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    • However, Two genes PATL and RASSF

    2021-10-08

    Two genes (PATL2 and RASSF1), whose relationship to HIV infection had not previously been reported, were identified in this study. Although PATL2 and RASSF1 have been implicated in cell division and tumor suppression, respectively (Scheller et al., 2007, Rather et al., 2014, Liu et al., 2002), their patterns of down-regulation were similar in the three HIV patients during HAART, as judged by RNA-Seq (Fig. 3B) and qRT-PCR (Fig. 5). This finding suggested that the production of PATL2 and RASSF1 increased during the HIV infection before treatment. Because all three HIV patients shared these two DEGs despite the tremendous inter-individual variations (Fig. 1, Fig. 2, Fig. 3A; Supplementary Fig. S1), HIV infection likely resulted in the over-expressions of PATL2 and RASSF1. Therefore, further investigations to determine the relationships of these two proteins with HIV pathogenesis will be worthwhile for treatment development. Fourteen genes (ACSL1, GPR84, CXCL1, ADM, S100P, AQP9, GPR97, BASP1, MMP9, SOD2, LRG1, LIMK2, IL1R2 and BCL2A1) were up-regulated by HAART in HIV patients compared with the healthy controls. It is worth to note that HAART up-regulation indicated HIV down-regulation but was not correlated to CD4+ cell enrichment in these samples. Based on the commonly accepted notion that there is no “signature genes” in CD4+ cells (Palmer et al., 2006), up-regulations of the genes mentioned above should not be due to the increase of CD4+ cells. Indeed, the CD4+ cell counts did not increase (less than half-fold in P2 and P3, Table 1) proportionally to the RKPM changes (Supplementary Table S4) indicating that the DEGs we recorded (with more than two-fold RKPM change) were not largely due to the increase of CD4+ cell counts although contributions of the CD4+ cells could not be ruled out completely. Therefore, it was mainly the HIV infection that suppressed the expressions of these genes. The relationships of the majority of these genes (9 out 14) with HIV infection had already been reported (Supplementary Table S3). Interestingly, some of the five new genes (ACSL1, ADM, GPR84, GPR97 and LRG1) play key roles in fatty However, metabolism, cell cycle arrest and immunological dysfunction (Fig. 6). For example, GPR97 is an orphan adhesion protein-coupled receptor that binds to chemokines on the surfaces of immune cells. GPR97 has been suggested to regulate the migration of lymphatic endothelial cells (Valtcheva et al., 2013) and B-cell development (Wang et al., 2013), but it has not yet been specifically associated with the host immune responses to a virus. The up-regulation of GPR97 by HAART suggests that HIV may interfere with some G-protein coupled receptors that are relevant to chemokine signaling pathways, which may be critical for effective antiviral immune responses. Cardiovascular disease (CVD) has emerged as one of most critical complications of HIV infection. Several clinical studies demonstrated that the rates of CVD among HIV-infected patients were approximately 1.5–2-fold higher than uninfected controls (Triant et al., 2007, Obel et al., 2007, Lang et al., 2010, Klein et al., 2015). However, the cause of HIV contributing to an increased risk of CVD is still unclear. It has been suggested that HIV-associated CVD may link to T-cell activation, chronic infection, monocyte and macrophage related inflammation and dysfunctional immune regulatory responses (Hsue et al., 2006, Ridker et al., 2002, Baliga et al., 2005, Shikuma et al., 2005, Troseid et al., 2014, Triant et al., 2010, Lang et al., 2012). We found the up-regulation of ADM expression in HIV patients was associated with the decease of HIV load after HAART although ADM had not been reported for association with HIV infection before. ADM has physiological and pathophysiological functions in the cardiovascular system including vasodilation, natriuresis, stimulation of NO production and inhibition of apoptosis (Funke-Kaiser et al., 2014, Nishikimi et al., 2013, Sata et al., 2000). ADM also plays a protective role in various pathological conditions including hypertension, myocardial infarction, renal failure and heart failure (Wong et al., 2012, Holmes et al., 2013). As we showed that HAART elevated the level of ADM expression in HIV patients but not in HIV negative volunteers, it strongly suggested that HIV infection suppressed the expression of ADM in PBMC. Although direct evidence is needed to clarify the relationship between HIV activity and ADM levels, it is tempting to consider the therapeutic possibility that ADM may be used to treat HIV-associated diseases as ADM is involved in many biological functions (Fig. 6).