Protein kinase CK2 modulates HSJ1 function through phosphorylation of the UIM2 domain.

HSJ1 (DNAJB2), a member of the DNAJ family of molecular chaperones, is a key player in neuronal proteostasis maintenance. It binds ubiquitylated proteins through its Ubiquitin Interacting Motifs (UIMs) and facilitates their delivery to the proteasome for degradation. Mutations in the DNAJB2 gene lead to inherited neuropathies such as Charcot-Marie-Tooth type-2, distal hereditary motor neuropathies, spinal muscular atrophy with parkinsonism and the later stages can resemble amyotrophic lateral sclerosis. HSJ1 overexpression can reduce aggregation of neurodegeneration-associated proteins in vitro and in vivo; however, the regulation of HSJ1 function is little understood. Here we show that CK2, a ubiquitous and constitutively active protein kinase, phosphorylates HSJ1 within its second UIM, at the dominant site Ser250 and the hierarchical site Ser247. A phospho-HSJ1 specific antibody confirmed phosphorylation of endogenous HSJ1a and HSJ1b. A tandem approach of phospho-site mutation and treatment with CK2 specific inhibitors demonstrated that phosphorylation at these sites is accompanied by a reduced ability of HSJ1 to bind ubiquitylated clients and to exert its chaperone activity. Our results disclose a novel interplay between ubiquitin- and phosphorylation-dependent signalling, and represent the first report of a regulatory mechanism for UIM-dependent function. They also suggest that CK2 inhibitors could release the full neuroprotective potential of HSJ1, and deserve future interest as therapeutic strategies for neurodegenerative disease.

Re-evaluation of protein kinase CK2 pleiotropy: new insights provided by a phosphoproteomics analysis of CK2 knockout cells.

CK2 denotes a ubiquitous and pleiotropic protein kinase whose holoenzyme is composed of two catalytic (α and/or α') and two regulatory ß subunits. The CK2 consensus sequence, S/T-x-x-D/E/pS/pT is present in numerous phosphosites, but it is not clear how many of these are really generated by CK2. To gain information about this issue, advantage has been taken of C2C12 cells entirely deprived of both CK2 catalytic subunits by the CRISPR/Cas9 methodology. A comparative SILAC phosphoproteomics analysis reveals that, although about 30% of the quantified phosphosites do conform to the CK2 consensus, only one-third of these are substantially reduced in the CK2α/α'(-/-) cells, consistent with their generation by CK2. A parallel study with C2C12 cells deprived of the regulatory ß subunit discloses a role of this subunit in determining CK2 targeting. We also find that phosphosites notoriously generated by CK2 are not fully abrogated in CK2α/α'(-/-) cells, while some phosphosites unrelated to CK2 are significantly altered. Collectively taken our data allow to conclude that the phosphoproteome generated by CK2 is not as ample and rigidly pre-determined as it was believed before. They also show that the lack of CK2 promotes phosphoproteomics perturbations attributable to kinases other than CK2.

Protein kinase CK2-dependent phosphorylation of the human Regulators of Calcineurin reveals a novel mechanism regulating the calcineurin-NFATc signaling pathway.

Cyclosporine A and FK506 produce immunosuppression by blocking calcineurin phosphatase activity and consequently activation of cytosolic Nuclear Factor of Activated T-cell (NFATc) transcription factor. Due to the chronic toxicity associated with their administration, the development of more specific immunosuppressants is currently an important unmet medical need. In this context, an immunosuppressant peptide derived from the CIC motif of the human Regulators of Calcineurin (RCAN) proteins has been shown to inhibit NFATc signaling without affecting general phosphatase activity of calcineurin. Here we show that protein kinase CK2 phosphorylates a conserved serine residue within the CIC motif of vertebrate RCANs, which increases its affinity for calcineurin and consequently its inhibition of NFATc-dependent gene expression in activated T-cells. Molecular modeling studies have led us to identify a positively charged interaction site on the surface of calcineurin where the phosphorylated serine residue of the CIC motif would normally locate. Finally, we have also identified RCAN3 as a new phosphoprotein with multiple phosphorylation sites. Therefore, our findings reveal for the first time a novel molecular mechanism underlying the regulation of calcineurin-NFATc signaling by means of phosphorylation of the CIC motif of RCAN proteins. The knowledge of how RCAN proteins modulate the calcineurin-NFATc pathway paves the way for the development of potent novel selective immunosuppressant drugs.

