Type III and I Interferons Increase HIV Uptake and Replication in Human Cells That Overexpress CD4, CCR5, and CXCR4

Abstract

The newly discovered type III interferon lambda (IFN-lambda) has antiviral activity against a broad spectrum of viruses and potent immune-related activities. Its major producers are peripheral blood mononuclear cells (PBMCs) and dendritic cells. The above functions and cells are deeply involved in AIDS pathogenesis, but there is no information so far on IFN-lambda effects on HIV. Therefore we addressed the sensitivity of HIV-1 replication to cell exposure to human IFN-lambda2. Human PBMCs and C8166 T cells were treated with human Type III or Type I IFNs, and the ability of HIV-1 to bind and replicate in untreated and IFN-treated cells was investigated. Virus amounts were quantified by infectivity and p24 assays. In parallel, we evaluated the possible antiproliferative effects of IFN-lambda2 and the expression of CD4, CXCR4, and CCR5 genes, whose transcripts were quantified by real time RT-PCR. Data showed increased adsorption of HIV to IFN-treated cells in a dose-dependent fashion. Virus yields increased accordingly. In both systems the accumulation of CD4, CXCR4, and CCR5 transcripts was increased, particularly in PBMCs. Antiproliferative activity and classical antiviral state were instead detected on PBMCs, but not on C8166 cells. We concluded that pretreatment of PBMCs and C8166 cells with Type III and Type I IFNs causes increased HIV binding and replication. These effects are likely to be due to increased expression of HIV receptors and coreceptors on the plasma membrane. These findings indicate another mechanism utilized by HIV for subversion of host defenses.

Despite IFN-λ receptor expression, blood immune cells, but not keratinocytes or melanocytes, have an impaired response to type III interferons: implications for therapeutic applications of these cytokines

“…In contrast to these investigations, some studies did propose direct effects of IFN-ls on monocytes, 32,33 DCs 34 and T cells. [35][36][37][38][39][40] We currently cannot explain the discrepancy in these observations in terms of whether IFN-ls influence, for example, monocytes or T cells. As we demonstrated, it seems that the preactivation with cell-specific stimuli or virus-mimicking agents could not confer any clear responsiveness to these cytokines on peripheral immune cells.…”

IFN-α-Induced Upregulation of CCR5 Leads to Expanded HIV Tropism In Vivo

“…Indeed, recent data indicate that IFN-α treatment causes significant increases in CCR5 mRNA expression in PBMC cultures from both HIV-infected and uninfected individuals [53],[54], and IFN-α treatment of patients with uveitis resulted in increases of CCR5 expression on peripheral blood CD4 + T cells [55]. Even if these events are restricted to thymic pDC, residual thymic function that persists in some adults with HIV disease [1] might thereby be abrogated.…”

Expression and Activation by Epstein Barr Virus of Human Endogenous Retroviruses-W in Blood Cells and Astrocytes: Inference for Multiple Sclerosis

“…The comparison of the relative amounts of the two sequences in RNAs was carried out by the 2 −ΔCt and 2 −ΔΔCt Methods, based on the different amplification of the gene of interest with respect to the glyceraldehyde-3-phosphate dehydrogenase housekeeping gene [85].…”