*8.1. Human Immunodeficiency Virus (HIV)*

HIV is a retrovirus that infects and depletes CD4 T lymphocytes, causing slowly progressive immunodeficiency [225]. Despite antiretroviral therapy, people infected with HIV continue to develop comorbidities such as dyslipidemia, atherosclerosis and diabetes [228].

The role of the viral negative factor (Nef) protein and its association with cardiometabolic comorbidities has become of great interest in recent years (Figure 2). Nef is a multifunctional viral protein that alters the expression of different macromolecules on the surface of the host cell [233]. Nef decreases *ABCA1* gene expression, increases ABCA1 protein degradation in lysosomes and proteasomes by displacing it from the lipid rafts, and alters its maturation and folding in the endoplasmic reticulum by blocking its interaction with calnexin [234–238]. These events induce the accumulation of intracellular cholesterol in the host cell and increase the number of nonfunctional lipid rafts allowing virus survival and increasing virion production [228,239–242]. In addition, recent studies have shown that Nef can be released from infected cells through extracellular vesicles altering cholesterol metabolism in uninfected recipient cells [237,243–245].

**Figure 2.** Effects of the viral negative factor (Nef) protein in human immunodeficiency virus (HIV) infected cells. HIV enters cells by binding to the chemokine receptor 5 (CCR5) and chemokine receptor type 4 (CXCR4) and uses the host cell machinery to synthesize viral proteins such as Nef. Nef increases cholesterol biosynthesis and induces lipid raft formation, required to produce new virions. Nef also inhibits cholesterol efflux by suppressing ABCA1 activity, inducing structural and functional modifications of high-density lipoproteins (HDL). In addition, Nef blocks the interaction of the endoplasmic reticulum (ER) chaperon calnexin (CNX) with ABCA1, altering its folding and maturation. Nonfunctional and misfolded ABCA1 is retained in the ER and degraded in the proteasome, resulting in further accumulation of intracellular cholesterol, creating a favorable microenvironment for viral replication and release.

β

It is well known that HIV patients develop dyslipidemia, and their HDL-C plasma concentrations can be as low as those of TD patients [60,246,247]. The Nef protein causes dyslipidemia, as it affects cholesterol efflux by reducing the expression of ABCA1 in in vitro and in vivo models [237,248–250]. Similarly, the accumulation of cholesterol in pancreatic β-cells alters their function, decreasing insulin release, predisposing HIV patients to diabetes [105,109,251]. In this context, some studies have shown that antiretroviral therapy not only reduces the viral load [249] but also increases ABCA1 expression, restoring cholesterol efflux and increasing HDL-C plasma concentrations [249,252]. A recent prospective study reported that new antiretroviral therapies mitigate the cardiometabolic effects of HIV, at least in the short term [246]. However, not all studies report cardiometabolic improvement [253,254]. Moreover, long-term antiretroviral therapy is associated with dyslipidemia, although it does not occur in all patients [255]. A study assessing the impact of 192 SNPs in HIV patients receiving antiretroviral therapy identified that the *ABCA1* rs4149313 was associated with decreased TG and increased HDL-C circulating levels [256], while an independent study reported that *ABCA1* rs2066714 was associated with a greater risk of dyslipidemia in patients under antiretroviral treatment [257]. In addition, because of the role of ABCA1 in viral replication, ongoing studies are also investigating whether functional ABCA1 gene variants affect HIV progression or severity.