Deciphering the role of protein kinase CK2 in the maturation/stability of F508del-CFTR.

F508del-CFTR, the most common mutation in cystic fibrosis (CF) patients, impairs CFTR trafficking to plasma membrane leading to its premature proteasomal degradation. Several post-translational modifications have been identified on CFTR with multiple roles in stability, localization and channel function, and the possibility to control the enzymes responsible of these modifications has been long considered a potential therapeutic strategy. Protein kinase CK2 has been previously suggested as an important player in regulating CFTR functions and it has been proposed as a pharmacological target in a combinatory therapy to treat CF patients. However, the real implication of CK2 in F508del-CFTR proteostasis, and in particular the hypothesis that its inhibition could be important in CF therapies, is still elusive. Here, by using immortalized cell lines, primary human cells, and knockout cell lines deprived of CK2 subunits, we do not disclose any direct correlation between F508del-CFTR proteostasis and CK2 expression/activity. Rather, our data indicate that the CK2α' catalytic subunit should be preserved rather than inhibited for F508del rescue by the correctors of class-1, such as VX-809, disclosing new important features in CF therapeutic approaches.

Effects of CK2ß subunit down-regulation on Akt signalling in HK-2 renal cells.

The PI3K/Akt pathway is interconnected to protein kinase CK2, which directly phosphorylates Akt1 at S129. We have previously found that, in HK-2 renal cells, downregulation of the CK2 regulatory subunit ß (shCK2ß cells) reduces S129 Akt phosphorylation. Here, we investigated in more details how the different CK2 isoforms impact on Akt and other signaling pathways. We found that all CK2 isoforms phosphorylate S129 in vitro, independently of CK2ß. However, in HK-2 cells the dependence on CK2ß was confirmed by rescue experiments (CK2ß re-expression in shCK2ß HK-2 cells), suggesting the presence of additional components that drive Akt recognition by CK2 in cells. We also found that CK2ß downregulation altered the phosphorylation ratio between the two canonical Akt activation sites (pT308 strongly reduced, pS473 slightly increased) in HK-2 cells. Similar results were found in other cell lines where CK2ß was stably knocked out by CRISPR-Cas9 technology. The phosphorylation of rpS6 S235/S236, a downstream effector of Akt, was strongly reduced in shCK2ß HK-2 cells, while the phosphorylation of two Akt direct targets, PRAS40 T246 and GSK3ß S9, was increased. Differently to what observed in response to CK2ß down-regulation, the chemical inhibition of CK2 activity by cell treatment with the specific inhibitor CX-4945 reduced both the Akt canonical sites, pT308 and pS473. In CX-4945-treated cells, the changes in rpS6 pS235/S236 and GSK3ß pS9 mirrored those induced by CK2ß knock-down (reduction and slight increase, respectively); on the contrary, the effect on PRAS40 pT246 phosphorylation was sharply different, being strongly reduced by CK2 inhibition; this suggests that this Akt target might be dependent on Akt pS473 status in HK-2 cells. Since PI3K/Akt and ERK1/2/p90rsk pathways are known to be interconnected and both modulated by CK2, with GSK3ß pS9 representing a convergent point, we investigated if ERK1/2/p90rsk signaling was affected by CK2ß knock-down and CX-4945 treatment in HK-2 cells. We found that p90rsk was insensitive to any kind of CK2 targeting; therefore, the observation that, similarly, GSK3ß pS9 was not reduced by CK2 blockade suggests that GSK3ß phosphorylation is mainly under the control of p90rsk in these cells. However, we found that the PI3K inhibitor LY294002 reduced GSK3ß pS9, and concomitantly decreased Snail1 levels (a GSK3ß target and Epithelial-to-Mesenchymal transition marker). The effects of LY294002 were observed also in CK2ß-downregulated cells, suggesting that reducing GSK3ß pS9 could be a strategy to control Snail1 levels in any situation where CK2ß is defective, as possibly occurring in cancer cells.

