title: Provirus activation plus CD59 blockage triggers antibody-dependent complement-mediated lysis of latently HIV-1-infected cells.
abstract: Latently HIV-1-infected cells are recognized as the last barrier toward viral eradication and cure. To purge these cells, we combined a provirus stimulant with a blocker of human CD59, a key member of the regulators of complement activation, to trigger Ab-dependent complement-mediated lysis. Provirus stimulants including prostratin and histone deacetylase inhibitors such as romidepsin and suberoylanilide hydroxamic acid activated proviruses in the latently HIV-1-infected T cell line ACH-2 as virion production and viral protein expression on the cell surface were induced. Romidepsin was the most attractive provirus stimulant as it effectively activated proviruses at nanomolar concentrations that can be achieved clinically. Antiretroviral drugs including two protease inhibitors (atazanavir and darunavir) and an RT inhibitor (emtricitabine) did not affect the activity of provirus stimulants in the activation of proviruses. However, saquinavir (a protease inhibitor) markedly suppressed virus production, although it did not affect the percentage of cells expressing viral Env on the cell surface. Provirus-activated ACH-2 cells expressed HIV-1 Env that colocalized with CD59 in lipid rafts on the cell surface, facilitating direct interaction between them. Blockage of CD59 rendered provirus-activated ACH-2 cells and primary human CD4(+) T cells that were latently infected with HIV-1 sensitive to Ab-dependent complement-mediated lysis by anti-HIV-1 polyclonal Abs or plasma from HIV-1-infected patients. Therefore, a combination of provirus stimulants with regulators of complement activation blockers represents a novel approach to eliminate HIV-1.
authors.affiliation: Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN 46202; Center for AIDS Research, Indiana University School of Medicine, Indianapolis, IN 46202;
authors.forename: Jie
authors.initials: J
authors.lastname: Lan
authors.affiliation: Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN 46202; Center for AIDS Research, Indiana University School of Medicine, Indianapolis, IN 46202; Zhejiang Provincial Key Laboratory for Technology and Application of Model Organisms, Wenzhou Medical College, Wenzhou 325035, China;
authors.forename: Kai
authors.initials: K
authors.lastname: Yang
authors.affiliation: Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN 46202; Center for AIDS Research, Indiana University School of Medicine, Indianapolis, IN 46202;
authors.forename: Daniel
authors.initials: D
authors.lastname: Byrd
authors.affiliation: Zhejiang Provincial Key Laboratory for Technology and Application of Model Organisms, Wenzhou Medical College, Wenzhou 325035, China;
authors.forename: Ningjie
authors.initials: N
authors.lastname: Hu
authors.affiliation: Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN 46202; Center for AIDS Research, Indiana University School of Medicine, Indianapolis, IN 46202;
authors.forename: Tohti
authors.initials: T
authors.lastname: Amet
authors.affiliation: Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN 46202; Center for AIDS Research, Indiana University School of Medicine, Indianapolis, IN 46202;
authors.forename: Nicole
authors.initials: N
authors.lastname: Shepherd
authors.affiliation: Division of Infectious Diseases, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202; and.
authors.forename: Mona
authors.initials: M
authors.lastname: Desai
authors.affiliation: Zhejiang Provincial Key Laboratory for Technology and Application of Model Organisms, Wenzhou Medical College, Wenzhou 325035, China;
authors.forename: Jimin
authors.initials: J
authors.lastname: Gao
authors.affiliation: Division of Infectious Diseases, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202; and.
authors.forename: Samir
authors.initials: S
authors.lastname: Gupta
authors.affiliation: Department of Infectious Diseases, Tangdu Hospital, Fourth Military Medical University, Xi'an 710038, China.
authors.forename: Yongtao
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN 46202; Center for AIDS Research, Indiana University School of Medicine, Indianapolis, IN 46202; Division of Infectious Diseases, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202; and andyu@iupui.edu.
authors.forename: Qigui
authors.initials: Q
authors.lastname: Yu
mesh_terms: D000293:Adolescent; D000328:Adult; D019380:Anti-HIV Agents / Q000008:administration & dosage; D000920:Antibody-Dependent Cell Cytotoxicity; D018957:CD59 Antigens / Q000276:immunology*; D002460:Cell Line; D003167:Complement Activation; D003165:Complement System Proteins / Q000276:immunology*; D005260:Female; D015483:HIV Antibodies / Q000276:immunology*; D019302:HIV Envelope Protein gp160 / Q000276:immunology; D015658:HIV Infections / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D011533:Proviruses / Q000276:immunology*
chemical_list: D019380:Anti-HIV Agents; D018957:CD59 Antigens; D015483:HIV Antibodies; D019302:HIV Envelope Protein gp160; C051590:CD59 protein, human; D003165:Complement System Proteins