The BCL-2 Inhibitor Venetoclax Augments Immune Effector Function Mediated by Fas Ligand, TRAIL, and Perforin/Granzyme B, Resulting in Reduced Plasma Viremia and Decreased HIV Reservoir Size during Acute HIV Infection in a Humanized Mouse Model.

The BCL-2 prosurvival protein is implicated in HIV persistence and is a potential therapeutic target for HIV eradication efforts. We now know that cells harboring HIV are preferentially enriched for high BCL-2 expression, enabling their survival, and that the BCL-2 inhibitor venetoclax promotes the death of actively replicating HIV-infected cells in vitro and ex vivo. Herein, we assess the effect of venetoclax on immune clearance of infected cells and show that BCL-2 inhibition significantly enhances target cell killing induced by Fas ligand, TRAIL (tumor necrosis factor-related apoptosis-inducing ligand), and perforin/granzyme B and synergistically enhances autologous NK (natural killer) and CD8 cells' killing of target cells. In a humanized mouse model of acute HIV infection, venetoclax monotherapy significantly decreases plasma viremia and normalizes CD4:CD8 ratios, and results in more mice with undetectable provirus levels than control. In this model, treatment was associated with leukopenia, as has been described clinically in patients receiving venetoclax for other indications. These data confirm meaningful anti-HIV effects of venetoclax during HIV infection but suggest that venetoclax use should be combined with ART (antiretroviral therapy) to reduce toxicity. IMPORTANCE This study is the first to examine the applicability of BCL-2 inhibition in the setting of active HIV infection in vivo. Furthermore, this study demonstrates that venetoclax significantly enhances target cell killing induced by Fas ligand, TRAIL, and perforin/granzyme B and synergistically enhances autologous NK and CD8 cells' killing of target cells.

Detecting Sources of Immune Activation and Viral Rebound in HIV Infection.

Anti-retroviral therapy (ART) generally suppresses HIV replication to undetectable levels in peripheral blood, but immune activation associated with increased morbidity and mortality is sustained during ART, and infection rebounds when treatment is interrupted. To identify drivers of immune activation and potential sources of viral rebound, we modified RNAscope in situ hybridization to visualize HIV-producing cells as a standard against which to compare the following assays of potential sources of immune activation and virus rebound following treatment interruption: (i) envelope detection by induced transcription-based sequencing (EDITS) assay; (ii) HIV-Flow; (iii) Flow-FISH assays that can scan tissues and cell suspensions to detect rare cells expressing env mRNA, gag mRNA/Gag protein and p24; and (iv) an ultrasensitive immunoassay that detects p24 in cell/tissue lysates at subfemtomolar levels. We show that the sensitivities of these assays are sufficient to detect one rare HIV-producing/env mRNA+/p24+ cell in one million uninfected cells. These high-throughput technologies provide contemporary tools to detect and characterize rare cells producing virus and viral antigens as potential sources of immune activation and viral rebound. IMPORTANCE Anti-retroviral therapy (ART) has greatly improved the quality and length of life for people living with HIV, but immune activation does not normalize during ART, and persistent immune activation has been linked to increased morbidity and mortality. We report a comparison of assays of two potential sources of immune activation during ART: rare cells producing HIV and the virus' major viral protein, p24, benchmarked on a cell model of active and latent infections and a method to visualize HIV-producing cells. We show that assays of HIV envelope mRNA (EDITS assay), gag mRNA, and p24 (Flow-FISH, HIV-Flow. and ultrasensitive p24 immunoassay) detect HIV-producing cells and p24 at sensitivities of one infected cell in a million uninfected cells, thereby providing validated tools to explore sources of immune activation during ART in the lymphoid and other tissue reservoirs.

The Combination of Venetoclax and Ixazomib Selectively and Efficiently Kills HIV-Infected Cell Lines but Has Unacceptable Toxicity in Primary Cell Models.

