Intracellular Tat of human immunodeficiency virus type 1 activates lytic cycle replication of Kaposi's sarcoma-associated herpesvirus: role of JAK/STAT signaling.
Human immunodeficiency virus type 1 (HIV-1) infection significantly increases the risk of Kaposi's sarcoma (KS) occurrence in individuals infected with Kaposi's sarcoma-associated herpesvirus (KSHV). KSHV infection appears to be necessary but not sufficient for KS development without other cofactors. However, factors that facilitate KSHV to cause KS have not been well defined. Previously, we determined that human herpesvirus 6 was one of the cofactors that activated lytic cycle replication of KSHV. Here, we demonstrate that the Tat protein of HIV-1 is a potentially important factor in the pathogenesis of KS, as determined by production of lytic phase mRNA transcripts and viral proteins in BCBL-1 cells. Mechanistic studies showed ectopic expression of Tat induced the production of human interleukin-6 (huIL-6) and its receptor (huIL-6Ra) and activated STAT3 signaling. Neutralization of huIL-6 or huIL-6R or inhibition of STAT3 signaling enhanced the replication. In addition, IL-4/STAT6 signaling also partially contributed to Tat-induced KSHV replication. These findings suggest that Tat may participate in KS pathogenesis by inducing KSHV replication and increasing KSHV viral load. These data also suggest that JAK/STAT signaling may be of therapeutic value in AIDS-related KS patients.
Zeng
Yi
Y
Department of Microbiology and Immunology, Nanjing Medical University, Nanjing 210029, People's Republic of China.
Zhang
Xunhai
X
Huang
Zan
Z
Cheng
Lin
L
Yao
Shuihong
S
Qin
Di
D
Chen
Xiuying
X
Tang
Qiao
Q
Lv
Zhigang
Z
Zhang
Ling
L
Lu
Chun
C
D000818:Animals; D001483:Base Sequence; D002144:Callithrix; D002460:Cell Line; D017931:DNA Primers / Q000235:genetics; D015870:Gene Expression; D015696:Gene Products, tat / Q000235:genetics / Q000502:physiology*; D015756:Genes, tat; D015658:HIV Infections / Q000150:complications / Q000821:virology; D015497:HIV-1 / Q000235:genetics / Q000502:physiology*; D019288:Herpesvirus 8, Human / Q000235:genetics / Q000472:pathogenicity / Q000502:physiology*; D006801:Humans; D015847:Interleukin-4 / Q000235:genetics; D015850:Interleukin-6 / Q000235:genetics; D053612:Janus Kinases / Q000378:metabolism*; D051379:Mice; D041681:NIH 3T3 Cells; D019947:Receptors, Interleukin-6 / Q000235:genetics; D050791:STAT Transcription Factors / Q000378:metabolism*; D050800:STAT6 Transcription Factor / Q000235:genetics; D012514:Sarcoma, Kaposi / Q000209:etiology / Q000235:genetics / Q000821:virology; D015398:Signal Transduction; D014779:Virus Replication / Q000235:genetics / Q000502:physiology; D054322:tat Gene Products, Human Immunodeficiency Virus
D017931:DNA Primers; D015696:Gene Products, tat; C508598:IL4 protein, human; C508600:IL6 protein, human; D015850:Interleukin-6; D019947:Receptors, Interleukin-6; D050791:STAT Transcription Factors; D050800:STAT6 Transcription Factor; C494101:STAT6 protein, human; D054322:tat Gene Products, Human Immunodeficiency Virus; D015847:Interleukin-4; D053612:Janus Kinases