Prolonged administration of maraviroc reactivates latent HIV in vivo but it does not prevent antiretroviral-free viral rebound

María Rosa López-Huertas,Julián Olalla-Sierra,Santiago Moreno,Carolina Gutiérrez,Montserrat Plana,Nadia Madrid-Elena,María Ángeles Muñoz-Fernández,Beatriz Hernández-Novoa,Rafael Delgado,Rafael Rubio

doi:10.1038/s41598-020-79002-w

Abstract

Human immunodeficiency virus (HIV) remains incurable due to latent viral reservoirs established in non-activated CD4 T cells that cannot be eliminated via antiretroviral therapy. Current efforts to cure HIV are focused on identifying drugs that will induce viral gene expression in latently infected cells, commonly known as latency reversing agents (LRAs). Some drugs have been shown to reactivate latent HIV but do not cause a reduction in reservoir size. Therefore, finding new LRAs or new combinations or increasing the round of stimulations is needed to cure HIV. However, the effects of these drugs on viral rebound after prolonged treatment have not been evaluated. In a previous clinical trial, antiretroviral therapy intensification with maraviroc for 48 weeks caused an increase in residual viremia and episomal two LTR-DNA circles suggesting that maraviroc could reactivate latent HIV. We amended the initial clinical trial to explore additional virologic parameters in stored samples and to evaluate the time to viral rebound during analytical treatment interruption in three patients. Maraviroc induced an increase in cell-associated HIV RNA during the administration of the drug. However, there was a rapid rebound of viremia after antiretroviral therapy discontinuation. HIV-specific T cell response was slightly enhanced. These results show that maraviroc can reactivate latent HIV in vivo but further studies are required to efficiently reduce the reservoir size.

Highlights

The human immunodeficiency virus type 1 (HIV) currently affects 37.9 million people worldwide according to the United Nation’s Human immunodeficiency virus (HIV) program, UNAIDS1
We showed that maraviroc intensification was associated with a trend to decrease the HIV reservoir size in memory CD4 T cells, to transiently increase residual viremia, and to enhance the levels of episomal two long terminal repeat (LTR) DNA circles (2-LTR-DNA), which are regarded as markers of recent infection events[27]
The clinical trial was amended to include additional virologic measurements using the stored samples and to include an analytical treatment interruption (ATI) of the Antiretroviral therapy (ART) that patients were receiving in order to determine the impact of maraviroc on the latent HIV infection in vivo and on viral rebound, respectively

Summary

Introduction

The human immunodeficiency virus type 1 (HIV) currently affects 37.9 million people worldwide according to the United Nation’s HIV program, UNAIDS1. We showed that maraviroc intensification was associated with a trend to decrease the HIV reservoir size in memory CD4 T cells, to transiently increase residual viremia, and to enhance the levels of episomal two long terminal repeat (LTR) DNA circles (2-LTR-DNA), which are regarded as markers of recent infection events[27] These effects persisted up to 24 weeks after discontinuation of maraviroc[30] and raised the hypothesis that maraviroc could increase transcriptional activation of the latent virus and could be regarded as new LRA. Later, it was confirmed in an additional clinical trial (Trial registration: EudraCT 2012-003215-66) that maraviroc activates HIV replication in vitro[31] and more notably, caused an increase in the expression of CA-US-RNA in rCD4T cells from HIV-infected patients on ART3 2,33. The above-mentioned clinical trial (ClinicalTrials.gov NCT00795444) was amended in order to study additional virologic parameters in stored samples and, more notably, time to viral rebound during an analytical treatment interruption (ATI) in three patients

Methods

Results

Conclusion