Infection of CD4+ memory T cells by HIV-1 requires expression of phosphodiesterase 4.
Using PCR to monitor HIV-1 RNA genome reverse transcription and nuclear import of preintegration complexes, we found that memory, but not naive, CD4+ T cells could support transport of HIV-1 DNA to nuclei upon TCR/CD3 and IL-2 stimulation. Moreover, memory CD4+ T cells, unlike naive CD4+ T cells, express high levels of phosphodiesterase 4 (PDE4) constitutively. Selective blocking of PDE4 activity inhibited IL-2R expression and thereby led to abolishing HIV-1 DNA nuclear import in memory T cells; however, full-length viral DNA synthesis was not affected. Thus, blocking PDE4 prevents initiation of HIV-1 DNA circle formation in T cells. The fact that PDE4 is expressed constitutively at higher levels in memory vs naive CD4+ T cells may help HIV-1 readily infect memory T cells.
Regional Primate Research Center, Department of Pharmacology and Molecular, University of Washington, Seattle, WA 98195, USA.
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Sun
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Li
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Lau
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Beavo
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Clark
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000378:metabolism; D001693:Biological Transport, Active / Q000187:drug effects / Q000276:immunology; D015704:CD4 Antigens / Q000096:biosynthesis; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000201:enzymology* / Q000276:immunology / Q000821:virology*; D002467:Cell Nucleus / Q000187:drug effects / Q000235:genetics / Q000378:metabolism / Q000821:virology; D000242:Cyclic AMP / Q000502:physiology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000502:physiology; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D004279:DNA, Viral / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects / Q000276:immunology*; D006801:Humans; D007156:Immunologic Memory; D007399:Interphase / Q000276:immunology; D017493:Leukocyte Common Antigens / Q000096:biosynthesis; D015375:Receptors, Interleukin-2 / Q000096:biosynthesis; D020889:Rolipram / Q000494:pharmacology; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000201:enzymology* / Q000276:immunology / Q000821:virology*
D015704:CD4 Antigens; D004279:DNA, Viral; D004791:Enzyme Inhibitors; D015375:Receptors, Interleukin-2; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D017493:Leukocyte Common Antigens; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D020889:Rolipram