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Interferon Alpha Subtype-Specific Suppression of HIV-1 Infection In Vivo.
Lavender, Kerry J; Gibbert, Kathrin; Peterson, Karin E; Van Dis, Erik; Francois, Sandra; Woods, Tyson; Messer, Ronald J; Gawanbacht, Ali; Müller, Janis A; Münch, Jan; Phillips, Katie; Race, Brent; Harper, Michael S; Guo, Kejun; Lee, Eric J; Trilling, Mirko; Hengel, Hartmut; Piehler, Jacob; Verheyen, Jens; Wilson, Cara C; Santiago, Mario L; Hasenkrug, Kim J; Dittmer, Ulf.
Afiliação
  • Lavender KJ; Laboratory of Persistent Viral Diseases, Rocky Mountain Laboratories, NIAID, NIH, Hamilton, Montana, USA.
  • Gibbert K; Institute for Virology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
  • Peterson KE; Laboratory of Persistent Viral Diseases, Rocky Mountain Laboratories, NIAID, NIH, Hamilton, Montana, USA.
  • Van Dis E; Laboratory of Persistent Viral Diseases, Rocky Mountain Laboratories, NIAID, NIH, Hamilton, Montana, USA.
  • Francois S; Institute for Virology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
  • Woods T; Laboratory of Persistent Viral Diseases, Rocky Mountain Laboratories, NIAID, NIH, Hamilton, Montana, USA.
  • Messer RJ; Laboratory of Persistent Viral Diseases, Rocky Mountain Laboratories, NIAID, NIH, Hamilton, Montana, USA.
  • Gawanbacht A; Institute of Molecular Virology, University of Ulm, Ulm, Germany.
  • Müller JA; Institute of Molecular Virology, University of Ulm, Ulm, Germany.
  • Münch J; Institute of Molecular Virology, University of Ulm, Ulm, Germany.
  • Phillips K; Laboratory of Persistent Viral Diseases, Rocky Mountain Laboratories, NIAID, NIH, Hamilton, Montana, USA.
  • Race B; Laboratory of Persistent Viral Diseases, Rocky Mountain Laboratories, NIAID, NIH, Hamilton, Montana, USA.
  • Harper MS; Department of Medicine, University of Colorado Denver, Aurora, Colorado, USA.
  • Guo K; Department of Medicine, University of Colorado Denver, Aurora, Colorado, USA.
  • Lee EJ; Department of Medicine, University of Colorado Denver, Aurora, Colorado, USA.
  • Trilling M; Institute for Virology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
  • Hengel H; Institute for Virology, University Medical Center, Albert Ludwig University of Freiburg, Freiburg, Germany.
  • Piehler J; Department of Biology, University of Osnabrück, Osnabrück, Germany.
  • Verheyen J; Institute for Virology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
  • Wilson CC; Department of Medicine, University of Colorado Denver, Aurora, Colorado, USA.
  • Santiago ML; Department of Medicine, University of Colorado Denver, Aurora, Colorado, USA.
  • Hasenkrug KJ; Laboratory of Persistent Viral Diseases, Rocky Mountain Laboratories, NIAID, NIH, Hamilton, Montana, USA khasenkrug@nih.gov ulf.dittmer@uni-due.de.
  • Dittmer U; Institute for Virology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany khasenkrug@nih.gov ulf.dittmer@uni-due.de.
J Virol ; 90(13): 6001-6013, 2016 07 01.
Article em En | MEDLINE | ID: mdl-27099312
ABSTRACT
UNLABELLED Although all 12 subtypes of human interferon alpha (IFN-α) bind the same receptor, recent results have demonstrated that they elicit unique host responses and display distinct efficacies in the control of different viral infections. The IFN-α2 subtype is currently in HIV-1 clinical trials, but it has not consistently reduced viral loads in HIV-1 patients and is not the most effective subtype against HIV-1 in vitro We now demonstrate in humanized mice that, when delivered at the same high clinical dose, the human IFN-α14 subtype has very potent anti-HIV-1 activity whereas IFN-α2 does not. In both postexposure prophylaxis and treatment of acute infections, IFN-α14, but not IFN-α2, significantly suppressed HIV-1 replication and proviral loads. Furthermore, HIV-1-induced immune hyperactivation, which is a prognosticator of disease progression, was reduced by IFN-α14 but not IFN-α2. Whereas ineffective IFN-α2 therapy was associated with CD8(+) T cell activation, successful IFN-α14 therapy was associated with increased intrinsic and innate immunity, including significantly higher induction of tetherin and MX2, increased APOBEC3G signature mutations in HIV-1 proviral DNA, and higher frequencies of TRAIL(+) NK cells. These results identify IFN-α14 as a potent new therapeutic that operates via mechanisms distinct from those of antiretroviral drugs. The ability of IFN-α14 to reduce both viremia and proviral loads in vivo suggests that it has strong potential as a component of a cure strategy for HIV-1 infections. The broad implication of these results is that the antiviral efficacy of each individual IFN-α subtype should be evaluated against the specific virus being treated. IMPORTANCE The naturally occurring antiviral protein IFN-α2 is used to treat hepatitis viruses but has proven rather ineffective against HIV in comparison to triple therapy with the antiretroviral (ARV) drugs. Although ARVs suppress the replication of HIV, they fail to completely clear infections. Since IFN-α acts by different mechanism than ARVs and has been shown to reduce HIV proviral loads, clinical trials are under way to test whether IFN-α2 combined with ARVs might eradicate HIV-1 infections. IFN-α is actually a family of 12 distinct proteins, and each IFN-α subtype has different efficacies toward different viruses. Here, we use mice that contain a human immune system, so they can be infected with HIV. With this model, we demonstrate that while IFN-α2 is only weakly effective against HIV, IFN-α14 is extremely potent. This discovery identifies IFN-α14 as a more powerful IFN-α subtype for use in combination therapy trials aimed toward an HIV cure.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Antivirais / Replicação Viral / Infecções por HIV / HIV-1 / Interferon-alfa / Carga Viral Tipo de estudo: Prognostic_studies Limite: Animals / Humans Idioma: En Revista: J Virol Ano de publicação: 2016 Tipo de documento: Article País de afiliação: Estados Unidos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Antivirais / Replicação Viral / Infecções por HIV / HIV-1 / Interferon-alfa / Carga Viral Tipo de estudo: Prognostic_studies Limite: Animals / Humans Idioma: En Revista: J Virol Ano de publicação: 2016 Tipo de documento: Article País de afiliação: Estados Unidos