The antiapoptotic protein BCL2 inhibits death of HIV-infected cells. Previously, we showed that the BCL2 inhibitor venetoclax selectively kills acutely HIV-infected cells and reduces HIV DNA in latently infected CD4 T cells ex vivo after reactivation with anti-CD3/anti-CD28. However, there is a need to identify a combination therapy with venetoclax and a clinically relevant latency reversal agent. Ixazomib is an oral proteasome inhibitor which we have shown reactivates latent HIV and predisposes reactivated cells to cell death. Here, we determined that the combination of venetoclax and ixazomib kills more latently HIV-infected cells and leads to greater reduction in HIV replication than either treatment alone in vitro in a T cell model. However, combination treatment of ex vivo CD4 T cells from antiretroviral therapy (ART)-suppressed, HIV-positive participants resulted in unanticipated and unacceptable nonspecific toxicity in primary cells. Therefore, while we show proof of concept that multiple agents can enhance selective killing of HIV-infected cells, the combination of venetoclax and ixazomib has unacceptable toxicity in primary cells, and so further investigation is needed to identify a clinically relevant latency reversal agent to combine with venetoclax as a novel strategy to reduce the size of the HIV reservoir.IMPORTANCE A cure for HIV would require eliminating cells that contain the virus in a latent form from the body. Current antiretroviral medications are unable to rid the body of latently infected cells. Here, we show that a combination of investigational agents-ixazomib plus venetoclax-which reactivate latent virus and predispose infected cells to apoptosis may reduce latent virus in a T cell model, but at the expense of nonspecific toxicity in primary cells.

Reactivating latent HIV with PKC agonists induces resistance to apoptosis and is associated with phosphorylation and activation of BCL2.

Eradication of HIV-1 by the "kick and kill" strategy requires reactivation of latent virus to cause death of infected cells by either HIV-induced or immune-mediated apoptosis. To date this strategy has been unsuccessful, possibly due to insufficient cell death in reactivated cells to effectively reduce HIV-1 reservoir size. As a possible cause for this cell death resistance, we examined whether leading latency reversal agents (LRAs) affected apoptosis sensitivity of CD4 T cells. Multiple LRAs of different classes inhibited apoptosis in CD4 T cells. Protein kinase C (PKC) agonists bryostatin-1 and prostratin induced phosphorylation and enhanced neutralizing capability of the anti-apoptotic protein BCL2 in a PKC-dependent manner, leading to resistance to apoptosis induced by both intrinsic and extrinsic death stimuli. Furthermore, HIV-1 producing CD4 T cells expressed more BCL2 than uninfected cells, both in vivo and after ex vivo reactivation. Therefore, activation of BCL2 likely contributes to HIV-1 persistence after latency reversal with PKC agonists. The effects of LRAs on apoptosis sensitivity should be considered in designing HIV cure strategies predicated upon the "kick and kill" paradigm.

TRAILshort Protects against CD4 T Cell Death during Acute HIV Infection.

CD4 T cells from HIV-1 infected patients die at excessive rates compared to those from uninfected patients, causing immunodeficiency. We previously identified a dominant negative ligand that antagonizes the TRAIL-dependent pathway of cell death, which we called TRAILshort. Because the TRAIL pathway has been implicated in CD4 T cell death occurring during HIV-1 infection, we used short hairpin RNA knockdown, CRISPR deletion, or Abs specific for TRAILshort to determine the effect of inhibiting TRAILshort on the outcome of experimental acute HIV infection in vitro. Strikingly, all three approaches to TRAILshort deletion/inhibition enhanced HIV-induced death of both infected and uninfected human CD4 T cells. Thus, TRAILshort impacts T cell dynamics during HIV infection, and inhibiting TRAILshort causes more HIV-infected and uninfected bystander cells to die. TRAILshort is, therefore, a host-derived, host-adaptive mechanism to limit the effects of TRAIL-induced cell death. Further studies on the effects of TRAILshort in other disease states are warranted.

