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HIV-1 viral protein R (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-kappa B-mediated transcription from host cells. Collectively, these effects support that Vpr could influence immune activation in vivo. However, this effect of Vpr has not been explored previously. Here we examined the effect of Vpr expression in an in vivo model system on the induction of antigen-specific immune responses using a DNA vaccine model. Vpr co-vaccination significantly altered the immune response to co-delivered antigen. Specifically, in the presence of Vpr, inflammation was markedly reduced compared to antigen alone. Vpr reduced antigen-specific CD8-mediated cytotoxic T lymphocyte activity and suppressed T(h)1 immune responses in vivo as evidenced by lower levels of IFN-gamma. In the presence of Vpr, there is a profound shift in isotype towards a T(h)2 response as determined by the IgG2a:IgG1 ratio. The data support that Vpr compromises antigen-specific immune responses and ultimately effector cell function, thus confirming a strong selective advantage to the virus at the expense of the host.

Human immunodeficiency virus-1 (HIV-1) Vpr encodes a 14 kDa protein that has been implicated in viral pathogenesis through in vitro modulation of several host cell functions. Vpr modulates cellular proliferation, cell differentiation, apoptosis and host cell transcription in a manner that involves the glucocorticoid pathway. To better understand the role of HIV-1 Vpr in host gene expression, approximately 9600 cellular RNA transcripts were assessed for their modulation in primary APC after treatment with a bioactive recombinant Vpr (rVpr) by DNA micro-array. As an extracellular delivered protein, Vpr down-modulated the expression of several immunologically important molecules including CD40, CD80, CD83 and CD86 costimulatory molecules on MDM (monocyte-derived macrophage) and MDDC (monocyte-derived dendritic cells). Maturation of dendritic cells (DC) is known to result in a decreased capacity to produce HIV due to a post-entry block of the HIV-1 replicative cycle. Based on the changes observed in the gene array, we analyzed maturation of DC generated from monocytes in tissue culture as influenced by Vpr. We observed that Vpr-treated immature MDM and MDDC were unable to acquire high levels of costimulatory molecules and failed to develop into mature DC, even in the presence of maturation signals. These studies have importance for understanding the interaction of HIV with the host immune system.