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The increase in life expectancy in association with the long\u2010term use of the above antiviral agents, however, have generated novel morbidities and complications. Central among them is the quite common AIDS\u2010related insulin resistance and lipodystrophy syndrome, which is characterized by a striking phenotype and marked metabolic disturbances. To look for the pathologic causes of this particular syndrome, we focused on one of the HIV\u20101 accessory proteins, Vpr, which has multiple functions, such as virion incorporation, nuclear translocation of the HIV\u20101 preintegration complex, nucleo\u2010cytoplasmic shuttling, transcriptional activation, and induction of apoptosis. Vpr may also act like a hormone, which is secreted into the extracellular space and affects the function of distant organs. Vpr functions as a coactivator of the glucocorticoid receptor and potentiates the action of glucocorticoid hormones, thereby inducing tissue glucocorticoid hypersensitivity. Vpr also arrests host cells at the G2\/M phase of the cell cycle by interacting with novel 14\u20103\u20103 proteins. Vpr facilitates the interaction of 14\u20103\u20103 and its partner protein Cdc25C, which is critical for the transition of G2\/M checkpoint in the cell cycle, and suppresses its activity by segregating it into the cytoplasm. The same Vpr protein also suppresses the association of 14\u20103\u20103 with other partner molecules, the Foxo transcription factors. Since the Foxo proteins function as negative transcription factors for insulin, Vpr may cause resistance of tissues to insulin. Through these two newly identified functions of Vpr, namely, coactivation of glucocorticoid receptor activity and inhibition of insulin effects on Foxo proteins, Vpr may participate in the development of AIDS\u2010related insulin resistance\/lipodystrophy syndrome.<\/jats:p>","DOI":"10.1196\/annals.1321.013","type":"journal-article","created":{"date-parts":[[2004,7,20]],"date-time":"2004-07-20T22:57:47Z","timestamp":1090364267000},"page":"153-167","source":"Crossref","is-referenced-by-count":32,"title":["Human Immunodeficiency Virus Type\u20101 Accessory Protein Vpr: A Causative Agent of the AIDS\u2010Related Insulin Resistance\/Lipodystrophy Syndrome?"],"prefix":"10.1111","volume":"1024","author":[{"given":"TOMOSHIGE","family":"KINO","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"GEORGE P.","family":"CHROUSOS","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2006,1,12]]},"reference":[{"key":"e_1_2_6_2_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199302043280508"},{"key":"e_1_2_6_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0891-5520(05)70136-7"},{"key":"e_1_2_6_4_2","doi-asserted-by":"crossref","first-page":"306","DOI":"10.1097\/00126334-200012010-00003","article-title":"Multicenter review of protease inhibitors in 89 pregnancies","volume":"25","author":"Morris A.B.","year":"2000","journal-title":"J. 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