title: β-Catenin/TCF-4 signaling regulates susceptibility of macrophages and resistance of monocytes to HIV-1 productive infection.
abstract: Cells of the monocyte/macrophage lineage are an important target for HIV-1 infection. They are often at anatomical sites linked to HIV-1 transmission and are an important vehicle for disseminating HIV-1 throughout the body, including the central nervous system. Monocytes do not support extensive productive HIV-1 replication, but they become more susceptible to HIV-1infection as they differentiate into macrophages. The mechanisms guiding susceptibility of HIV-1 replication in monocytes versus macrophages are not entirely clear. We determined whether endogenous activity of β-catenin signaling impacts differential susceptibility of monocytes and monocyte-derived macrophages (MDMs) to productive HIV-1 replication. We show that monocytes have an approximately 4-fold higher activity of β-catenin signaling than MDMs. Inducing β-catenin in MDMs suppressed HIV-1 replication by 5-fold while inhibiting endogenous β-catenin signaling in monocytes by transfecting with a dominant negative mutant for the downstream effector of β- catenin (TCF-4) promoted productive HIV-1 replication by 6-fold. These findings indicate that β-catenin/TCF-4 is an important pathway for restricted HIV-1 replication in monocytes and plays a significant role in potentiating HIV-1 replication as monocytes differentiate into macrophages. Targeting this pathway may provide a novel strategy to purge the latent reservoir from monocytes/macrophages, especially in sanctuary sites for HIV-1 such as the central nervous system.
authors.forename: Yosra
authors.initials: Y
authors.lastname: Aljawai
authors.forename: Maureen H
authors.initials: MH
authors.lastname: Richards
authors.forename: Melanie S
authors.initials: MS
authors.lastname: Seaton
authors.forename: Srinivas D
authors.initials: SD
authors.lastname: Narasipura
authors.affiliation: Rush University Medical Center, Department of Immunology and Microbiology, 1735 W. Harrison Street, 614 Cohn, Chicago, IL 60612, USA. lalharth@rush.edu.
authors.forename: Lena
authors.initials: L
authors.lastname: Al-Harthi
mesh_terms: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000378:metabolism*; D015497:HIV-1 / Q000276:immunology / Q000502:physiology*; D006801:Humans; D008264:Macrophages / Q000276:immunology* / Q000821:virology; D009000:Monocytes / Q000276:immunology* / Q000821:virology; D015398:Signal Transduction; D000073940:Transcription Factor 4; D014157:Transcription Factors / Q000378:metabolism*; D014779:Virus Replication; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; C532096:TCF4 protein, human; D000073940:Transcription Factor 4; D014157:Transcription Factors; D051176:beta Catenin