramatic effect on blocking CD4 responses.
In conclusion, the data support that Vpr compromises antigen-specific immune responses and ultimately effector cell function as a codelivered antigen. Importantly this effect is observed as part of a novel adenoviral particle. This function likely gives a strong selective advantage to the HIV-1 virus at the expense of the host in vivo.
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