The regulatory beta subunit of protein kinase CK2 contributes to the recognition of the substrate consensus sequence. A study with an eIF2 beta-derived peptide.

CK2 is a ubiquitous and pleiotropic Ser/Thr-specific protein kinase that phosphorylates more than 300 protein substrates at sites specified by an acidic consensus sequence in which positions n + 3 and n + 1 are particularly important. Recognition of substrates by CK2 is known to rely on basic residues located in the catalytic site of the alpha subunit which make electrostatic contacts with the negative charges in the substrate consensus sequence, thereby assuring optimal binding; the regulatory beta subunit is believed to play a protective and stabilizing role. We describe a biochemical and structural analysis of CK2-mediated phosphorylation of a 22-mer synthetic peptide corresponding to the N-terminal tail of the eukaryotic translation initiation factor eIF2beta. Results demonstrate that this peptide still displays phosphorylation features similar to full-length eIF2beta and the CK2 beta subunit also contributes to recognition of the protein substrate by establishing both polar and hydrophobic interactions with specificity determinants located downstream from the phosphoacceptor site. In particular, the N-terminal domain of the beta subunit appears to be of crucial importance for optimizing high-affinity phosphorylation of the eIF2beta peptide. This domain includes an acidic cluster whose electrostatic contacts with basic residues of the substrate attenuate intrasteric pseudosubstrate inhibition while strengthening substrate-kinase binding.

The importance of negative determinants as modulators of CK2 targeting. The lesson of Akt2 S131.

CK2 is a pleiotropic S/T protein kinase (formerly known as casein kinase 2) which is attracting increasing interest as therapeutic target, and the identification of its substrates is a crucial step in determining its involvement in different pathological conditions. We recently found that S131 of Akt2 (homologous to the well established CK2 target S129 of Akt1) is not phosphorylated by CK2 either in vitro or in vivo, although the consensus sequence recognized by CK2 (S/T-x-x-E/D/pS/pT) is conserved in it. Here, by exploiting synthetic peptides, in cell transfection experiments, and computational analysis, we show that a single sequence element, a T at position n+1, hampers phosphorylation, causing an α-helix structure organization which prevents the recognition of its own consensus by CK2. Our results highlight the role of negative determinants as crucial modulators of CK2 targeting and corroborate the concept that Akt1 and Akt2 display isoform specific features. Experiments with synthetic peptides suggest that Akt2 S131 could be phosphorylated by kinases of the Plk (Polo-like kinase) family, which are insensitive to the presence of the n+1 T. The low phylogenetic conservation of the Akt2 sequence around S131, as opposed to the extremely well-conserved Akt1 homologous sequence, would indicate a dominant positive role in the selective pressure only for the Akt1 phosphoacceptor site committed to undergo phosphorylation by CK2. By contrast, Akt2 S131 may mediate the response to specific physio/pathological conditions, being consequently shielded against basal CK2 targeting.

Dependence of HSP27 cellular level on protein kinase CK2 discloses novel therapeutic strategies.

