Charles E. L. B. Davis

Outcomes of Kidney Transplantation in HIV-Infected Recipients

BACKGROUND The outcomes of kidney transplantation and immunosuppression in people infected with human immunodeficiency virus (HIV) are incompletely understood. METHODS We undertook a prospective, nonrandomized trial of kidney transplantation in HIV-infected candidates who had CD4+ T-cell counts of at least 200 per cubic millimeter and undetectable plasma HIV type 1 (HIV-1) RNA levels while being treated with a stable antiretroviral regimen. Post-transplantation management was provided in accordance with study protocols that defined prophylaxis against opportunistic infection, indications for biopsy, and acceptable approaches to immunosuppression, management of rejection, and antiretroviral therapy. RESULTS Between November 2003 and June 2009, a total of 150 patients underwent kidney transplantation; survivors were followed for a median period of 1.7 years. Patient survival rates (±SD) at 1 year and 3 years were 94.6±2.0% and 88.2±3.8%, respectively, and the corresponding mean graft-survival rates were 90.4% and 73.7%. In general, these rates fall somewhere between those reported in the national database for older kidney-transplant recipients (≥65 years) and those reported for all kidney-transplant recipients. A multivariate proportional-hazards analysis showed that the risk of graft loss was increased among patients treated for rejection (hazard ratio, 2.8; 95% confidence interval [CI], 1.2 to 6.6; P=0.02) and those receiving antithymocyte globulin induction therapy (hazard ratio, 2.5; 95% CI, 1.1 to 5.6; P=0.03); living-donor transplants were protective (hazard ratio, 0.2; 95% CI, 0.04 to 0.8; P=0.02). A higher-than-expected rejection rate was observed, with 1-year and 3-year estimates of 31% (95% CI, 24 to 40) and 41% (95% CI, 32 to 52), respectively. HIV infection remained well controlled, with stable CD4+ T-cell counts and few HIV-associated complications. CONCLUSIONS In this cohort of carefully selected HIV-infected patients, both patient- and graft-survival rates were high at 1 and 3 years, with no increases in complications associated with HIV infection. The unexpectedly high rejection rates are of serious concern and indicate the need for better immunotherapy. (Funded by the National Institute of Allergy and Infectious Diseases; ClinicalTrials.gov number, NCT00074386.).

Immune cell function testing: An adjunct to therapeutic drug monitoring in transplant patient management

Abstract:  Each year, 55 000 organ transplants are performed worldwide. Cumulatively, the number of living organ recipients is now estimated to be over 300 000. Most of these transplant recipients will remain on immunosuppressive drugs for the remainder of their lives to prevent rejection episodes. Controlled doses of these drugs are required to prevent over‐medication, which may leave the patient susceptible to opportunistic infection and drug toxicity effects, or under‐dosing, which may lead to shortened graft survival because of rejection episodes.

HIV-infected liver and kidney transplant recipients: 1- and 3-year outcomes.

Improvements in human immunodeficiency virus (HIV)‐associated mortality make it difficult to deny transplantation based upon futility. Outcomes in the current management era are unknown. This is a prospective series of liver or kidney transplant recipients with stable HIV disease. Eleven liver and 18 kidney transplant recipients were followed for a median of 3.4 years (IQR [interquartile range] 2.9–4.9). One‐ and 3‐year liver recipients’ survival was 91% and 64%, respectively; kidney recipients’ survival was 94%. One‐ and 3‐year liver graft survival was 82% and 64%, respectively; kidney graft survival was 83%. Kidney patient and graft survival were similar to the general transplant population, while liver survival was similar to the older population, based on 1999–2004 transplants in the national database. CD4+ T‐cell counts and HIV RNA levels were stable; and there were two opportunistic infections (OI). The 1‐ and 3‐year cumulative incidence (95% confidence intervals [CI]) of rejection episodes for kidney recipients was 52% (28–75%) and 70% (48–92%), respectively. Two‐thirds of hepatitis C virus (HCV)‐infected patients, but no patient with hepatitis B virus (HBV) infection, recurred. Good transplant and HIV‐related outcomes among kidney transplant recipients, and reasonable outcomes among liver recipients suggest that transplantation is an option for selected HIV‐infected patients cared for at centers with adequate expertise.

synergistic Inhibition of Hiv-1 in Activated and Resting Peripheral Blood Mononuclear Cells, Monocyte-derived Macrophages, and Selected Drug-resistant Isolates With Nucleoside Analogues Combined With a Natural Product, Resveratrol