The Role of the BCL-2 Family of Proteins in HIV-1 Pathogenesis and Persistence.

Advances in HIV-1 therapy have transformed the once fatal infection into a manageable, chronic condition, yet the search for a widely applicable approach to cure remains elusive. The ineffectiveness of antiretroviral therapy (ART) in reducing the size of the HIV-1 latent reservoir has prompted investigation into the mechanisms of HIV-1 latency and immune escape. One of the major regulators of apoptosis, the BCL-2 protein, alongside its homologous family members, is a major target of HIV-1-induced change. Recent studies have now demonstrated the association of this protein with cells that support proviral forms in the setting of latency and have helped identify BCL-2 as a novel and promising therapeutic target for HIV-1 therapy directed at possible cure. This review aims to systematically review the interactions of HIV-1 with BCL-2 and its homologs and to examine the possibility of using BCL-2 inhibitors in the study and elimination of the latent reservoir.

Both HIV-Infected and Uninfected Cells Express TRAILshort, Which Confers TRAIL Resistance upon Bystander Cells within the Microenvironment.

TNF-related apoptosis-inducing ligand (TRAIL) was initially described to induce apoptosis of tumor cells and/or virally infected cells, although sparing normal cells, and has been implicated in the pathogenesis of HIV disease. We previously identified TRAILshort, a TRAIL splice variant, in HIV-infected patients and characterized it as being a dominant negative ligand to subvert TRAIL-mediated killing. Herein, using single-cell genomics we demonstrate that TRAILshort is produced by HIV-infected cells, as well as by uninfected bystander cells, and that the dominant stimulus which induces TRAILshort production are type I IFNs and TLR7, TLR8, and TLR9 agonists. TRAILshort has a short t1/2 by virtue of containing a PEST domain, which targets the protein toward the ubiquitin proteasome pathway for degradation. Further we show that TRAILshort binds preferentially to TRAIL receptors 1 and 2 with significantly reduced interaction with the decoy TRAIL receptors 3 and 4. Recombinant TRAILshort is sufficient to protect cells against TRAIL-induced killing, whereas immunodepletion of TRAILshort with a specific Ab restores TRAIL sensitivity. Importantly we show that TRAILshort is shed in microvesicles into the cellular microenvironment and therefore confers TRAIL resistance not only on the cell which produces it, but also upon neighboring bystander cells. These results establish a novel paradigm for understanding and overcoming TRAIL resistance, in particular how HIV-infected cells escape immune elimination by the TRAIL:TRAILshort receptor axis.

Risks and Outcomes of Allogeneic Hematopoietic Stem Cell Transplantation for Hematologic Malignancies in Patients with HIV Infection.

Allogeneic hematopoietic cell transplantation (allo-HCT) is a potentially curative therapy for hematologic malignancies in persons living with HIV (PLHIV), however, uncertainties exist in many domains related to their care, including optimal donor selection, conditioning regimen, immunosuppression for graft-versus-host disease (GVHD), and long-term outcomes. We undertook a comprehensive systematic review from multiple databases to evaluate the foregoing uncertainties. The final sample comprised 49 patients (median age at HCT, 34 years; 46 males [93.8%]). Acute GVHD (aGVHD) was reported in 19 patients (59.3%) in the overall cohort, with grade II in 12 (37.5%) and grade III in 2 (6.2%). In the entire cohort, overall survival (OS) was 81.6% at 6 months and 56.6% at 12 months. Among 32 patients, the OS at 6 months was 73.3% for patients who received myeloablative conditioning (MAC) and 88.2% for those who received reduced-intensity conditioning (RIC), and OS at 12 months was 53.3% for MAC and 58.8% for RIC. Twenty-four patients were alive in complete remission on long-term follow-up, with 25 deaths reported. Fifteen deaths (60%) occurred due to relapse, including 3 (12%) from infection, 2 (8%) from GVHD, and 5 (20%) from other causes, including renal failure, respiratory failure, and liver failure. To our knowledge, this is the largest series of allo-HCT in PLHIV reported to date, and our results indicate that clinical outcomes (including engraftment, infection rate, and survival) are not significantly different from those in patients without HIV (historical controls). RIC regimens are associated with a slightly greater likelihood of survival compared with MAC regimens. Prospective trials are critically needed to evaluate the optimal conditioning regimens, ideal donor source, and most appropriate GVHD prophylaxis.