BACKGROUND: HSP27 plays a role in various diseases, including neurodegenerative diseases, ischemia, and atherosclerosis. It is particularly important in the regulation of the development, progression and metastasis of cancer as well as cell apoptosis and drug resistance. However, the absence of an ATP binding domain, that is, instead, present in other HSPs such as HSP90 and HSP70, hampers the development of small molecules as inhibitors of HSP27. METHODS: Knockout cell lines generated by Crispr/Cas9 gene editing tool, specific kinase inhibitors and siRNA transfections were exploited to demonstrate that the expression of HSP27 is dependent on the integrity/activity of protein kinase CK2 holoenzyme. The interaction between these proteins has been confirmed by co-immunoprecipitation, confocal immunofluorescence microscopy, and by density gradient separation of protein complexes. Finally, using a proliferation assay this study demonstrates the potential efficacy of a combinatory therapy of heath shock and CK2 inhibitors in cancer treatment. RESULTS: Our data demonstrate that CK2 is able to regulate HSP27 turnover by affecting the expression of its ubiquitin ligase SMURF2 (Smad ubiquitination regulatory factor 2). Moreover, for the first time we show an increased sensitivity of CK2-inhibited tumour cells to hyperthermia treatment. CONCLUSION: Being HSP27 involved in several pathological conditions, including protein conformational diseases (i.e Cystic Fibrosis) and cancer, the need of drugs to modulate its activity is growing and CK2-targeting could represent a new strategy to reduce cellular HSP27 level. GENERAL SIGNIFICANCE: This study identifies CK2 as a molecular target to control HSP27 cellular expression.

Under-expression of CK2ß subunit in ccRCC represents a complementary biomarker of p-STAT3 Ser727 that correlates with patient survival.

Clear cell renal cell carcinoma (ccRCC) is the most common and aggressive subtype of renal cancer. STAT3 pathway is altered in these tumors and p-STAT3 Ser727 is an independent prognostic factor for ccRCC. Protein kinase CK2 is altered in different types of tumors and overexpression of CK2α is considered predictive of bad prognosis and metastatic risk. CK2 subunits analyses in ccRCC samples showed increased CK2α/α' nuclear content in all cases, but decreased cytosolic CK2ß (CK2ßcyt) levels in the more advanced tumors. Stable downregulation of CK2ß in renal proximal tubular (HK-2) and clear cell adenocarcinoma (786-O) cells triggered changes in E-cadherin, vimentin and Snail1 protein levels indicative of epithelial-to-mesenchymal transition (EMT), and increased HIF-α. Moreover, CK2ß was required in order to observe STAT3 Ser727 phosphorylation in HK-2 but not in 786-O cells. We also observed that CK2ß improved the prognostic value of p-STAT3 Ser727, as CK2ßcyt>41 (median value) discriminates patients free of disease for a period of 10 years upon surgery, from those with CK2ßcyt<41, when p-STAT3 Ser727levels are low. We conclude that CK2ß down-regulation might represent a mechanism to support EMT and angiogenesis and that CK2ßcyt levels are instrumental to refine prognosis of ccRCC patients with low p-STAT3 Ser727 levels.

Targeting Protein Kinase CK2: Evaluating CX-4945 Potential for GL261 Glioblastoma Therapy in Immunocompetent Mice.

Glioblastoma (GBM) causes poor survival in patients even with aggressive treatment. Temozolomide (TMZ) is the standard chemotherapeutic choice for GBM treatment but resistance always ensues. Protein kinase CK2 (CK2) contributes to tumour development and proliferation in cancer, and it is overexpressed in human GBM. Accordingly, targeting CK2 in GBM may benefit patients. Our goal has been to evaluate whether CK2 inhibitors (iCK2s) could increase survival in an immunocompetent preclinical GBM model. Cultured GL261 cells were treated with different iCK2s including CX-4945, and target effects evaluated in vitro. CX-4945 was found to decrease CK2 activity and Akt(S129) phosphorylation in GL261 cells. Longitudinal in vivo studies with CX-4945 alone or in combination with TMZ were performed in tumour-bearing mice. Increase in survival (p < 0.05) was found with combined CX-4945 and TMZ metronomic treatment (54.7 ± 11.9 days, n = 6) when compared to individual metronomic treatments (CX-4945: 24.5 ± 2.0 and TMZ: 38.7 ± 2.7, n = 6) and controls (22.5 ± 1.2, n = 6). Despite this, CX-4945 did not improve mice outcome when administered on every/alternate days, either alone or in combination with 3-cycle TMZ. The highest survival rate was obtained with the metronomic combined TMZ+CX-4945 every 6 days, pointing to the participation of the immune system or other ancillary mechanism in therapy response.

