title: HLA-C increases HIV-1 infectivity and is associated with gp120.
abstract: BACKGROUND
  A recently identified genetic polymorphism located in the 5' region of the HLA-C gene is associated with individual variations in HIV-1 viral load and with differences in HLA-C expression levels. HLA-C has the potential to restrict HIV-1 by presenting epitopes to cytotoxic T cells but it is also a potent inhibitor of NK cells. In addition, HLA-C molecules incorporated within the HIV-1 envelope have been shown to bind to the envelope glycoprotein gp120 and enhance viral infectivity. We investigated this last property in cell fusion assays where the expression of HLA-C was silenced by small interfering RNA sequences. Syncytia formation was analyzed by co-cultivating cell lines expressing HIV-1 gp120/gp41 from different laboratory and primary isolates with target cells expressing different HIV-1 co-receptors. Virus infectivity was analyzed using pseudoviruses. Molecular complexes generated during cell fusion (fusion complexes) were purified and analyzed for their HLA-C content.
  
  
  RESULTS
  HLA-C positive cells co-expressing HIV-1 gp120/gp41 fused more rapidly and produced larger syncytia than HLA-C negative cells. Transient transfection of gp120/gp41 from different primary isolates in HLA-C positive cells resulted in a significant cell fusion increase. Fusion efficiency was reduced in HLA-C silenced cells compared to non-silenced cells when co-cultivated with different target cell lines expressing HIV-1 co-receptors. Similarly, pseudoviruses produced from HLA-C silenced cells were significantly less infectious. HLA-C was co-purified with gp120 from cells before and after fusion and was associated with the fusion complex.
  
  
  CONCLUSIONS
  Virionic HLA-C molecules associate to Env and increase the infectivity of both R5 and X4 viruses. Genetic polymorphisms associated to variations in HLA-C expression levels may therefore influence the individual viral set point not only by means of a regulation of the virus-specific immune response but also via a direct effect on the virus replicative capacity. These findings have implications for the understanding of the HIV-1 entry mechanism and of the role of Env conformational modifications induced by virion-associated host proteins.
authors.affiliation: Laboratory of Molecular Biology, Department of Mother and Child, Biology and Genetics, Section of Biology and Genetics, University of Verona, Strada le Grazie 8, 37134, Verona, Italy. andrea.matucci@medicina.univr.it
authors.forename: Andrea
authors.initials: A
authors.lastname: Matucci
authors.forename: Paola
authors.initials: P
authors.lastname: Rossolillo
authors.forename: Miriam
authors.initials: M
authors.lastname: Baroni
authors.forename: Antonio G
authors.initials: AG
authors.lastname: Siccardi
authors.forename: Alberto
authors.initials: A
authors.lastname: Beretta
authors.forename: Donato
authors.initials: D
authors.lastname: Zipeto
mesh_terms: D000818:Animals; D016466:CHO Cells; D002459:Cell Fusion; D002460:Cell Line; D006224:Cricetinae; D003412:Cricetulus; D015870:Gene Expression; D015726:Giant Cells / Q000378:metabolism / Q000821:virology; D015699:HIV Envelope Protein gp120 / Q000235:genetics / Q000378:metabolism*; D015658:HIV Infections / Q000378:metabolism* / Q000821:virology; D015497:HIV-1 / Q000472:pathogenicity / Q000502:physiology*; D015236:HLA-C Antigens / Q000235:genetics / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D041681:NIH 3T3 Cells; D011485:Protein Binding
chemical_list: D015699:HIV Envelope Protein gp120; D015236:HLA-C Antigens