HIV Protease-Generated Casp8p41, When Bound and Inactivated by Bcl2, Is Degraded by the Proteasome.

HIV protease is known to cause cell death, which is dependent upon cleavage of procaspase 8. HIV protease cleavage of procaspase 8 generates Casp8p41, which directly binds Bak with nanomolar affinity, causing Bak activation and consequent cell death. Casp8p41 can also bind Bcl2 with nanomolar affinity, in which case cell death is averted. Central memory CD4 T cells express high levels of Bcl2, possibly explaining why those cells do not die when they reactivate HIV. Here, we determine that the Casp8p41-Bcl2 complex is polyubiquitinated and degraded by the proteasome. Ixazomib, a proteasome inhibitor in clinical use, blocks this pathway, increasing the abundance of Casp8p41 and causing more cells to die in a Casp8p41-dependent manner.IMPORTANCE The Casp8p41 pathway of cell death is unique to HIV-infected cells yet is blocked by Bcl2. Once bound by Bcl2, Casp8p41 is polyubiquitinated and degraded by the proteasome. Proteasome inhibition blocks degradation of Casp8p41, increasing Casp8p41 levels and causing more HIV-infected cells to die.

Risk of Suicidal Behavior With Use of Efavirenz: Results from the Strategic Timing of Antiretroviral Treatment Trial.

Background: Randomized trials have shown increased risk of suicidality associated with efavirenz (EFV). The START (Strategic Timing of Antiretroviral Treatment) trial randomized treatment-naive human immunodeficiency virus (HIV)-positive adults with high CD4 cell counts to immediate vs deferred antiretroviral therapy (ART). Methods: The initial ART regimen was selected prior to randomization (prespecified). We compared the incidence of suicidal and self-injurious behaviours (suicidal behavior) between the immediate vs deferred ART groups using proportional hazards models, separately for those with EFV and other prespecified regimens, by intention to treat, and after censoring participants in the deferred arm at ART initiation. Results: Of 4684 participants, 271 (5.8%) had a prior psychiatric diagnosis. EFV was prespecified for 3515 participants (75%), less often in those with psychiatric diagnoses (40%) than without (77%). While the overall intention-to-treat comparison showed no difference in suicidal behavior between arms (hazard ratio [HR], 1.07, P = .81), subgroup analyses suggest that initiation of EFV, but not other ART, is associated with increased risk of suicidal behavior. When censoring follow-up at ART initiation in the deferred group, the immediate vs deferred HR among those who were prespecified EFV was 3.31 (P = .03) and 1.04 (P = .93) among those with other prespecified ART; (P = .07 for interaction). In the immediate group, the risk was higher among those with prior psychiatric diagnoses, regardless of prespecified treatment group. Conclusions: Participants who used EFV in the immediate ART group had increased risk of suicidal behavior compared with ART-naive controls. Those with prior psychiatric diagnoses were at higher risk.

Maintenance of the HIV Reservoir Is Antagonized by Selective BCL2 Inhibition.

