Impact of APOL1 polymorphism and IL-1β priming in the entry and persistence of HIV-1 in human podocytes.
Patients of African ancestry with untreated HIV-1 infection and carrying the G1 or G2 kidney disease risk variants (Vs) at the APOL1 gene have a tenfold higher risk of developing HIV-associated nephropathy (HIVAN) compared to those with the non-risk wild type (WT) G0 variant. However, the mechanistic contribution of the APOL1 allelic state to kidney injury in HIV-1 infection remains to be elucidated.



Non-risk WT APOL1 is associated with lower intracellular levels of HIV-1 in conditionally immortalized human podocytes, while the over expression of G1 or G2 risk Vs significantly increases viral accumulation. The priming of podocytes with exogenous IL-1β facilitates HIV-1 entry, via the up-regulation of DC-SIGN. The over expression of APOL1 G1 and G2 risk Vs in combination with an increase in IL-1β levels causes a greater increase in viral concentration than either condition alone. In turn, HIV-1 and exogenous IL-1β together induce a de novo secretion of endogenous IL-1β and an increase of APOL1 gene expression.



Our findings indicate that the presence of risk Vs of APOL1 is permissive of HIV-1 persistence in human podocytes in synergy with IL-1β, a cytokine that characterizes the inflammatory milieu of acute and chronic phases of HIV-1 infection. The elucidation of these molecular mechanisms explains, at least in part, the higher frequency of HIVAN in populations carrying the risk polymorphic genetic variant of APOL1 gene.
Unit of Clinical and Experimental Immunology, Humanitas Clinical and Research Center, Rozzano, Milan, Italy. joanna.mikulak@humanitasresearch.it.|Istituto di Ricerca Genetica e Biomedica, UOS di Milano, Consiglio Nazionale delle Ricerche (UOS/IRGB/CNR), Rozzano, Milan, Italy. joanna.mikulak@humanitasresearch.it.
Joanna
0000-0001-8310-9543
J
Mikulak
Unit of Clinical and Experimental Immunology, Humanitas Clinical and Research Center, Rozzano, Milan, Italy.
Ferdinando
F
Oriolo
Unit of Clinical and Experimental Immunology, Humanitas Clinical and Research Center, Rozzano, Milan, Italy.
Federica
F
Portale
Unit of Clinical and Experimental Immunology, Humanitas Clinical and Research Center, Rozzano, Milan, Italy.
Paolo
P
Tentorio
Center for Excellence for Immunology and Inflammation, Feinstein Institute for Medical Research, Hofstra North Shore Long Island Jewish Medical School, New Hyde Park, NY, USA.
Xiqian
X
Lan
Children's Renal Unit and Academic Renal Unit, University of Bristol, Bristol, UK.
Moin A
MA
Saleem
Nephrology and Molecular Medicine, Technion Institute of Technology and Rambam Medical Center, Haifa, Israel.
Karl
K
Skorecki
Center for Excellence for Immunology and Inflammation, Feinstein Institute for Medical Research, Hofstra North Shore Long Island Jewish Medical School, New Hyde Park, NY, USA.
Pravin C
PC
Singhal
Unit of Clinical and Experimental Immunology, Humanitas Clinical and Research Center, Rozzano, Milan, Italy. domenico.mavilio@unimi.it.|Department of Medical Biotechnologies and Translational Medicine (BioMeTra), University of Milan, Milan, Italy. domenico.mavilio@unimi.it.
Domenico
0000-0001-6147-0952
D
Mavilio
D016263:AIDS-Associated Nephropathy / Q000235:genetics* / Q000276:immunology / Q000821:virology; D000349:Africa; D000483:Alleles; D000075944:Apolipoprotein L1; D001053:Apolipoproteins / Q000235:genetics*; D015815:Cell Adhesion Molecules / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease / Q000208:ethnology; D015658:HIV Infections / Q000208:ethnology / Q000235:genetics* / Q000276:immunology / Q000821:virology; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D053583:Interleukin-1beta / Q000096:biosynthesis / Q000276:immunology*; D037181:Lectins, C-Type / Q000235:genetics; D008075:Lipoproteins, HDL / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D050199:Podocytes / Q000821:virology*; D011110:Polymorphism, Genetic; D011956:Receptors, Cell Surface / Q000235:genetics; D053586:Virus Internalization; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin
D000075944:Apolipoprotein L1; D001053:Apolipoproteins; D015815:Cell Adhesion Molecules; D053583:Interleukin-1beta; D037181:Lectins, C-Type; D008075:Lipoproteins, HDL; D011956:Receptors, Cell Surface; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin; C108666:APOL1 protein, human
APOL1; DC-SIGN; HIV-1; HIVAN; IL-1β; Podocyte