Human Galectin-9 Is a Potent Mediator of HIV Transcription and Reactivation.

Mohamed Abdel-Mohsen,Sheila Keating,Satish K Pillai,Jonah B Sacha,Lishomwa C Ndhlovu,Leonard Chavez,Marion Lanteri,Mitsuomi Hirashima,Rebecca Hoh,Toshiro Niki,Philip J Norris,Xutao Deng,Michael L Samuels,Cecilia M Shikuma,Ravi Tandon,Ali Danesh,Steven G Deeks,Glen M Chew,Guido Silvestri

doi:10.1371/journal.ppat.1005677

Abstract

Identifying host immune determinants governing HIV transcription, latency and infectivity in vivo is critical to developing an HIV cure. Based on our recent finding that the host factor p21 regulates HIV transcription during antiretroviral therapy (ART), and published data demonstrating that the human carbohydrate-binding immunomodulatory protein galectin-9 regulates p21, we hypothesized that galectin-9 modulates HIV transcription. We report that the administration of a recombinant, stable form of galectin-9 (rGal-9) potently reverses HIV latency in vitro in the J-Lat HIV latency model. Furthermore, rGal-9 reverses HIV latency ex vivo in primary CD4+ T cells from HIV-infected, ART-suppressed individuals (p = 0.002), more potently than vorinostat (p = 0.02). rGal-9 co-administration with the latency reversal agent "JQ1", a bromodomain inhibitor, exhibits synergistic activity (p<0.05). rGal-9 signals through N-linked oligosaccharides and O-linked hexasaccharides on the T cell surface, modulating the gene expression levels of key transcription initiation, promoter proximal-pausing, and chromatin remodeling factors that regulate HIV latency. Beyond latent viral reactivation, rGal-9 induces robust expression of the host antiviral deaminase APOBEC3G in vitro and ex vivo (FDR<0.006) and significantly reduces infectivity of progeny virus, decreasing the probability that the HIV reservoir will be replenished when latency is reversed therapeutically. Lastly, endogenous levels of soluble galectin-9 in the plasma of 72 HIV-infected ART-suppressed individuals were associated with levels of HIV RNA in CD4+ T cells (p<0.02) and with the quantity and binding avidity of circulating anti-HIV antibodies (p<0.009), suggesting a role of galectin-9 in regulating HIV transcription and viral production in vivo during therapy. Our data suggest that galectin-9 and the host glycosylation machinery should be explored as foundations for novel HIV cure strategies.

Highlights

Antiretroviral therapy (ART) has demonstrated efficacy and durability in suppressing HIV replication in infected individuals
While antiretroviral therapy (ART) has significantly decreased the morbidity and mortality associated with HIV infection, a cure is not achieved due to the persistence of HIV latently-infected cells during treatment
Identifying the principal host immune determinants governing HIV transcription, latency, and infectivity in vivo will be a critical step in developing an effective curative strategy for HIV infection

Summary

Introduction

Antiretroviral therapy (ART) has demonstrated efficacy and durability in suppressing HIV replication in infected individuals. ART does not achieve viral eradication due to the persistence of latently infected long-lived cells [1,2]. Several recent studies demonstrating continued morbidity during suppressive ART have created profound interest in developing a cure for HIV infection. The elimination of the latent reservoir is critical to achieving HIV eradication, as demonstrated by resurgence of virus post ART-cessation [3,4]. A “functional cure” involving control of virus to undetectable levels in the absence of complete eradication may be established to minimize ART-associated morbidity and enable ART-independent suppression of HIV to clinically undetectable levels, as demonstrated in recent clinical studies [5]. Identifying host determinants governing HIV transcription, latency, and infectivity in vivo will be a critical step in developing both of these curative modalities for HIV infection

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