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. 2012 Aug;18(4):563-70.
doi: 10.1177/1753425911426893. Epub 2011 Oct 31.

Cellular resistance to HIV-1 infection in target cells coincides with a rapid induction of X-DING-CD4 mRNA: indication of the unique host innate response to virus regulated through function of the X-DING-CD4 gene

Rasheda Y Shilpi  1 , Rakhee Sachdeva, Malgorzata Simm
Affiliations

Cellular resistance to HIV-1 infection in target cells coincides with a rapid induction of X-DING-CD4 mRNA: indication of the unique host innate response to virus regulated through function of the X-DING-CD4 gene

Rasheda Y Shilpi et al. Innate Immun. 2012 Aug.

Abstract

Clinical reports indicate that some infected individuals control HIV-1 replication through undefined mechanisms. Our group reported that a human protein named X-DING-CD4 holds a potent antiviral activity, blocking transcription of HIV-1 LTR through the inhibition of NF-κB/DNA binding. Based on observations that transformed HIV-1 resistant CD4(+) T cells produce higher levels of soluble X-DING-CD4 protein upon their exposure to virus, we hypothesized that resistance to HIV-1 in these cells may be regulated through function of the X-DING-CD4 gene. Real-time PCR evaluations of X-DING-CD4 mRNA expression confirmed our hypothesis; HIV-1 exposure caused rapid up-regulation of X-DING-CD4 mRNA in resistant, but not susceptible, cells; and the burst of X-DING-CD4 mRNA expression correlated with restriction of HIV-1 transcription. Subsequently, we examined the activity of the X-DING-CD4 gene in monocytes and macrophages from (n = 13) HIV-negative donors. The assessment of HIV-1 gag mRNA showed that the majority of cells were permissive to virus replication; however, macrophages from four donors were refractory to HIV-1 infection. In response to virus, these cells up-regulated X-DING-CD4 gene expression by 2- to 1000-fold. These data provide evidence that the X-DING-CD4 gene contributes to early cellular protection from HIV infection in some individuals and this protection depends solely on the unique genetic regulation of the host.

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Figures

Fig. 1
Fig. 1. The expression of X-DING-CD4 mRNA is induced in HIV-1 resistant cells
The expression of X-DING-CD4 gene was tested by qRT-PCR using X-DING-CD4 gene specific primers. Different samples of cell cultures were exposed to HIV-1 as described in Materials and Methods throughout a period of one year. The fold change was calculated as a fold increase or decrease of the X-DING-CD4 mRNA absolute copy number between the experimental sample and the uninfected control. The X-DING-CD4(+) and X-DING-CD4(−) denote the HIV-1 resistant CD4+T cell line previously known as HRF(+) and HIV-1 susceptible CEM cells. The P value for 24hr time point was derived from the Mann-Whitney rank sum test; the alpha level was set at 0.050
Fig. 2
Fig. 2. The elevated expression of X-DING-CD4 mRNA associates with inhibition of HIV-1 vif gene transcription
X-DING-CD4 and HIV-1 vif mRNA expression was tested by qRT-PCR in (A) HIV-1-resistant (X-DING-CD4(+)); and (B) HIV-1-susceptible cell lines. Levels ofX-DING-CD4 mRNA (bars) are calculated on the left y axis; levels of HIV-1 vif mRNA (lines)are calculated on the right y axis. Expression of HIV-1 proteins was tested by immunofluorescence (IF). This figure summarizes results of three independent experiments.
Fig. 3
Fig. 3. Evaluation of the X-DING-CD4 and HIV-1 gag mRNA expression in human monocytes and monocyte - derived macrophages
(A) The X-DING-CD4 mRNA levels were tested in monocytes and macrophages from n=13 healthy HIV-1 negative donors. The IQR for each experimental system was calculated by SigmaPlot. Each data point for individual donor is derived from three amplifications of the sample. Monocytes denote the mitogen- and HIV-1-naïve cells. (B) – correlation between changes in the expression of X-DING-CD4 and HIV-1 gag mRNAs for each sample was calculated by GrapPad Prism 5 software. The HIV-1 gag mRNA was undetectable for macrophages from Donor 1. This figure (A and B) summarizes results of two independent real time PCR evaluations.
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