&NA;Resveratrol (trans‐3,5,4′‐trihydroxystilbene) is a phytoalexin present in grapes, wine, and certain plants, which has recently been reported to possess properties that may protect against atherosclerosis, certain cancers, and inflammation. We now report that resveratrol (RV) synergistically enhances the anti‐HIV‐1 activity of the nucleoside analogues zidovudine (AZT), zalcitabine (ddC), and didanosine (ddl). RV at 10 &mgr;M was not toxic to cells, and by itself reduced viral replication by 20% to 30%. In phytohemagglutinin (PHA)‐activated peripheral blood mononuclear cells (PBMCs) infected with HTLV‐IIIB, 10 &mgr;M RV reduced the 90 % inhibitory concentration (IC90) of AZT, ddC, and ddI by 3.5‐, 5.5‐, and 17.8‐fold, respectively. Similar antiviral activity was demonstrated when ddI was combined with 5 or 10 mM RV in PBMCs infected with clinical isolates of HIV‐1. The addition of RV resulted in a > 10‐fold augmentation of ddI‐antiviral activity in infected monocyte‐derived macrophages (MDMs). In a resting cell model of T lymphocytes which were infected with HTLV‐IIIB, RV plus ddI in combination, but not individually, suppressed establishment of a productive viral infection. In addition, RV plus ddI markedly inhibited the replication of four ddI‐resistant viral isolates, three of which presented mutations in the RT gene conferring RT‐multidrug resistance. Finally, when compared with hydroxyurea (HU), both 100 mM HU and 10 mM RV showed similar enhancement of ddI‐antiviral suppressive activity. However, RV was shown to have less of a cellular antiproliferative effect than HU.

Targeting of mTOR catalytic site inhibits multiple steps of the HIV-1 lifecycle and suppresses HIV-1 viremia in humanized mice

Significance Most HIV antiretrovirals target viral proteins. Unfortunately, HIV mutates under drug pressure, which can lead to drug resistance. Targeting cellular proteins that HIV necessitates in its lifecycle may help overcome HIV drug resistance because cellular proteins have lower mutations rates than do HIV proteins. Mammalian target of rapamycin (mTOR) is a cellular kinase that forms two complexes (mTORC-1 and -2), regulating protein translation and transduction signaling. We demonstrate that dual targeting of mTORC-1/2 with the catalytic inhibitor INK128 blocks HIV by interfering with entry and with transcription (basal and induced). Importantly, INK128 suppressed HIV in a preclinical animal model, suggesting that mTORC-1/2 catalytic inhibitors may help control HIV in patients, particularly in those with drug-resistant HIV. HIV necessitates host factors for successful completion of its life cycle. Mammalian target of rapamycin (mTOR) is a conserved serine/threonine kinase that forms two complexes, mTORC1 and mTORC2. Rapamycin is an allosteric inhibitor of mTOR that selectively inhibits mTORC1. Rapamycin interferes with viral entry of CCR5 (R5)-tropic HIV and with basal transcription of the HIV LTR, potently inhibiting replication of R5 HIV but not CXCR4 (X4)-tropic HIV in primary cells. The recently developed ATP-competitive mTOR kinase inhibitors (TOR-KIs) inhibit both mTORC1 and mTORC2. Using INK128 as a prototype TOR-KI, we demonstrate potent inhibition of both R5 and X4 HIV in primary lymphocytes (EC50 < 50 nM), in the absence of toxicity. INK128 inhibited R5 HIV entry by reducing CCR5 levels. INK128 also inhibited both basal and induced transcription of HIV genes, consistent with inhibition of mTORC2, whose activity is critical for phosphorylation of PKC isoforms and, in turn, induction of NF-κB. INK128 enhanced the antiviral potency of the CCR5 antagonist maraviroc, and had favorable antiviral interactions with HIV inhibitors of reverse transcriptase, integrase and protease. In humanized mice, INK128 decreased plasma HIV RNA by >2 log10 units and partially restored CD4/CD8 cell ratios. Targeting of cellular mTOR with INK128 (and perhaps others TOR-KIs) provides a potential strategy to inhibit HIV, especially in patients with drug resistant HIV strains.

Overview of e-Bug: an antibiotic and hygiene educational resource for schools

Antibiotic resistance is an increasing community problem and is related to antibiotic use. If antibiotic use could be reduced, the tide of increasing resistance could be stemmed. e-Bug is a European project involving 18 European countries, partly funded by The Directorate-General for Health and Consumers (DG SANCO) of the European Commission. It aims to develop and disseminate across Europe a junior and senior school teaching pack and web site (hosting the lesson plans and complementary games) that teach young people about prudent antibiotic use, microbes, transmission of infection, hygiene and vaccines. The aim of e-Bug is to increase young peoples understanding, through enjoyable activities, of why it is so important to use antibiotics correctly in order to control antibiotic resistance, and to have good hand and respiratory hygiene to help reduce the spread of infection. Within the senior school pack the sexual transmission of infections has also been included, as the peak age of chlamydial infection is in 16-24 year olds. Teachers, young people and the consortium of 18 countries were closely involved with agreeing learning outcomes and developing the resource activities. Young people helped create the characters and microbe artwork. The resources have been translated, adapted for and disseminated to schools across 10 countries in Europe, and endorsed by the relevant government departments of health and education. The web site has been accessed from >200 countries. The resources will be translated into all European Union languages, and have been used to promote European Antibiotic Awareness Day and better hand and respiratory hygiene during the influenza pandemic in 2009.

