4.6 Article

Maraviroc Is Associated with Latent HIV-1 Reactivation through NF-κB Activation in Resting CD4+ T Cells from HIV-Infected Individuals on Suppressive Antiretroviral Therapy

Journal

JOURNAL OF VIROLOGY
Volume 92, Issue 9, Pages -

Publisher

AMER SOC MICROBIOLOGY
DOI: 10.1128/JVI.01931-17

Keywords

HIV-1; maraviroc; NF-kappa B; latency; LRA; reservoir; persistence; HIV infected

Categories

Funding

  1. ViiV Healthcare
  2. Plan Nacional R + D + I [RD12/0017/0017]
  3. Instituto de Salud Carlos III (ISCIII)-Subdireccion General de Evaluacion
  4. Fondo Europeo de Desarrollo Regional (FEDER)

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Maraviroc is a CCR5 antagonist used in the treatment of HIV-1 infection. We and others have suggested that maraviroc could reactivate latent HIV-1. To test the latency-reversing potential of maraviroc and the mechanisms involved, we performed a phase II, single-center, open-label study in which maraviroc was administered for 10 days to 20 HIV-1-infected individuals on suppressive antiretroviral therapy (EudraCT registration no. 2012-003215-66). All patients completed full maraviroc dosing and follow-up. The primary endpoint was to study whether maraviroc may reactivate HIV-1 latency, eliciting signaling pathways involved in the viral reactivation. An increase in HIV-1 transcription in resting CD4(+) T cells, estimated by levels of HIV-1 unspliced RNA, was observed. Moreover, activation of the NF-kappa B transcription factor was observed in these cells. To elucidate the mechanism of NF-kappa B activation by maraviroc, we have evaluated in HeLa P4 C5 cells, which stably express CCR5, whether maraviroc could be acting as a partial CCR5 agonist, with no other mechanisms or pathways involved. Our results show that maraviroc can induce NF-kappa B activity and that NF-kappa B targets gene expression by CCR5 binding, since the use of TAK779, a CCR5 inhibitor, blocked NF-kappa B activation and functionality. Taking the results together, we show that maraviroc may have a role in the activation of latent virus transcription through the activation of NF-kappa B as a result of binding CCR5. Our results strongly support a novel use of maraviroc as a potential latency reversal agent in HIV-1-infected patients. IMPORTANCE HIV-1 persistence in a small pool of long-lived latently infected resting CD4(+) T cells is a major barrier to viral eradication in HIV-1-infected patients on antiretroviral therapy. A potential strategy to cure HIV-1-infection is the use of latency-reversing agents to eliminate the reservoirs established in resting CD4(+) T cells. As no drug has been shown to be completely effective so far, the search for new drugs and combinations remains a priority for HIV cure. We examined the ability of maraviroc, a CCR5 antagonist used as an antiretroviral drug, to activate latent HIV-1 in infected individuals on antiretroviral therapy. The study showed that maraviroc can activate NF-kappa B and, subsequently, induce latent HIV-1-transcription in resting CD4(+) T cells from HIV-1-infected individuals on suppressive antiretroviral therapy. Additional interventions will be needed to eliminate latent HIV-1 infection. Our results suggest that maraviroc may be a new latency-reversing agent to interfere with HIV-1 persistence during antiretroviral therapy.

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