A feedback regulatory pathway between LDL and alpha-1 proteinase inhibitor in chronic inflammation and infection.
Dietary lipids are transported via lymph to the liver and transformed to lipoproteins which bind to members of the low density lipoprotein receptor family (LDL-RFMs). Certain LDL-RFMs, e.g., very low density lipoprotein receptor (VLDLR), are also bound by inactivated proteinase inhibitors, the most abundant being α1proteinase inhibitor (α1PI, α1antitrypsin). Inflammation/infection, including HIV-1 infection, is accompanied by low levels of CD4+ T cells and active α1PI and high levels of inactivated α1PI. By inducing LDL-RFMs-mediated cellular locomotion, active α1PI regulates the number of CD4+ T cells. We sought to investigate whether CD4+ T cells and α1PI directly impact lipoprotein levels. At the cellular level, we show that active α1PI is required for VLDLR-mediated uptake of receptor-associated cargo, specifically CD4-bound HIV-1. We show that active α1PI levels linearly correlate with LDL levels in HIV-1 infected individuals (P<0.001) and that therapeutic, weekly infusions of active α1PI elevate the number of CD4+ T cells and HDL levels while lowering LDL levels in patients on antiretroviral therapy with controlled HIV-1. Based on the unusual combination of lipodystrophy and low levels of α1PI and CD4+ T cells in HIV-1 disease, we reveal that LDL and α1PI participate in a feedback regulatory pathway. We demonstrate integral roles for sequentially acting active and inactive α1PI in the uptake and recycling of receptors and cargo aggregated with VLDLR including CD4 and chemokine receptors. Evidence supports a role for α1PI as a primary sentinel to deploy the immune system as a consequence of its role in lipoprotein transport.
Institute for Human Genetics and Biochemistry, Vesenaz, 1222, Switzerland and Department of Medicine, Weill Cornell Medical College, New York, New York 10065, USA.
Cynthia L
CL
Bristow
Rozbeh
R
Modarresi
Mariya A
MA
Babayeva
Michelle
M
LaBrunda
Roya
R
Mukhtarzad
Maylis
M
Trucy
Aaron
A
Franklin
Rudy E R
RE
Reeves
Allegra
A
Long
Michael P
MP
Mullen
Jose
J
Cortes
Ronald
R
Winston
D000328:Adult; D002460:Cell Line; D002478:Cells, Cultured; D004705:Endocytosis / Q000187:drug effects; D005434:Flow Cytometry; D015658:HIV Infections / Q000188:drug therapy / Q000276:immunology; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D007249:Inflammation / Q000188:drug therapy / Q000276:immunology; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D000515:alpha 1-Antitrypsin / Q000494:pharmacology / Q000627:therapeutic use*
D015842:Serine Proteinase Inhibitors; D000515:alpha 1-Antitrypsin