In this issue of AIDS, Parrinello et al. present the results of analyses conducted within the Women's Interagency HIV Study that reinforce the idea that HIV infection, inflammation and atherosclerosis are actors playing a complex and tightly interactive game. Thus, they describe how the magnitude of increase of high-density lipoprotein cholesterol (HDLc), but not the modification of low-density lipoprotein cholesterol (LDLc) levels, that is detected among HIV-infected women after initiation of therapy, correlates with the decrease of a number of proinflammatroy markers, including sCD14, tumor necrosis factor (TNF)α, soluble interleukin (IL)2 receptor and monocyte chemoattractant protein-1. These data lead to the conclusion that the reduction in HIV plasma viremia that follows therapy is associated with an inverse correlation between HDLc lipoprotein and inflammation. These results shed light on the pathogenesis of cardiovascular diseases (CVDs) in HIV infection and confirm recent data  obtained in a cross-sectional study. In that study, it was suggested that atherosclerosis in HIV infection has a prevalent inflammatory pathogenesis and is also associated with a severe impairment of pro-thrombotic, inflammatory and endothelial indexes in naive HIV-infected patients, whereas metabolic alterations are predominant in antiretroviral therapy (ART)-treated individuals.
HDLc are the most widely distributed lipoproteins in fluid tissues, and several studies  have concluded that HDLc concentration is a powerful predictor of CVD: thus, high levels of plasma HDLs have been repeatedly proven to have a beneficial protective effect, lowering the risk of coronary artery disease. HDL-related athero-protection remains nevertheless controversial and not fully understood, as has recently been underscored by data indicating that the capacity of HDLc to accept cholesterol from macrophages (cholesterol efflux capacity) has a strong inverse association with both carotid intima-media thickness and angiographic coronary artery disease regardless of HDLc levels . Probably, the most important athero-protection mechanism of HDLc results from their ability to uptake peripheral cholesterol from monocytes and transport it to the liver for excretion in the bile and faeces. This mechanism, called reverse cholesterol transport, is believed to be a fundamental protective factor against atherosclerosis . More recently, a variety of other functions of HDL was described; these include anti-inflammatory, antioxidant, antiglycation, antithrombotic, nitric oxide inducing and antimicrobial activities (in this regard, it is important to underline that HDLc is one of the main actor in the elimination of lipopolysaccharide (LPS) molecules from circulation) .
HIV may impair HDLs’ levels and favour foam cells transformation by altering the expression and the function of the adenosine triphosphate binding protein (ABCA-1) transporter in macrophages. This impairment is directly mediated by the viral protein nef. The virus can also trigger and exacerbate atherosclerosis as a consequence of its inflammatory effect, as witnessed by the increases of interleukin-6 (IL-6), TNFα, adhesion molecules, LPS and C-reactive protein that are observed during HIV infection. We recently reported that an upregulation of ABCA-1, higher levels of HDLc and a reduction of inflammatory indexes are seen in HIV-infected individuals undergoing therapy. These data, along with the ones by Parrinello et al., suggest that the lower intracellular lipid accumulation seen in monocytes of HIV-suppressed patients, and demonstrated by HDLc normalization, could be one of the mechanisms by which ART reduces the generation of proinflammatory cytokines. In other words, nef-induced foam cell transformation alone could be sufficient to increase inflammatory cytokines production from macrophages. Thus, the engulfing of macrophages by cholesterol that is induced and facilitated by nef as a consequence of its inhibitory effect on ABCA1 not only increases lipid rafts formation, hence facilitating HIV replication, but also might be one of the main pathogenic mechanism, along with LPS/Toll-like receptor-dependent immune activation, sustaining systemic inflammation in HIV disease.
Notably, Parrinello et al. did not find a change in CVD risk (Framingham score) in spite of the significant increases in HDL seen after 18 months of therapy. These puzzling findings could be explained in different ways. Thus, first, the relatively short period of follow up could not be sufficient to draw definite conclusions. Second, the modification of HDL level observed in the study, although consistent, might not reach a ‘biologically-significant threshold’ (in the Framingham Heart Study, only each 0.26 mmol/l increase in HDL was associated with significant decreases in the relative risk of CVD mortality). Third, measurement of plasma HDL alone might not be sensitive enough. In this light, it was suggested that the precise determination of CVD risk may not merely be associated with HDL levels, as the influence of genetic background is likely to be preponderant in determining such risk . Notably, this aspect seems to be confirmed by the results of recent clinical trials aimed at reducing the risk of coronary heart disease by raising HDLc levels. These trials have not reached satisfactory results and have led to the suggestion that having a functional HDLc might be a more desirable target than simply elevating its levels.
In conclusion, the longitudinal studies of Parrinello et al. and our cross-sectional studies show the presence of a detrimental and self-perpetuating link between viral replication, increased production of macrophage inflammatory cytokines and HDLc levels in HIV viremic patients; this link is broken by ART. These data suggest a new and complex model that explains the inflammatory pathogenesis of HIV infection that is worth evaluating with ad hoc designed in-vitro and in-vivo studies. Finally, if confirmed with more extended analyses, the measure and monitoring of HDLc and their precursors could represent a novel factor to be added to those already in use to decide when to initiate ART.
We are grateful to Dr Giuliano Rizzardini, L. Sacco Hospital, Milano and Professor Daria Trabattoni, University of Milano, Milano, Italy, for the useful discussions and for revising the manuscript.
Conflicts of interest
There are no conflicts of interest.
1. Parrinello CM, Landay AL, Hodis HN, Gange SJ, Norris PJ, Young M, et al.Treatment-related changes in serum lipids and inflammation: clinical relevance remain unclear. Analyses from the women's interangency HIV Study.
AIDS (in press).
2. Piconi S, Parisotto S, Rizzardini G, Passerini S, Meraviglia P, Schiavini M, et al. Atherosclerosis is associated with multiple pathogenetic mechanisms in HIV-infected antiretroviral-naive or treated individuals
. AIDS 2012; 27:381–389.
3. Movva IR, Rader D. Laboratory assessment of HDL heterogeneity and function
. Clin Chem 2008; 54:788–800.
4. Khera AV, Cuchel M, de la Llera-Moya M, Rodrigues A, Burke MF, Jafri K, et al. Cholesterol efflux capacity, high-density lipoprotein function and atherosclerosis
. N Engl J Med 2011; 364:127–135.
5. Rosenson RS, Brewer HB Jr, Davidson WS, Fayad ZA, Fuster V, Goldstein J, et al. Cholesterol efflux and atheroprotection: advancing the concept of reverse cholesterol transport
. Circulation 2012; 125:1905–1919.
6. Wendel M, Paul R, Heller AR. Lipoproteins in inflammation and sepsis
. Clin Aspects Intensive Care Med 2007; 33:25–35.
7. Mujawar Z, Rose H, Morrow MP, Pushkarsky T, Dubrovsky L, Mukhamedova N, et al. Human immunodeficiency virus impairs reverse cholesterol transport from macrophages
. PLoS Biol 2006; 4:e365.
8. Savel J, Lafitte M, Pucheu Y, Pradeau V, Tabarin A, Couffinhal T. Very low level of HDL cholesterol and atherosclerosis, a variable relationship-a review of LCAT deficiency
. Vasc Health Risk Manag 2012; 8:357–361.