HAVCR/KIM-1 activates the IL-6/STAT-3 pathway in clear cell renal cell carcinoma and determines tumor progression and patient outcome.

Renal cell carcinoma (RCC), the third most prevalent urological cancer, claims more than 100,000 lives/year worldwide. The clear cell variant (ccRCC) is the most common and aggressive subtype of this disease. While commonly asymptomatic, more than 30% of ccRCC are diagnosed when already metastatic, resulting in a 95% mortality rate. Notably, nearly one-third of organ-confined cancers treated by nephrectomy develop metastasis during follow-up care. At present, diagnostic and prognostic biomarkers to screen, diagnose, and monitor renal cancers are clearly needed. The gene encoding the cell surface molecule HAVCR1/KIM-1 is a suggested susceptibility gene for ccRCC and ectodomain shedding of this molecule may be a predictive biomarker of tumor progression. Microarray analysis of 769-P ccRCC-derived cells where HAVCR/KIM-1 levels have been upregulated or silenced revealed relevant HAVCR/KIM-1-related targets, some of which were further analyzed in a cohort of 98 ccRCC patients with 100 month follow-up. We found that HAVCR/KIM-1 activates the IL-6/STAT-3/HIF-1A axis in ccRCC-derived cell lines, which depends on HAVCR/KIM-1 shedding. Moreover, we found that pSTAT-3 S727 levels represented an independent prognostic factor for ccRCC patients. Our results suggest that HAVCR/KIM-1 upregulation in tumors might represent a novel mechanism to activate tumor growth and angiogenesis and that pSTAT-3 S727 is an independent prognostic factor for ccRCC.

Hepatitis A virus cellular receptor 1/kidney injury molecule-1 is a susceptibility gene for clear cell renal cell carcinoma and hepatitis A virus cellular receptor/kidney injury molecule-1 ectodomain shedding a predictive biomarker of tumour progression.

AIM OF THE STUDY: To correlate hepatitis A virus cellular receptor (HAVCR)/kidney injury molecule-1 (KIM-1) expression in clear cell renal cell carcinoma (ccRCC) tumours with patient outcome and study the consequences of HAVCR/KIM-1 ectodomain shedding. METHODS: HAVCR/KIM-1 expression in ccRCC, oncocytomes, papillary carcinomas and unaffected tissue counterparts was evaluated. Minimal change disease and pre-clamping normal and ccRCC tissue biopsies were included. Tissue microarrays from 98 ccRCC tumours were analysed. Tumour registry data and patient outcome were retrospectivelly collected. Deletions in HAVCR/KIM-1 ectodomain and lentiviral infection of 786-O cells with HAVCR/KIM-1 mutated constructs to determine their subcellular distribution and invasive capacity were performed. RESULTS: HAVCR/KIM-1 was expressed in ccRCC, papillary tumours and in tubule cells of adjacent and distal unaffected counterparts of ccRCC tumours. The latest was not related to ischemic or tumour-related paracrine effects since pre-clamping normal biopsies were positive for HAVCR/KIM-1 and unaffected counterparts of papillary tumours were negative. HAVCR/KIM-1 analyses in patients and the invasive capacity of HAVCR/KIM-1 shedding mutants in cell lines demonstrated that: (i) relative low HAVCR/KIM-1 membrane levels correlate with activated shedding in ccRCC patients and mutant cell lines; (ii) augmented shedding directly correlates with higher invasiveness and tumour malignancy. CONCLUDING STATEMENTS: Constitutive expression of HAVCR/KIM-1 in kidney might constitute a susceptibility trait for ccRCC tumour development. Enhanced HAVCR/KIM-1 ectodomain shedding promotes invasive phenotype in vitro and more aggressive tumours in vivo.

[Ethical and legal features of living donor kidney transplantation. Management and coordination of the process of living donation]. / Aspectos éticos y legales del trasplante renal de donante vivo. Gestion y coordinacion del proceso de donacion de vivo.

