Attenuation of pathogenic immune responses during infection with human and simian immunodeficiency virus (HIV/SIV) by the tetracycline derivative minocycline.

Julia L Drewes,M Christine Zink,Gene M Shearer,David R Graham,Zhaohao Liao,Elizabeth L Engle,Gregory L Szeto

doi:10.1371/journal.pone.0094375

Abstract

HIV immune pathogenesis is postulated to involve two major mechanisms: 1) chronic innate immune responses that drive T cell activation and apoptosis and 2) induction of immune regulators that suppress T cell function and proliferation. Both arms are elevated chronically in lymphoid tissues of non-natural hosts, which ultimately develop AIDS. However, these mechanisms are not elevated chronically in natural hosts of SIV infection that avert immune pathogenesis despite similarly high viral loads. In this study we investigated whether minocycline could modulate these pathogenic antiviral responses in non-natural hosts of HIV and SIV. We found that minocycline attenuated in vitro induction of type I interferon (IFN) and the IFN-stimulated genes indoleamine 2,3-dioxygenase (IDO1) and TNF-related apoptosis inducing ligand (TRAIL) in human plasmacytoid dendritic cells and PBMCs exposed to aldrithiol-2 inactivated HIV or infectious influenza virus. Activation-induced TRAIL and expression of cytotoxic T-lymphocyte antigen 4 (CTLA-4) in isolated CD4+ T cells were also reduced by minocycline. Translation of these in vitro findings to in vivo effects, however, were mixed as minocycline significantly reduced markers of activation and activation-induced cell death (CD25, Fas, caspase-3) but did not affect expression of IFNβ or the IFN-stimulated genes IDO1, FasL, or Mx in the spleens of chronically SIV-infected pigtailed macaques. TRAIL expression, reflecting the mixed effects of minocycline on activation and type I IFN stimuli, was reduced by half, but this change was not significant. These results show that minocycline administered after infection may protect against aspects of activation-induced cell death during HIV/SIV immune disease, but that in vitro effects of minocycline on type I IFN responses are not recapitulated in a rapid progressor model in vivo.

Highlights

In the absence of antiretroviral therapy, the majority of HIVinfected patients develop chronic immune activation, immunosuppression and eventually AIDS in a disease process representative of HIV/SIV infection in non-natural hosts (NNH)
IFNs and downstream IFN-stimulated genes (ISGs) such as TNF-related apoptosis inducing ligand (TRAIL), Fas ligand (FasL), and programmed death ligand 1 (PDL1) in chronic infection of NNH compared to NH suggests that IFN responses are a point of divergence between pathogenic and nonpathogenic HIV/SIV infection and represent a potential target for immunotherapy [5,6,7,8,9]
Differences between NH and NNH suggest that chronic induction of the IFN and IDO pathways are at the root of immune pathogenesis seen in HIV infection [42]

Summary

Introduction

In the absence of antiretroviral therapy, the majority of HIVinfected patients develop chronic immune activation, immunosuppression and eventually AIDS in a disease process representative of HIV/SIV infection in non-natural hosts (NNH). IDO activity and TRAIL (both soluble and membraneassociated) remain elevated even in patients on suppressive cART [13,14,15] In addition to their purported role in chronic HIV/SIV infection, many of these genes are thought to be involved in the ‘‘cytokine storm’’ that contributes to pervasive inflammation, lymphocytopenia, and apoptosis during highly pathogenic influenza infections [16,17,18,19]. These immune responses represent potential therapeutic targets for HIV infection and other pathogenic viral infections such as influenza

Methods

Results

Conclusion