Association between Longer Duration of HIV-Suppressive Therapy and Partial Recovery of the Vγ2 T Cell Receptor Repertoire

Human immunodeficiency virus (HIV) infection alters the function and repertoire of peripheral blood gamma delta T cells expressing the V gamma 2/V delta 2 T cell receptor (TCR). A cross-sectional comparison of the V gamma 2 TCR repertoire was performed for 56 HIV-infected subjects, 51 of whom were receiving highly active antiretroviral therapy (HAART), to measure changes in the V gamma 2 TCR repertoire. Longer durations of HAART were associated with partial recovery of the normal TCR repertoire, and recovery was greatest in subjects with complete virus suppression. Changes in the V gamma 2 TCR repertoire are sensitive measures for the effects of HAART and of residual HIV replication.

Impact of age, gender, and race on circulating γδ T cells

A major subset of human peripheral blood γδ T cells expresses the Vγ2Vδ2 T cell receptor and responds to malignant or infectious diseases. We noted significant differences in the numbers of Vγ2Vδ2 T cells in blood samples from healthy Caucasian CA or African American (AA) donors. On average, CA donors had 3.71% ± 4.37% Vδ2 cells (as a percentage of total lymphocytes) compared with 1.18% ± 2.14% Vδ2 cells for AA donors (p < 0.0001). Age and race had the greatest impact on Vδ2 cell levels; the effect of age was similar for both racial groups. The Vδ2 cell population was dominated, for both donor groups, by cells expressing the Vγ2-Jγ1.2 Vδ2 T cell receptor, an apparent result of strong positive selection and there was substantial overlap in the public Vγ2 clonotypes from both racial groups. Mechanisms for selection and amplification of Vδ2 cells are nearly identical for both groups, despite the significant difference in baseline levels. These data show that appropriate controls, matched for age and race, may be required for clinical studies of Vγ2Vδ2 T cells in infectious disease or cancer and raise important questions about the mechanisms regulating the levels of circulating Vδ2 cells.

Impacts of HIV infection on Vγ2Vδ2 T cell phenotype and function: a mechanism for reduced tumor immunity in AIDS

HIV infection causes rapid and lasting defects in the population of Vγ2Vδ2 T cells. To fully describe the impact of HIV, we examined PBMC samples from HIV+ patients receiving highly active antiretroviral therapy, who had displayed prolonged viral control and CD4 counts above 300 cells/mm3. We observed lower frequencies of CD27–/CD45RA– Vγ2Vδ2 cells in HIV+ individuals when compared with controls, coupled with an increased proportion of CD45RA+ cells. These changes were common among 24 HIV+ patients and were not related to CD4 cell count or viral RNA burden. Vγ2 cells from HIV+ individuals had lower expression of Granzyme B and displayed reduced cytotoxicity against Daudi targets after in vitro stimulation. There was increased expression of FasR (CD95) on Vγ2 cells from HIV+ PBMC that may be a mechanism for depletion of Vγ2 cells during disease. In addition to the well‐characterized defects in the Vγ2 repertoire and functional responses to phosphoantigen, the proportion of CD27–/CD45RA– Vγ2Vδ2 T cells after isopentenyl pyrophosphate stimulation was reduced sharply in HIV+ donors versus controls. Thus, HIV infection has multiple impacts on the circulating Vγ2Vδ2 T cell population that combine to reduce the potential effector activity in terms of tumor cytotoxicity. Changes in Vγ2Vδ2 T cells, along with concomitant effects on NK and NKT cells that also contribute to tumor surveillance, may be important factors for elevating the risk of malignancy during AIDS.

Higher Antigen Content Improves the Immune Response to 2009 H1N1 Influenza Vaccine in HIV-Infected Adults: A Randomized Clinical Trial

BACKGROUND The immunogenicity of a high hemagglutinin (HA) dose or a second dose of influenza vaccine in human immunodeficiency virus (HIV)-infected individuals has not been fully explored. METHODS One hundered ninety-two HIV-infected individuals aged 18-64 years were stratified by CD4 cell count (<200 cells/mL or ≥200 cells/mL) and randomized to receive 2 doses of 15 μg or 30 μg HA 2009 H1N1 vaccine 21 days apart. Hemagglutination inhibition (HAI) and microneutralization (MN) antibodies were measured on days 0, 10, 21, 31, 42, and 201. RESULTS Recipients of 30 μg HA had significantly higher HAI geometric mean titers (GMTs), compared with recipients of 15 μg HA on days 10 (139.0 vs 51.9; P = .01), 21 (106.7 vs 51.9; P = .001), and 31 (130.0 vs 73.7; P = .03) but not on days 42 (91.8 vs 61.6; P = .11) and 201 (43.0 vs 27.0; P = .08). When analyzed by CD4 cell count stratum, HAI GMTs were significantly higher among 30 μg HA recipients than among 15 μg HA in the CD4 cell count <200 cells/mL stratum on days 21 and 31 and the MN GMTs on days 10, 21, 31, and 42 (P < .05). In the CD4 cell count ≥200 cells/mL stratum, MN GMTs were significantly higher among recipients of 30 μg HA than among recipients of 15 μg HA on day 10 (P = .03). CONCLUSION Increasing the HA dose of the 2009 H1N1 vaccine improves the vaccines immunogenicity in HIV-infected individuals. CLINICAL TRIALS REGISTRATION NCT00992433.