OBJECTIVES: Living donors for kidney transplantation have attracted interest from different points of view because medical issues are accompanied by other features involving ethical, legal and social issues. We analyze all aspects involved in living donation for kidney transplantation. METHODS: We analyze: (1) ETHICAL ISSUES: requirements to become living donor, donor-receptor relationship, informed consent, donor's motivations, risk/benefit. (2) Legal issues: We review Spanish laws and Council of Europe's recommendations. (3) We also analyze how to coordinate the process in order to guarantee protection to donors. RESULTS/CONCLUSIONS: Living donor kidney transplantation is a growing therapeutic option. The process of living donation should comply with several legal and ethical requirements, and cooperation between different professionals to guarantee protection to donors.

[GESIDA/GESITRA-SEIMC, PNS and ONT consensus document on solid organ transplant (SOT) in HIV-infected patients in Spain (March, 2005)]. / Documento de consenso GESIDA/GESITRA-SEIMC, SPNS y ONT sobre trasplante de órgano sólido en pacientes infectados por el VIH en España (marzo 2005).

Solid organ transplant may be the only therapeutic alternative in some HIV-infected patients. Experience in North America and Europe during the last five years shows that survival at three years after an organ transplant is similar to that observed in HIV-negative patients. The criteria agreed upon to select HIV patients for transplant are: no opportunistic infections (except tuberculosis, oesophageal candidiasis or P. jiroveci -previously carinii- pneumonia), CD4 lymphocyte count above 200 cells/.L (100 cells/.L in the case of liver transplant) and an HIV viral load which is undetectable or suppressible with antiretroviral therapy. Another criterion is a two-year abstinence from heroin and cocaine, although the patient may be in a methadone programme. The main problems in the post-transplant period are pharmacokinetic and pharmacodynamic interactions between antiretorivirals and immunosuppressors, rejection and the management of relapse of HCV infection, which is one of the main causes of post-liver transplant mortality. Up to now, experience with pegylated interferon and ribavirin is scarce in this population. The English version of the manuscript is available at http://www.gesidaseimc.com.

Percutaneous renal artery embolisation of non-functioning renal allografts with clinical intolerance.

The aim of the study was to evaluate the efficacy and safety of percutaneous renal artery embolisation of non-functioning renal allografts in patients with graft intolerance syndrome (GIS). Transcatheter artery embolisation was performed in 30 kidney transplant recipients with GIS. The duration of graft function had been 60+/-45 months. Infectious disease was ruled out in all patients. Embolisation consisted of the injection of polyvinyl alcohol microspheres followed by the insertion of a stainless steel coil in the renal artery branches. Symptoms of GIS included: fever-graft pain (44%, n=13), fever-hematuria-pain (20%, n=6), fever-hematuria (13%, n=4) and fever alone (23%, n=7). Latency time between graft failure and embolisation was 184+/-227 (17-1181) days. Embolisation was clinically successful with the prolonged disappearance of GIS in 24 patients (80%). Six patients showed initial clinical improvement, but GIS reappeared at 40+/-18 days, and graft nephrectomy was required. There were no major complications associated with embolisation and no deaths. Perirenal collateral supply was a risk factor for the reappearance of GIS. Renal vascular embolisation is a simple, safe and effective technique for treating renal allograft intolerance syndrome and could be a feasible alternative for the first-line treatment.

Aspectos éticos y legales del trasplante renal de donante vivo. Gestión y coordinación del proceso de donación de vivo / Ethical and legal features of living donor kidney transplantation. Management and coordination of the process of living donation

OBJETIVO: El donante vivo renal hagenerado interés desde distintos puntos de vista, ya queal tema puramente médico se añaden otros aspectosque abarcan cuestiones éticas, legislativas, sociales...Se trata por tanto de analizar todos aquellos aspectosque se derivan de la donación de vivo.MÉTODO: Se analizan desde el punto de vista ético:los requisitos que debe tener un donante vivo, el tipo derelación donante-receptor, cómo debe ser el consentimientoinformado, las motivaciones del donante, larelación riesgo/beneficio. Desde el punto de vistalegal: se revisa la legislación española y las recomendacionesdel Consejo de Europa. Se analiza tambiéncómo coordinar el proceso para garantizar la proteccióndel donante.RESULTADOS/CONCLUSIONES: El trasplante deriñón con donante vivo es una alternativa terapéuticacada vez más extendida. El proceso de la donación devivo debe cumplir una serie de requisitos legales y éticos,y la colaboración de diferentes profesionales paragarantizar una correcta protección del donante

