title: The effect of CD4 receptor downregulation and its downstream signaling molecules on HIV-1 latency.
abstract: HIV-1 can establish a latent infection in memory CD4+T cells to evade the host immune response. CD4 molecules can act not only as the HIV-1 receptor for entry but also as the trigger in an intracellular signaling cascade for T-cell activation and proliferation via protein tyrosine kinases. Novel chronic HIV-1-infected A3.01-derived (NCHA) cells were used to examine the involvement of CD4 downstream signaling in HIV-1 latency. CD4 receptors in NCHA cells were dramatically downregulated on its surface but were slightly decreased in whole-cell lysates. The expression levels of CD4 downstream signaling molecules, including P56(Lck), ZAP-70, LAT, and c-Jun, were sharply decreased in NCHA cells. The lowered histone modifications of H3K4me3 and H3K9ac correlated with the downregulation of P56(Lck), ZAP-70, and LAT in NCHA cells. AP-1 binding activity was also reduced in NCHA cells. LAT and c-Jun suppressed in NCHA cells were highly induced after PMA treatment. In epigenetic analysis, other signal transduction molecules which are associated with active and/or latent HIV-1 infection showed normal states in HIV-1 latently infected cells compared to A3.01 cells. In conclusion, we demonstrated that the HIV-1 latent state is sustained by the reduction of downstream signaling molecules via the downregulation of CD4 and the attenuated activity of transcription factor as AP-1. The HIV-1 latency model via T-cell deactivation may provide some clues for the development of the new antireservoir therapy.
authors.affiliation: National Institute of Health, Chungbuk, Republic of Korea.
authors.forename: Kyung-Chang
authors.initials: KC
authors.lastname: Kim
authors.forename: Hyeon Guk
authors.initials: HG
authors.lastname: Kim
authors.forename: Tae-Young
authors.initials: TY
authors.lastname: Roh
authors.forename: Jihwan
authors.initials: J
authors.lastname: Park
authors.forename: Kyung-Min
authors.initials: KM
authors.lastname: Jung
authors.forename: Joo-Shil
authors.initials: JS
authors.lastname: Lee
authors.forename: Sang-Yun
authors.initials: SY
authors.lastname: Choi
authors.forename: Sung Soon
authors.initials: SS
authors.lastname: Kim
authors.forename: Byeong-Sun
authors.initials: BS
authors.lastname: Choi
mesh_terms: D015704:CD4 Antigens / Q000235:genetics / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002460:Cell Line; D015536:Down-Regulation; D015658:HIV Infections / Q000276:immunology* / Q000821:virology*; D015497:HIV-1 / Q000502:physiology*; D006657:Histones / Q000378:metabolism; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008213:Lymphocyte Activation; D018808:Transcription Factor AP-1 / Q000378:metabolism; D017735:Virus Latency / Q000235:genetics / Q000276:immunology*
chemical_list: D015704:CD4 Antigens; D006657:Histones; D018808:Transcription Factor AP-1; D048031:JNK Mitogen-Activated Protein Kinases