Decay of the HIV reservoir is slowed over time in part by expansion of the pool of HIV-infected cells. This expansion reflects homeostatic proliferation of infected cells by interleukin-7 (IL-7) or antigenic stimulation, as well as new rounds of infection of susceptible target cells. As novel therapies are being developed to accelerate the decay of the latent HIV reservoir, it will be important to identify interventions that prevent expansion and/or repopulation of the latent HIV reservoir. Our previous studies showed that HIV protease cleaves the host protein procaspase 8 to generate Casp8p41, which can bind and activate Bak to induce apoptosis of infected cells. In circumstances where expression of the anti-apoptotic protein BCL2 is high, Casp8p41 instead binds BCL2, and cell death does not occur. This effect can be overcome by treating cells with the clinically approved BCL2 antagonist venetoclax, which prevents Casp8p41 from binding BCL2, thereby allowing Casp8p41 to bind Bak and kill the infected cell. Here we assess whether the events that maintain the HIV reservoir are also antagonized by venetoclax. Using the J-Lat 10.6 model of persistent infection, we demonstrate that proliferation and HIV expression are countered by the use of venetoclax, which causes preferential killing of the HIV-expressing cells. Similarly, during new rounds of infection of primary CD4 T cells, venetoclax causes selective killing of HIV-infected cells, resulting in decreased numbers of HIV DNA-containing cells.IMPORTANCE Cure of HIV infection requires an intervention that reduces the HIV reservoir size. A variety of approaches are being tested for their ability to impact HIV reservoir size. Even if successful, however, these approaches will need to be combined with additional complementary approaches that prevent replenishment or repopulation of the HIV reservoir. Our previous studies have shown that the FDA-approved BCL2 antagonist venetoclax has a beneficial effect on the HIV reservoir size following HIV reactivation. Here we demonstrate that venetoclax also has a beneficial effect on HIV reservoir size in a model of homeostatic proliferation of HIV as well as in acute spreading infection of HIV in primary CD4 T cells. These results suggest that venetoclax, either alone or in combination with other approaches to reducing HIV reservoir size, is a compound worthy of further study for its effects on HIV reservoir size.

Extensive virologic and immunologic characterization in an HIV-infected individual following allogeneic stem cell transplant and analytic cessation of antiretroviral therapy: A case study.

BACKGROUND: Notwithstanding 1 documented case of HIV-1 cure following allogeneic stem cell transplantation (allo-SCT), several subsequent cases of allo-SCT in HIV-1 positive individuals have failed to cure HIV-1 infection. The aim of our study was to describe changes in the HIV reservoir in a single chronically HIV-infected patient on suppressive antiretroviral therapy who underwent allo-SCT for treatment of acute lymphoblastic leukemia. METHODS AND FINDINGS: We prospectively collected peripheral blood mononuclear cells (PBMCs) by leukapheresis from a 55-year-old man with chronic HIV infection before and after allo-SCT to measure the size of the HIV-1 reservoir and characterize viral phylogeny and phenotypic changes in immune cells. At day 784 post-transplant, when HIV-1 was undetectable by multiple measures-including PCR measurements of both total and integrated HIV-1 DNA, replication-competent virus measurement by large cell input quantitative viral outgrowth assay, and in situ hybridization of colon tissue-the patient consented to an analytic treatment interruption (ATI) with frequent clinical monitoring. He remained aviremic off antiretroviral therapy until ATI day 288, when a low-level virus rebound of 60 HIV-1 copies/ml occurred, which increased to 1,640 HIV-1 copies/ml 5 days later, prompting reinitiation of ART. Rebounding plasma HIV-1 sequences were phylogenetically distinct from proviral HIV-1 DNA detected in circulating PBMCs before transplantation. The main limitations of this study are the insensitivity of reservoir measurements, and the fact that it describes a single case. CONCLUSIONS: allo-SCT led to a significant reduction in the size of the HIV-1 reservoir and a >9-month-long ART-free remission from HIV-1 replication. Phylogenetic analyses suggest that the origin of rebound virus was distinct from the viruses identified pre-transplant in the PBMCs.

Prime, Shock, and Kill: Priming CD4 T Cells from HIV Patients with a BCL-2 Antagonist before HIV Reactivation Reduces HIV Reservoir Size.