OBJECTIVES: Living donors for kidney ;;transplantation have attracted interest from different ;;points of view because medical issues are accompanied ;;by other features involving ethical, legal and social ;;issues. We analyze all aspects involved in living donation ;;for kidney transplantation. ;;METHODS: we analyze: 1. Ethical issues: requirements ;;to become living donor, donor-receptor relationship, ;;informed consent, donor’s motivations, risk/benefit. 2. ;;Legal issues: We review Spanish laws and Council of ;;Europe’s recommendations. 3. We also analyze how to ;;coordinate the process in order to guarantee protection ;;to donors. ;;RESULTS/CONCLUSIONS: Living donor kidney transplantation ;;is a growing therapeutic option. The process ;;of living donation should comply with several legal and ;;ethical requirements, and cooperation between ;;different professionals to guarantee protection to ;;donors

Documento de consenso GESIDA/GESITRA-SEIMC, SPNS y ONT sobre trasplante de órgano sólido en pacientes infectados por el VIH en España (marzo 2005) / Consensus document from GESIDA/GESITRA-SIMC, SPNS and ONT on solid organ transplantation in patients with HIV infection in Spain (March 2005)

El trasplante de órgano sólido puede ser la única alternativa terapéutica en ciertos pacientes infectados por el virus de la inmunodeficiencia humana (VIH). La experiencia acumulada en América del Norte y Europa en los últimos 5 años indica que la supervivencia a los 3 años del trasplante de órgano sólido es similar a la de los pacientes no infectados por el VIH. Los criterios consensuados para seleccionar a los pacientes infectados por el VIH con indicación de trasplante son: no haber tenido infecciones oportunistas (a excepción de la tuberculosis, candidiasis esofágica o neumonía por Pneumocystis jiroveci ­antes carinii­), tener una cifra de linfocitos CD4 > 200 cél./μl (100 cél./μl en el caso del trasplante hepático) y una carga viral del VIH indetectable o suprimible con tratamiento antirretroviral. También se exige una abstinencia a la heroína y cocaína de 2 años de duración, pudiendo estar el paciente en programa de metadona. Los principales problemas del período postrasplante son las interacciones farmacocinéticas y farmacodinámicas entre los antirretrovirales y los inmunosupresores, el rechazo y la posibilidad de que la recidiva de la infección por el virus de la hepatitis C (VHC), que es una de las principales causas de mortalidad postrasplante hepático, siga una evolución peor. La experiencia del tratamiento con interferón pegilado y ribavirina es escasa en esta población hasta el momento actual (AU)

Solid organ transplantation may be the only therapeutic option for some human inmunodeficience virus (HIV)-infected patients. Experience in North America and Europe over the last five years has shown that three-year survival of these patients following organ transplantation is similar to that of HIV-negative patients. The consensus criteria for the selection of HIV patients for transplantation include the following: no opportunistic infections (except tuberculosis, esophageal candidiasis or Pneumocystis jiroveci ­ previously carinii ­ pneumonia), CD4 lymphocyte count above 200 cells/μl (100 cells/μl in the case of liver transplantation) and HIV viral load that is undetectable or suppressible with antiretroviral therapy. Also required is a two-year abstinence from heroin and cocaine, although the patient may be in a methadone program. The main problems in the post-transplantation period in these patients are pharmacokinetic and pharmacodynamic interactions between antiretorivirals and immunosuppressors, rejection, and the fact that the risk of relapsed HCV infection is exacerbated, and this is one of the main causes of post-liver transplantation (..) (AU)