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    • br Materials and methods br Results br Discussion Metabolic

    2022-08-12


    Materials and methods
    Results
    Discussion Metabolic abnormalities and systemic immune dysfunctions are common during HIV infection and/or antiretroviral therapy. Although some transcriptomic studies of HIV infection have revealed global changes in the mRNA and microRNA expression profiles (Ryndak et al., 2014, Wu et al., 2013b, Tran et al., 2014, Zhang et al., 2013), the molecular mechanisms that contribute to these dysfunctions have remained elusive, and the relationship between the PBMC transcriptomic profiles and the differential responses to antiretroviral therapy has been limited for HIV patients. Using transcriptomic analysis based on RNA-Seq, we identified a number of transcriptional features and specific genes that may contribute to the HIV associated dysfunction in vivo and provided further insights into the molecular mechanisms of antiretroviral therapy effects on HIV patients. The differentially expressed genes (DEGs) significantly differed among the five individual subjects (Fig. 2A). H1, who was a healthy volunteer, only expressed 13 HAART down-regulated and 28 up-regulated genes, showing that HAART may only minimally affect the PBMC gene expressions in a healthy person. Despite of the inter-individual variations, 25 DEGs shared by the three HIV patients were identified, demonstrating the power of the comparative transcriptome analyses. Among the 11 HAART-down-regulated genes, the relevance of nine had already been reported in HIV infection (CD160, CD244, SIGLEC1, IFIT1, IFI44, IFI27, CX3CR1, IFI44L and MX1). These genes could directly interact with HIV, take part in immune activation and participate in host defenses that partially control infection (Supplementary Tables S2 & S3). For example, CD160 and CD244 are negative surface receptors expressed on NK SCH 39166 hydrobromide australia and activated T cells (Ostrowski et al., 2005, Larsson et al., 2013). The co-expression of multiple distinct inhibitory receptors is associated with greater T cell exhaustion and rapid HIV disease progression (Larsson et al., 2013). HIV exploits the effects of the molecular immune inhibitory response to facilitate the virus's escape under the surveillance of the immune system (Aldy et al., 2011). Several studies found that the suppression of HIV replication by antiretroviral therapy could reduce the surface expression of inhibitory molecules on HIV-specific immune cells (Sivro et al., 2014, Zhang et al., 1999, Mateen et al., 2013, Palella and Phair, 2011), which was also supported by our results. Four of our detected HAART down-regulated genes (IFIT1, IFI44, IFI27 and Mx1) belong to the interferon (IFN) inducible gene family and are related to immune activation and immune defenses. After HIV infection, interferon signaling leads to the induction of IFN-stimulated gene (ISGs) expression, which results in the diverse effects of IFNs, including anti-viral replication, immune modulation and antitumor activity. Previous array studies documented that both HIV-1 infection and viral proteins increased the expression of IFN-inducible genes, and ART efficiently mitigated aberrant gene expression (da Conceicao et al., 2014, Wie et al., 2013, Izmailova et al., 2003, Borjabad et al., 2011). Most prominently, MxA (Mx1), a known interferon-induced restriction factor for a diverse range of viruses, may represent a valuable marker to monitor the clinical response to therapy in HIV patients because the levels of serum interferon-alpha and MxA mRNA were significantly higher in HIV-infected patients with low CD4 T-cell counts, and the expression of MxA directly correlated with HIV RNA copy numbers (Badolato et al., 2008). Clinical trials also showed that the CD4 T-cell count increased and the HIV-induced cytokine IFN-alpha and its downstream effector MxA decreased in the plasma of HIV patients after seven years of antiviral treatment (Jung et al., 2012). CX3CR1 is a co-receptor for HIV-1, and some variations increases the susceptibility to HIV-1 infection and rapid progression to AIDS (Becker, 2007). SIGLEC1 (CD169), which is expressed on IFN-induced monocytes, binds HIV-1 and enhances infectivity (van der Kuyl et al., 2007). These two factors, which are up-regulated after HIV-1 infection and increase during disease progression (Krishnan et al., 2014), directly interact with HIV and may be potential molecular targets associated with the inhibition of virus spread (Yu et al., 2014). Li et al. (2004) proposed a disease model in which the host rapidly responds to HIV-1 infection by increasing the expression of a large number of genes related to the innate and adaptive defenses after HIV infection. The suppression of viral replication by HAART would relieve the stimulus from HIV, thus leading to the decreased expression of these genes (Li et al., 2009b). Our results support these previous reports, which demonstrate that the comparative transcriptome approach can efficiently extract valuable information from a large number of detected genes using a small sample set, i.e. samples from three HIV-patients and two HIV negative volunteers.