UNLABELLED: Understanding how some HIV-infected cells resist the cytotoxicity of HIV replication is crucial to enabling HIV cure efforts. HIV killing of CD4 T cells that replicate HIV can involve HIV protease-mediated cleavage of procaspase 8 to generate a fragment (Casp8p41) that directly binds and activates the mitochondrial proapoptotic protein BAK. Here, we demonstrate that Casp8p41 also binds with nanomolar affinity to the antiapoptotic protein Bcl-2, which sequesters Casp8p41 and prevents apoptosis. Further, we show that central memory CD4 T cells (TCM) from HIV-infected individuals have heightened expression of BCL-2 relative to procaspase 8, possibly explaining the persistence of HIV-infected TCMdespite generation of Casp8p41. Consistent with this hypothesis, the selective BCL-2 antagonist venetoclax induced minimal killing of uninfected CD4 T cells but markedly increased the death of CD4 T cells and diminished cell-associated HIV DNA when CD4 T cells from antiretroviral therapy (ART)-suppressed HIV patients were induced with αCD3/αCD28 to reactivate HIVex vivo Thus, priming CD4 T cells from ART suppressed HIV patients with a BCL-2 antagonist, followed by HIV reactivation, achieves reductions in cell-associated HIV DNA, whereas HIV reactivation alone does not. IMPORTANCE: HIV infection is incurable due to a long-lived reservoir of HIV(+)memory CD4 T cells, and no clinically relevant interventions have been identified that reduce the number of these HIV DNA-containing cells. Since postintegration HIV replication can result in HIV protease generation of Casp8p41, which activates BAK, causing infected CD4 T cell death, we sought to determine whether this occurs in memory CD4 T cells. Here, we demonstrate that memory CD4 T cells can generate Casp8p41 and yet are intrinsically resistant to death induced by diverse stimuli, including Casp8p41. Furthermore, BCL-2 expression is relatively increased in these cells and directly binds and inhibits Casp8p41's proapoptotic effects. Antagonizing BCL-2 with venetoclax derepresses this antagonism, resulting in death, preferentially in HIV DNA containing cells, since only these cells generate Casp8p41. Thus, BCL-2 antagonism is a clinically relevant intervention with the potential to reduce HIV reservoir size in patients.

Epidemiology, risk factors, and outcomes of infections in patients undergoing liver transplantation for hilar cholangiocarcinoma.

The epidemiology of infection after liver transplantation for hilar cholangiocarcinoma has not been systematically investigated. In this study of 124 patients, 255 infections occurred in 105 patients during the median follow-up of 4.2 years. The median time to first infection was 15.1 weeks (IQR 1.6-62.6). The most common sites were the abdomen, bloodstream, and musculoskeletal system. Risk factors for any post-transplant infection were pre-transplant VRE colonization (Hazard Ratio [HR] 1.9, P=.002), living donor transplantation (HR 6.6, P<.001), longer cold ischemia time (HR 1.05 per 10 minutes, P<.001), donor CMV seropositivity (HR 2.2, P<.001), hepatic artery thrombosis (HR 2.6, P=.005), biliary stricture (HR 3.8, P=.002), intra-abdominal fluid collection (HR 4.2, P<.001), and re-operations within 1 month after transplantation (HR 1.7, P=.020). Abdominal infections were independently associated with hemodialysis requirement within 1 month after transplantation (HR 5.6, P=.006), hepatic artery thrombosis (HR 3.3, P=.007), biliary stricture (HR 5.2, P<.001), and abdominal fluid collection (HR 3.7, P=.0002). Bloodstream infections were independently associated with allograft ischemia (HR 17.8, P<.001), biliary stricture (HR 6.5, P=.005), and recipient VRE colonization (HR 4, P<.001). Abdominal infections (HR 2.3, P=.02) and Clostridium difficile infections (HR 4.6, P=.01) were independently associated with increased mortality.

Anti-apoptotic mechanisms of HIV: lessons and novel approaches to curing HIV.

