title: Inhibition of Heat Shock Protein 90 Prevents HIV Rebound.
abstract: HIV evades eradication because transcriptionally dormant proviral genomes persist in long-lived reservoirs of resting CD4(+) T cells and myeloid cells, which are the source of viral rebound after cessation of antiretroviral therapy. Dormant HIV genomes readily produce infectious virus upon cellular activation because host transcription factors activated specifically by cell stress and heat shock mediate full-length HIV transcription. The molecular chaperone heat shock protein 90 (Hsp90) is overexpressed during heat shock and activates inducible cellular transcription factors. Here we show that heat shock accelerates HIV transcription through induction of Hsp90 activity, which activates essential HIV-specific cellular transcription factors (NF-κB, NFAT, and STAT5), and that inhibition of Hsp90 greatly reduces gene expression mediated by these factors. More importantly, we show that Hsp90 controls virus transcription in vivo by specific Hsp90 inhibitors in clinical development, tanespimycin (17-(allylamino)-17-demethoxygeldanamycin) and AUY922, which durably prevented viral rebound in HIV-infected humanized NOD scid IL-2Rγ(-/-) bone marrow-liver-thymus mice up to 11 weeks after treatment cessation. Despite the absence of rebound viremia, we were able to recover infectious HIV from PBMC with heat shock. Replication-competent virus was detected in spleen cells from these nonviremic Hsp90 inhibitor-treated mice, indicating the presence of a tissue reservoir of persistent infection. Our novel findings provide in vivo evidence that inhibition of Hsp90 activity prevents HIV gene expression in replication-competent cellular reservoirs that would typically cause rebound in plasma viremia after antiretroviral therapy cessation. Alternating or supplementing Hsp90 inhibitors with current antiretroviral therapy regimens could conceivably suppress rebound viremia from persistent HIV reservoirs.
authors.affiliation: From the Division of Experimental Medicine, Department of Medicine, San Francisco General Hospital, University of California, San Francisco, California 94110.
authors.forename: Pheroze
authors.initials: P
authors.lastname: Joshi
authors.affiliation: From the Division of Experimental Medicine, Department of Medicine, San Francisco General Hospital, University of California, San Francisco, California 94110.
authors.forename: Ekaterina
authors.initials: E
authors.lastname: Maidji
authors.affiliation: From the Division of Experimental Medicine, Department of Medicine, San Francisco General Hospital, University of California, San Francisco, California 94110 cheryl.stoddart@ucsf.edu.
authors.forename: Cheryl A
authors.initials: CA
authors.lastname: Stoddart
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology; D016227:Benzoquinones / Q000494:pharmacology; D015153:Blotting, Western; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D005260:Female; D015658:HIV Infections / Q000378:metabolism / Q000517:prevention & control* / Q000821:virology; D015497:HIV-1 / Q000302:isolation & purification; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D047029:Lactams, Macrocyclic / Q000494:pharmacology; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D017735:Virus Latency / Q000187:drug effects*
chemical_list: D000998:Antiviral Agents; D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; C112765:tanespimycin
keywords: heat shock protein 90 (Hsp90); human immunodeficiency virus (HIV); hyperthermia; persistent reservoir; transcription factor; viral rebound; viral transcription