Altered Lipidome Composition Is Related to Markers of Monocyte and Immune Activation in Antiretroviral Therapy Treated Human Immunodeficiency Virus (HIV) Infection and in Uninfected Persons

Abstract

Background: HIV infection and antiretroviral therapy (ART) have both been linked to dyslipidemia and increased cardiovascular disease (CVD) risk. Alterations in the composition of saturated (SaFA), monounsaturated (MUFA), and polyunsaturated (PUFA) fatty acids are related to inflammation and CVD progression in HIV-uninfected (HIV–) populations. The relationships among the lipidome and markers of monocyte and immune activation in HIV-infected (HIV+) individuals are not well understood. Methods: Concentrations of serum lipids and their fatty acid composition were measured by direct infusion-tandem mass spectrometry in samples from 20 ART-treated HIV+ individuals and 20 HIV– individuals. Results: HIV+ individuals had increased levels of free fatty acids (FFAs) with enrichment of SaFAs, including palmitic acid (16:0) and stearic acid (18:0), and these levels were directly associated with markers of monocyte (CD40, HLA-DR, TLR4, CD36) and serum inflammation (LBP, CRP). PUFA levels were reduced significantly in HIV+ individuals, and many individual PUFA species levels were inversely related to markers of monocyte activation, such as tissue factor, TLR4, CD69, and SR-A. Also in HIV+ individuals, the composition of lysophosphatidylcholine (LPC) was enriched for SaFAs; LPC species containing SaFAs were directly associated with IL-6 levels and monocyte activation. We similarly observed direct relationships between levels of SaFAs and inflammation in HIV uninfected individuals. Further, SaFA exposure altered monocyte subset phenotypes and inflammatory cytokine production in vitro . Conclusions: The lipidome is altered in ART-treated HIV infection, and may contribute to inflammation and CVD progression. Detailed lipidomic analyses may better assess CVD risk in both HIV+ and HIV– individuals than does traditional lipid profiling.

Macrophage maturation from blood monocytes is altered in people with HIV, and is linked to serum lipid profiles and activation indices: A model for studying atherogenic mechanisms

“…These gene expression profiles are suggestive of a pro-inflammatory, pro-atherosclerotic phenotype of MDMs in PWH [16]. Monocyte subset proportions are altered in PWH and have differential expression of activation and adhesion molecules [13,[25][26][27]. Here, we confirm enrichment of inflammatory (CD14 + CD16 + ) and patrolling (CD14 dim CD16 + ) monocytes, and increased levels of innate immune receptors and activation markers, including TLR4, SR-A, CD163, Tissue Factor (TF), and CD36 on monocytes from PWH compared to those from people without HIV.…”

“…Certain lipid classes and lipid species are associated with CVD in PWH and in the general population, and may drive vascular inflammation and myeloid cell activation [27,[35][36][37][38][39]. Elevated https://doi.org/10.1371/journal.ppat.1008869.g002…”

Harvard HIV and Aging Workshop: Perspectives and Priorities from Claude D. Pepper Centers and Centers for AIDS Research

“…There is a growing appreciation that traditional lipid measurements (low-density lipoprotein, high-density lipoprotein, and total cholesterol) may inadequately capture dyslipidemia and CVD risk in PWH receiving ART. 56 Members of the Funderburg group 57,58 and others 59 have recently reported substantial differences in lipid classes and lipid species in PWH and uninfected populations, even when traditional lipid measurements between these groups were not different. These advanced lipid analyses have also linked alterations in the lipidome to inflammation, monocyte activation, and atherosclerosis.…”

Standardization of sampling and sample preparation for analysis of human monocyte subsets in peripheral blood

“…Intermediate monocytes are suggested to be more likely to fuse into multinucleated giant cells and be precursors of osteoclasts [159,160]. [34,115,[164][165][166][167][168][169][170][171][172]. However, the detailed definition of each cell subset of each monocyte subset remains a matter of debate (see Table 5 for more detailed descriptions).…”

“…Defined in mice. [94] Classical monocytes Intermediate monocytes Non-classical CD33 high , CD86 +/high , CD64 + , HLA-DR + , CCR2 high CD33 high CD86 +/high CD64 + HLA-DR high CCR2 low CD33 low CD86 high [175] Classical monocytes Intermediate monocytes Non-classical CD300e high CD14 high CD16 negative CD300e hi CD14 hi CD16 + CD300e hi CD14 low/-CD16 + [111] Classical monocytes Intermediate monocytes Non-classical CD14 ++ CD16 − CD14 ++ CD16 + CD14 + CD16 ++ [34,165,[168][169][170][171][172]176]* *There is a great variation in the overall antibody panel and gating strategy applied, but all the studies identified monocyte subsets by CD14 and CD16 expression.…”