Past efforts at curing infection with the human immunodeficiency virus (HIV) have been blocked by the resistance of some infected cells to viral cytopathic effects and the associated development of a latent viral reservoir. Furthermore, current efforts to clear the viral reservoir by means of reactivating latent virus are hampered by the lack of cell death in the newly productively infected cells. The purpose of this review is to describe the many anti-apoptotic mechanisms of HIV, as well as the current limitations in the field. Only by understanding how infected cells avoid HIV-induced cell death can an effective strategy to kill infected cells be developed.

Stability in the cumulative incidence, severity and mortality of 101 cases of invasive mucormycosis in high-risk patients from 1995 to 2011: a comparison of eras immediately before and after the availability of voriconazole and echinocandin-amphotericin combination therapies.

As invasive mucormycosis (IM) numbers rise, clinicians suspect prior voriconazole worsens IM incidence and severity, and believe combination anti-fungal therapy improves IM survival. To compare the cumulative incidence (CI), severity and mortality of IM in eras immediately before and after the commercial availability of voriconazole all IM cases from 1995 to 2011 were analysed across four risk-groups (hematologic/oncologic malignancy (H/O), stem cell transplantation (SCT), solid organ transplantation (SOT) and other), and two eras, E1 (1995-2003) and E2, (2004-2011). Of 101 IM cases, (79 proven, 22 probable): 30 were in E1 (3.3/year) and 71 in E2 (8.9/year). Between eras, the proportion with H/O or SCT rose from 47% to 73%, while 'other' dropped from 33% to 11% (P = 0.036). Between eras, the CI of IM did not significantly increase in SCT (P = 0.27) or SOT (P = 0.30), and patterns of anatomic location (P = 0.122) and surgical debridement (P = 0.200) were similar. Significantly more patients received amphotericin-echinocandin combination therapy in E2 (31% vs. 5%, P = 0.01); however, 90-day survival did not improve (54% vs. 59%, P = 0.67). Since 2003, the rise of IM reflects increasing numbers at risk, not prior use of voriconazole. Frequent combination of anti-fungal therapy has not improved survival.

Heme oxygenase-1 regulates the immune response to influenza virus infection and vaccination in aged mice.

Underlying mechanisms of individual variation in severity of influenza infection and response to vaccination are poorly understood. We investigated the effect of reduced heme oxygenase-1 (HO-1) expression on vaccine response and outcome of influenza infection. HO-1-deficient and wild-type (WT) mice (kingdom, Animalia; phylum, Chordata; genus/species, Mus musculus) were infected with influenza virus A/PR/8/34 with or without prior vaccination with an adenoviral-based influenza vaccine. A genome-wide association study evaluated the expression of single-nucleotide polymorphisms (SNPs) in the HO-1 gene and the response to influenza vaccination in healthy humans. HO-1-deficient mice had decreased survival after influenza infection compared to WT mice (median survival 5.5 vs. 6.5 d, P=0.016). HO-1-deficient mice had impaired production of antibody following influenza vaccination compared to WT mice (mean antibody titer 869 vs. 1698, P=0.02). One SNP in HO-1 and one SNP in the constitutively expressed isoform HO-2 were independently associated with decreased antibody production after influenza vaccination in healthy human volunteers (P=0.017 and 0.014, respectively). HO-1 deficient mice were paired with sex- and age-matched WT controls. HO-1 affects the immune response to both influenza infection and vaccination, suggesting that therapeutic induction of HO-1 expression may represent a novel adjuvant to enhance influenza vaccine effectiveness.

Non-tuberculous mycobacteria infection presenting as a hepatic allograft abscess.

Nontuberculous mycobacteria (NTM) are mycobacterial species other than Mycobacterium tuberculous and Mycobacterium leprae [1]. They are environmental organisms which have been implicated in a wide array of clinical syndromes. Here we describe a case of a Mycobacterium fortuitum complex liver abscess in a liver transplant recipient.