HDL and Viral Infections

Changes in plasma HDL-C levels have been reported to occur also during infection with viruses including human immunodeficiency virus (HIV) and hepatitis C virus (HCV). Furthermore, proteins related to HDL life cycle, such as SR-BI, were shown to play a key role in HCV infection. So far HDLs were proposed to increase virus infection and inhibit virus neutralizing antibodies; however, recent findings are challenging previous data and proposing a more complicated picture based on the ability of virus to take advantage of HDL–lipid transfer activity in host cells. Most of the available evidences linking HDL to viral infection are available for HIV and HCV.

HIV Infection

HIV infects and depletes CD4 lymphocytes, resulting in immunodeficiency and a slowly progressive disease. HIV is associated with dyslipidemia, namely, hypocholesterolemia, low levels of LDL, and hypertriglyceridemia (Riddler et al. 2003; Shor-Posner et al. 1993). HIV infection is commonly associated also with hypoalphalipoproteinemia; however, it is unclear whether virion replication plays a causative role in these changes. Some data suggest that hypoalphalipoproteinemia in patients with HIV is likely to be secondary to HIV infection itself (Rose et al. 2006). Systemic inflammation has been shown to lower the antioxidant and anti-inflammatory activity by transforming HDL to a pro-oxidant, pro-inflammatory acute-phase HDL (Kelesidis et al. 2013; Norata et al. 2006). A small pilot study of HIV-1-infected individuals with suppressed viremia on combination antiretroviral therapy showed that oxidative stress and inflammation in HIV-1 are associated with a marked reduction of HDL antioxidant–anti-inflammatory activities. In vitro, these abnormalities were significantly improved by treatment with the apoA-1 mimetic peptide 4F (Kelesidis et al. 2011). HIV infection is associated with modified HDL metabolism redirecting cholesterol to the apoBcontaining lipoproteins and likely reducing the functionality of reverse cholesterol transport (Rose et al. 2008). Of note, the HIV-1 Nef protein can impair ABCA1 cholesterol efflux from macrophages, thus supporting atherosclerosis. This viral inhibition of efflux was correlated with a direct interaction between ABCA1 and Nef (Fitzgerald et al. 2010; Mujawar et al. 2006). More recently it was shown that

Nef downregulates ABCA1 function by a posttranslational mechanism that stimulates ABCA1 degradation but does not require the ability of Nef to bind ABCA1 (Mujawar et al. 2010).

Not all data are however concordant on this, and although HDL cholesterol and preβ1-HDL were significantly lower in all HIV-infected groups ( p < 0.05), mean levels of apoA-I and the ability of plasma to promote cholesterol efflux were similar in treatment-na¨ıve HIV-infected patients or in HIV-infected patients on long therapy break. Of note a positive correlation between apoA-I and levels of CD4+ cells was also observed (r2 ¼ 0.3, p < 0.001) (Rose et al. 2008). Furthermore apoAI, the major protein component of high-density lipoprotein, and its amphipathic peptide analogue were found to inhibit cell fusion, both in HIV-1-infected T cells and in recombinant vaccinia-virus-infected CD4+ HeLa cells expressing HIV envelope protein on their surfaces (Srinivas et al. 1990). The amphipathic peptides inhibited the infectivity of HIV-1. The inhibitory effects were manifest when the

virus, but not cells, was pretreated with the peptides. Also, a reduction in HIV-induced cell killing was observed when virus-infected cell cultures were maintained in the presence of amphipathic peptides. These results have potential implications for HIV biology and therapy (Srinivas et al. 1990).

An aspect debated is how much the HIV infection and/or treatment contribute to the changes in HDL-C levels. With highly active antiretroviral therapy (HAART) intervention, mortality due to HIV was greatly reduced (Madamanchi et al. 2002). However, there have been several reports of increases in cardiovascular complications in patients with HIV. It is now established that some HAART regimens cause severe dyslipidemia, characterized by high levels of TC and LDL-C, hypertriglyceridemia, and hypoalphalipoproteinemia (Riddler et al. 2003). This clearly pro-atherogenic lipoprotein profile is associated with a rise in the incidence of CAD (Depairon et al. 2001). The rate of inflammation predicts changes in HDL-C and apoA-I following the initiation of antiretroviral therapy and indeed in a subgroup of participants not taking ART at study entry who were randomized in the Strategies for Management of Antiretroviral Therapy (SMART) to immediately initiate ART (“VS group”) or to defer it (“DC group”); HDL-C and ApoA-I levels increased among VS participants (n ¼ 128) after starting ART compared to DC. The effect of starting ART on changes in HDL-C and apoA-I was greater for those with higher versus lower baseline levels of IL-6 or hsCRP indicating that the activation of inflammatory pathways could contribute to HIV-associated changes in HDL (Baker et al. 2011). Also non-nucleoside reverse transcriptase inhibitors (NNRTI), such as nevirapine (NVP), were shown to increase apoA-I production, which contributes to the HDL-C increase after introduction of NVP-containing regimens. In view of the potent anti-atherogenic effects of apoA-I, the observed increase was suggested to contribute to the favorable cardiovascular profile of NVP (Franssen et al. 2009). Also efavirenz, another NNRTI antiretroviral treatment, was associated with HDL particles with a better antioxidant function, i.e., with a higher PON-1 activity. The PON-1 activity of black patients is higher than that found in whites regardless of treatment suggesting that ethnicity should be taken into consideration when studying drug effects on PON-1 activity (Pereira et al. 2009).

Overall the available evidences suggest that HIV infection could be associated with modified HDL metabolism redirecting cholesterol to the apoB-containing lipoproteins and likely reducing the functionality of reverse cholesterol transport and promote atherosclerosis. Additional pro-atherogenic mechanisms could be associated with a decrease in the anti-inflammatory properties of HDL.

 
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