Nef expressed from human immunodeficiency virus type 1 extrachromosomal DNA downregulates CD4 on primary CD4+ T lymphocytes: implications for integrase inhibitors.
Recently developed integrase inhibitors targeting the HIV-1 integrase (IN) protein block integration of HIV DNA in the target cell, preventing subsequent virus replication. In the absence of integration, viral DNA is shunted towards the formation of extrachromosomal DNA (E-DNA). Although HIV-1 E-DNA does not support productive replication, it is transcriptionally active and produces viral proteins. However, the significance of E-DNA in virus replication and pathogenesis is poorly understood. In this study, the functional activity of the HIV-1 Nef protein expressed in the absence of viral integration was analysed. Using both a recombinant HIV-1 IN defective virus and a diketo acid IN inhibitor, evidence was provided showing that Nef expressed from E-DNA downregulates CD4 surface expression on primary CD4(+) T lymphocytes. These results suggest that proteins expressed in the absence of integration may have potential clinical consequences, an issue that should be further explored with the introduction of IN inhibitors.
Gillim-Ross
Laura
L
Mount Sinai School of Medicine, Division of Infectious Diseases, 1 Gustave L. Levy Place, Box 1090, New York, NY 10029, USA.
Cara
Andrea
A
Laboratory of Virology, Istituto Superiore di Sanita, 00161 Roma, Italy.
Klotman
Mary E
ME
Mount Sinai School of Medicine, Division of Infectious Diseases, 1 Gustave L. Levy Place, Box 1090, New York, NY 10029, USA.
D015704:CD4 Antigens / Q000378:metabolism*; D015496:CD4-Positive T-Lymphocytes / Q000821:virology*; D002478:Cells, Cultured; D004279:DNA, Viral / Q000235:genetics; D015536:Down-Regulation; D015693:Gene Products, nef / Q000096:biosynthesis; D019427:HIV Integrase / Q000378:metabolism*; D019428:HIV Integrase Inhibitors / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics / Q000502:physiology; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D016662:Virus Integration / Q000187:drug effects* / Q000235:genetics; D014779:Virus Replication / Q000187:drug effects; D054311:nef Gene Products, Human Immunodeficiency Virus
D015704:CD4 Antigens; D004279:DNA, Viral; D015693:Gene Products, nef; D019428:HIV Integrase Inhibitors; D054311:nef Gene Products, Human Immunodeficiency Virus; D019427:HIV Integrase