HIV-1-Mediated BAFF Secretion in Macrophages Does Not Require Endosomal TLRs, Type-I IFN, and Nef, but Depends on the Cellular Phenotype Status

J Immunol. 2016 May 1;196(9):3806-17. doi: 10.4049/jimmunol.1501249. Epub 2016 Mar 28.

Abstract

HIV-1 infection is characterized by persistent viral replication, chronic immune activation, and CD4(+) T cell depletion. Moreover, several immune dysfunctions are observed in cells that are not targeted by the virus, such as B cells. Some B cell abnormalities include hypergammaglobulinemia, nonspecific B cell activation, class switching, increased cell turnover, breakage of tolerance, and a loss of the capacity to generate and maintain memory. Several cytokines and growth factors that are increased in the serum of HIV-1-infected individuals have been suggested to directly or indirectly trigger B cell activation, and one of these is BAFF. In this study, we investigate the ability of fully competent (R5-tropic) HIV-1 to induce BAFF production by monocyte-derived macrophages (MDMs). We demonstrate here that HIV-1 drives BAFF production in MDMs in a type-I IFN- and TLR-independent manner. Moreover, we determine that HIV-1 Nef accessory protein is dispensable in BAFF upregulation as a nef-deleted HIV-1 strain is still able to increase BAFF at levels similar to the wild type strain. Finally, we show that the macrophage phenotype status affects HIV-1 replication and BAFF induction, as both were abrogated in MDMs displaying a M1 phenotype. This study provides new useful information about the increased levels of BAFF observed during HIV-1 infection and highlights the importance of macrophages as a source of BAFF, a phenomenon that might contribute to B cell dysfunctions at inflammatory tissue sites in infected individuals.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • B-Cell Activating Factor / metabolism*
  • Cell Differentiation
  • Cells, Cultured
  • Cytokines / metabolism
  • Endosomes / metabolism
  • HIV Infections / immunology*
  • HIV-1 / immunology*
  • Humans
  • Interferon Type I / metabolism
  • Macrophages / immunology*
  • Macrophages / virology
  • Phenotype
  • RNA, Small Interfering / genetics
  • Th1 Cells / immunology
  • Toll-Like Receptors / metabolism
  • nef Gene Products, Human Immunodeficiency Virus / genetics
  • nef Gene Products, Human Immunodeficiency Virus / metabolism*

Substances

  • B-Cell Activating Factor
  • Cytokines
  • Interferon Type I
  • RNA, Small Interfering
  • TNFSF13B protein, human
  • Toll-Like Receptors
  • nef Gene Products, Human Immunodeficiency Virus
  • nef protein, Human immunodeficiency virus 1