title: Alpha-1-antitrypsin interacts with gp41 to block HIV-1 entry into CD4+ T lymphocytes.
abstract: Study of a clinic case reveals that alpha-1-antitrypsin (AAT) deficiency is related to CD4+ T cell count decline and AIDS progression, suggesting that AAT might be an endogenous inhibitor of HIV/AIDS. Previous study shows that AAT inhibits HIV-1 replication in infected host cells and the C-terminus fragment of AAT, VIRIP, interferes with HIV-1 infection. However, it is still unclear whether and how intact AAT inhibits HIV-1 infection. It is also unknown what the mechanism of AAT is and which critical step(s) are involved.
  
  
  
  In the present study, the C-terminus of AAT (C) was synthesized. C terminus-truncated AAT (ΔAAT) was also prepared by digesting AAT with metalloproteinase. Primary CD4+ T cells were then co-cultured with HIV-1 with the presence or absence of AAT/C/ΔAAT to detect cis-infection of HIV-1. The interaction between AAT/C/ΔAAT and gp120/gp41 was also measured. Meanwhile, HIV-1 reverse transcriptase activity and viral DNA integration were also detected in these lymphocytes. The results demonstrated that AAT and C, not ΔAAT, inhibited HIV-1 entry by directly interacting with gp41. Meanwhile, AAT, C and ΔAAT could not directly interfere with the steps of viral RNA reverse transcription and viral DNA integration.
  
  
  
  AAT inhibits HIV-1 entry by directly interacting with gp41 through its C-terminus and thereby inhibits HIV-1 infection.
authors.affiliation: Clinic Services Program, Leidos Biomedical Research Inc., Frederick National Laboratory for Cancer Research, Frederick, MD, 21702, USA. xueyuan.zhou@nih.gov.
authors.forename: Xueyuan
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Hainan Key Laboratory for Sustainable Utilization of Tropical Bioresources, College of Agriculture, Hainan University, Haikou, Hainan, 570228, China. zhuliu@hainu.edu.cn.
authors.forename: Zhu
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Department of Chemistry, University of Alabama at Birmingham, Birmingham, AL, 35294, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Clinic Services Program, Leidos Biomedical Research Inc., Frederick National Laboratory for Cancer Research, Frederick, MD, 21702, USA.
authors.forename: Joseph W
authors.initials: JW
authors.lastname: Adelsberger
authors.affiliation: Clinic Services Program, Leidos Biomedical Research Inc., Frederick National Laboratory for Cancer Research, Frederick, MD, 21702, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Yang
authors.affiliation: Department of Chemistry and Biochemistry, Brigham Young University, Provo, UT, 84602, USA.
authors.forename: Gregory F
authors.initials: GF
authors.lastname: Burton
mesh_terms: D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000821:virology*; D002478:Cells, Cultured; D018920:Coculture Techniques; D004279:DNA, Viral / Q000187:drug effects; D015699:HIV Envelope Protein gp120 / Q000187:drug effects; D015700:HIV Envelope Protein gp41 / Q000187:drug effects*; D015658:HIV Infections / Q000821:virology; D054303:HIV Reverse Transcriptase; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development; D006801:Humans; D019426:Integrases; D045726:Metalloproteases / Q000378:metabolism; D060066:Protein Interaction Maps; D012367:RNA, Viral; D019713:Receptors, CCR5 / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000378:metabolism; D016662:Virus Integration / Q000187:drug effects; D053586:Virus Internalization / Q000187:drug effects*; D014779:Virus Replication / Q000187:drug effects*; D000515:alpha 1-Antitrypsin / Q000378:metabolism / Q000494:pharmacology*
chemical_list: C584933:CCR5 protein, human; C527276:CXCR4 protein, human; D004279:DNA, Viral; D015699:HIV Envelope Protein gp120; D015700:HIV Envelope Protein gp41; D012367:RNA, Viral; D019713:Receptors, CCR5; D019718:Receptors, CXCR4; D000515:alpha 1-Antitrypsin; C514787:gp41 protein, Human immunodeficiency virus 1; D019426:Integrases; C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase; D045726:Metalloproteases
keywords: Alpha-1-antitrypsin; HIV-1; Integrase; Reverse transcriptase; gp41