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When transplanted simultaneously, the liver allograft has been thought to have an immunoprotective role on other organs; however, detailed analyses in simultaneous heart–liver transplantation (SHLT) have not been done to date. We analyzed patient outcomes and incidence of immune‐mediated injury in 22 consecutive SHLTversus 223 isolated heart transplantation (IHT) recipients between January 2004 and December 2013, by reviewing 3912 protocol‐ and indication‐specific cardiac allograft biopsy specimens. Overall survival was similar (86.4%, 86.4%, and 69.1% for SHLTand 93.3%, 84.7%, and 70.0% for IHTat 1, 5, and 10 years; p = 0.83). Despite similar immunosuppression, the incidence of T cell–mediated rejection (TCMR) was lower in SHLT(31.8%) than in IHT(84.8%) (p < 0.0001). Although more SHLTpatients had preexisting donor‐specific HLA antibody(22.7% versus 8.1%; p = 0.04), the incidence of antibody‐mediated rejection was not different in SHLTcompared with IHT(4.5% versus 14.8%, p = 0.33). While the left ventricular ejection fraction was comparable in both groups at 5 years, the incidence and severity of cardiac allograft vasculopathy were reduced in the SHLTrecipients (42.9% versus 66.8%, p = 0.03). Simultaneously transplanted liver allograft was associated with reduced risk of TCMR(odds ratio [OR]0.003, 95% confidence interval [CI]0–0.02; p < 0.0001), antibody‐mediated rejection (OR0.04, 95% CI0–0.46; p = 0.004), and cardiac allograft vasculopathy (OR0.26, 95% CI0.07–0.84; p = 0.02), after adjusting for other risk factors. These data suggest that the incidence of alloimmune injury in the heart allograft is reduced in SHLTrecipients. The authors analyze the incidence and severity of cardiac allograft rejection and vasculopathy in simultaneous heart–liver transplant recipients in comparison to solitary heart transplant recipients, demonstrating the immunoprotective role of the liver allograft.

IL28Bpolymorphisms are strongly associated with response to treatment for HCV infection. IL28Bacts on interferon‐stimulated genes via the JAK‐STAT pathway, which has been implicated in development of insulin resistance. We investigated whether IL28Bpolymorphisms are associated with posttransplant diabetes mellitus (DM). Consecutive HCV patients who underwent liver transplantation between 1–1995 and 1–2011 were studied. Genotyping of the polymorphism rs12979860 was performed on DNA collected from donors and recipients. Posttransplant DM was screened for by fasting blood glucoses every 1–3 months. Of 221 included patients, 69 developed posttransplant DM (31%). Twenty‐two patients with recipient IL28Bgenotype TT (48%), 25 with IL28Bgenotype CT (25%) and 22 with IL28Bgenotype CC (29%) developed posttransplant DM. TT genotype was statistically significantly associated with posttransplant DM over time (log rank p = 0.012 for TT vs. CT and p = 0.045 for TT vs. CC). Multivariate Cox regression analysis correcting for donor age, body mass index, baseline serum glucose, baseline serum cholesterol, recipient age and treated rejection, showed that recipient IL28Bgenotype TT was independently associated with posttransplant DM (hazard ratio 2.51; 95% confidence interval 1.17–5.40; p = 0.011). We conclude that the risk of developing posttransplant DM is significantly increased in recipients carrying the TT polymorphism of the IL28Bgene.

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Retroviral proteins are synthesized as polyprotein precursors that undergo proteolytic cleavages to yield the mature viral proteins. The role of the human immunodeficiency virus (HIV) protease in the viral replication cycle was examined by use of a site-directed mutation in the protease gene. The HIV protease gene product was expressed in Escherichia coli and observed to cleave HIV gag p55 to gag p24 and gag p17 in vitro. Substitution of aspartic acid residue 25 (Asp-25) of this protein with an asparagine residue did not affect the expression of the protein, but it eliminated detectable in vitro proteolytic activity against HIV gag p55. A mutant HIV provirus was constructed that contained the Asn-25 mutation within the protease gene. SW480 human colon carcinoma cells transfected with the Asn-25 mutant proviral DNA produced virions that contained gag p55 but not gag p24, whereas virions from cells transfected with the wild-type DNA contained both gag p55 and gag p24. The mutant virions were not able to infect MT-4 lymphoid cells. In contrast, these cells were highly sensitive to infection by the wild-type virions. These results demonstrate that the HIV protease is an essential viral enzyme and, consequently, an attractive target for anti-HIV drugs.

The protease of human immunodeficiency virus has been expressed in Escherichia coliand purified to apparent homogeneity. Immunoreactivity toward anti-protease peptide sera copurified with an activity that cleaved the structural polyprotein gagp55 and the peptide corresponding to the sequence gag128–135. The enzyme expressed as a nonfusion protein exhibits proteolytic activity with a pH optimum of 5.5 and is inhibited by the aspartic protease inhibitor pepstatin with a Kiof 1.1 µM. Replacement of the conserved residue Asp-25 with an Asn residue eliminates proteolytic activity. Analysis of the minimal peptide substrate size indicates that 7 amino acids are required for efficient peptide cleavage. Size exclusion chromatography is consistent with a dimeric enzyme and circular dichroism spectra of the purified enzyme are consistent with a proposed structure of the protease (Pearl, L.H., and Taylor, W.R. (1987) Nature329, 351–354). These data support the classification of the human immunodeficiency virus protease as an aspartic protease, likely to be structurally homologous with the well characterized family that includes pepsin and renin.