Differential induction of interleukin-10 in monocytes by HIV-1 clade B and clade C Tat proteins.
The clade B human immunodeficiency virus, type 1 (HIV-1) Tat (trans-acting regulatory protein) induces interleukin-10 (IL-10) production in monocytes. IL-10, an anti-inflammatory cytokine, down-regulates proinflammatory cytokines and suppresses the immune response, leading to a rapid progression from HIV-1 infection to AIDS. Nine clades of HIV-1 are responsible for the majority of infections worldwide. Recent studies demonstrate that different HIV-1 clades have biological differences in relation to transmission, replication, and disease progression. In this study, we show that the cysteine to serine mutation at position 31, found in >90% of HIV-1 clade C Tat proteins, results in a marked decrease in IL-10 production in monocytes compared with clade B Tat. Additionally, the C31S mutation found in C Tat is responsible for the inability of these Tat proteins to produce high IL-10 levels in monocytes due to its inability to induce intracellular calcium flux through L-type calcium channels. Moreover, we show that p38alpha/p38beta and phosphoinositide 3-kinase are crucial to Tat-induced IL-10 production. These findings provide further evidence that HIV-1 clades differ in their biological properties that may impact HIV-1 pathogenesis and disease progression.
Wong
Justine K
JK
Department of Pediatrics, Division of Infectious Diseases, University of California, San Diego,La Jolla, California 92093, USA.
Campbell
Grant R
GR
Spector
Stephen A
SA
D000595:Amino Acid Sequence; D016207:Cytokines / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005434:Flow Cytometry / Q000379:methods; D015497:HIV-1 / Q000378:metabolism*; D006801:Humans; D007249:Inflammation; D016753:Interleukin-10 / Q000378:metabolism*; D007963:Leukocytes, Mononuclear / Q000166:cytology; D048290:Mitogen-Activated Protein Kinase 11 / Q000378:metabolism*; D048308:Mitogen-Activated Protein Kinase 14 / Q000378:metabolism*; D008969:Molecular Sequence Data; D009000:Monocytes / Q000821:virology*; D009154:Mutation; D017386:Sequence Homology, Amino Acid; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000378:metabolism*
D016207:Cytokines; D004791:Enzyme Inhibitors; D054322:tat Gene Products, Human Immunodeficiency Virus; D016753:Interleukin-10; D048290:Mitogen-Activated Protein Kinase 11; D048308:Mitogen-Activated Protein Kinase 14