# Cardiovascular Risk in HIV Patients: Ageing Analysis of the Involved Genes
## 3 Results
### Increasing and Decreasing Genes in Patients with HIV  
An integrated Scopus and PubMed search revealed clinical data for only TLR4, mTOR, CXCR4, IRS1, and NCF4. A total of 266 TLR4 articles were identified through a search in SCOPUS and 310 through a search in PUBMED. Using a PRIMSA-based screening strategy (see Figure A11 of the Appendix A), we identified 38 studies. A growing body of research utilizing various cell types from individuals with HIV suggests that TLR4 plays a crucial role in controlling the progression of viral infections [30]. Elevated levels of TLR4 expression and the production of inflammatory cytokines have been observed in HIV-infected individuals, with some studies  
Figure 5: The TLR4 levels in coronary tissue levels in aortic tissue by age. The term GE stands for gene expression and represents the gene expression of a gene evaluated by applying a linear model to the GTEx data [18]. The reported \(p\)-values represent a sensible change in the expression of the genes at a precise age interval represented in the x interval. Reported \(p\)-values represent expression alterations over age; \(p\)-values are for the moderated t-statistics of differential gene expression associated with the effect of age. noting higher expression levels in patients not undergoing HAART treatment [31; 32]. Several studies have highlighted a link between specific TLR4 genetic variations and HIV susceptibility [33]. Carriers of variants A+896G (rs4986790) and C+1196T (rs4986791) have shown reduced inflammatory responses to inhaled LPS compared to non-carriers [34]. Additionally, SNPs in TLR4 such as 1063A/G and 1363C/T have been linked to changes in CD4 cell counts, viral load, and disease progression in HIV infection [35]. The presence of the TLR4 Asp299 Gly heterozygous genotype has been found to be higher in HIV-1 infected individuals [36] and independently associated with cardiovascular diseases in HIV-infected patients, potentially due to its proinflammatory effects contributing to atherosclerosis [37]. Furthermore, HIV entry into host cells requires interaction with the CD4 receptor on the cell membrane and relies on the activation of the co-receptor CXCR4 [38], which is notably increased in patients with advanced HIV disease [39]. A total of 3825 articles on CXCR4 were identified in SCOPUS, and 3970 in PUBMED. Using a PRISMA-based screening approach (refer to Appendix A Figure 12), 62 relevant studies were identified. In this case, no correlation emerged between the disease and specific polymorphisms, but natural ligands for CXCR4, such as peptidic compounds T22 (an 18-mer), T134 (a 14-mer), ALX40-4C (a 9-mer), and CGP 64222 (also a 9-mer), have been identified as CXCR4 antagonists with anti-HIV properties [40; 41; 42]. Another new technology consists of a small-molecule inhibitor, ALX40-4C, that inhibits HIV-1 envelope (Env)-mediated membrane fusion and viral entry directly at the level of the coreceptor use [43]. In the future, HIV entry/fusion inhibitors will become important new antiviral agents to combat AIDS. Mutations in the CXCR4 gene are generally rare and have not been implicated in HIV-1/AIDS pathogenesis. Comprehensive mutation analysis of the CXCR4 gene confirm a high degree of genetic conservation within the coding region of this ancient population [44]. mTOR also plays a crucial role since one hundred fifty-one mTOR articles were identified through a search in SCOPUS and 187 through a search in PUBMED. Using a PRIMSA-based screening strategy (see Figure 13 of the Appendix A), we identified 19 studies. CD4+ and CD8+ T cells from PLWHs play a role in cell adhesion, apoptosis, and migration processes involved in atherosclerosis, and the upregulated mTOR pathway mediates these atherogenic processes [21; 45]. The HIV-1 viral life cycle depends on mTOR because it drives signalling and metabolic pathways required for viral entry, replication, and latency. In HIV-1 pathogenesis, mTOR alters host cell metabolism to create an optimal environment for viral replication [45].