title: Human Galectin-9 Is a Potent Mediator of HIV Transcription and Reactivation.
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.
authors.affiliation: Blood Systems Research Institute, San Francisco, California, United States of America.|University of California, San Francisco, California, United States of America.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Abdel-Mohsen
authors.affiliation: Blood Systems Research Institute, San Francisco, California, United States of America.
authors.forename: Leonard
authors.initials: L
authors.lastname: Chavez
authors.affiliation: School of Biotechnology, Jawaharlal Nehru University, New Delhi, India.
authors.forename: Ravi
authors.initials: R
authors.lastname: Tandon
authors.affiliation: Hawaii Center for AIDS, John A. Burns School of Medicine, University of Hawaii, Honolulu, Hawaii, United States of America.
authors.forename: Glen M
authors.initials: GM
authors.lastname: Chew
authors.affiliation: Blood Systems Research Institute, San Francisco, California, United States of America.
authors.forename: Xutao
authors.initials: X
authors.lastname: Deng
authors.affiliation: Blood Systems Research Institute, San Francisco, California, United States of America.|University of California, San Francisco, California, United States of America.
authors.forename: Ali
authors.initials: A
authors.lastname: Danesh
authors.affiliation: Blood Systems Research Institute, San Francisco, California, United States of America.
authors.forename: Sheila
authors.initials: S
authors.lastname: Keating
authors.affiliation: Blood Systems Research Institute, San Francisco, California, United States of America.
authors.forename: Marion
authors.initials: M
authors.lastname: Lanteri
authors.affiliation: RainDance Technologies, Inc., Billerica, Massachusetts, United States of America.
authors.forename: Michael L
authors.initials: ML
authors.lastname: Samuels
authors.affiliation: University of California, San Francisco, California, United States of America.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Hoh
authors.affiliation: Vaccine & Gene Therapy Institute, Oregon Health & Science University, Portland, Oregon, United States of America.|Oregon National Primate Research Center, Oregon Health & Science University, Portland, Oregon, United States of America.
authors.forename: Jonah B
authors.initials: JB
authors.lastname: Sacha
authors.affiliation: Blood Systems Research Institute, San Francisco, California, United States of America.|University of California, San Francisco, California, United States of America.
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Norris
authors.affiliation: GalPharma Co., Ltd., Takamatsu-shi, Kagawa, Japan.|Department of Immunology and Immunopathology, Kagawa University, Kagawa, Japan.
authors.forename: Toshiro
authors.initials: T
authors.lastname: Niki
authors.affiliation: Hawaii Center for AIDS, John A. Burns School of Medicine, University of Hawaii, Honolulu, Hawaii, United States of America.
authors.forename: Cecilia M
authors.initials: CM
authors.lastname: Shikuma
authors.affiliation: GalPharma Co., Ltd., Takamatsu-shi, Kagawa, Japan.|Department of Immunology and Immunopathology, Kagawa University, Kagawa, Japan.
authors.forename: Mitsuomi
authors.initials: M
authors.lastname: Hirashima
authors.affiliation: University of California, San Francisco, California, United States of America.
authors.forename: Steven G
authors.initials: SG
authors.lastname: Deeks
authors.affiliation: Hawaii Center for AIDS, John A. Burns School of Medicine, University of Hawaii, Honolulu, Hawaii, United States of America.
authors.forename: Lishomwa C
authors.initials: LC
authors.lastname: Ndhlovu
authors.affiliation: Blood Systems Research Institute, San Francisco, California, United States of America.|University of California, San Francisco, California, United States of America.
authors.forename: Satish K
authors.initials: SK
authors.lastname: Pillai
mesh_terms: D019380:Anti-HIV Agents / Q000627:therapeutic use; D015153:Blotting, Western; D015496:CD4-Positive T-Lymphocytes / Q000821:virology*; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D037161:Galectins / Q000378:metabolism*; D020869:Gene Expression Profiling; D015658:HIV Infections / Q000188:drug therapy / Q000378:metabolism* / Q000821:virology; D015497:HIV-1 / Q000502:physiology; D006801:Humans; D016133:Polymerase Chain Reaction; D014158:Transcription, Genetic / Q000502:physiology; D059467:Transcriptome; D014775:Virus Activation / Q000502:physiology*; D017735:Virus Latency / Q000502:physiology*
chemical_list: D019380:Anti-HIV Agents; D037161:Galectins; C105032:LGALS9 protein, human