Merceditas Villanueva

Efficiency of MHC class I antigen processing: A quantitative analysis

Listeria monocytogenes is an intracellular pathogen that secretes proteins into host cell cytosol. One such protein, the murein hydrolase p60, is processed by the host cell into the nonamer peptide p60 217-225 and presented to cytotoxic T lymphocytes by the H-2Kd MHC class I molecule. Using strains of L. monocytogenes that secrete different amounts of p60, we show that the rate of p60 217-225 production is proportional to the quantity of intracellular antigen. The appearance of p60 217-225 is coupled to the degradation of newly synthesized p60. By accounting for the rate of intracellular antigen secretion and degradation, we estimate that approximately 35 p60 molecules are degraded to produce one p60 217-225 epitope. These findings provide an estimate of the efficiency of antigen processing and shed light on the capacity of the MHC class I antigen processing pathway to accommodate foreign antigens.

MHC class I antigen processing of Listeria monocytogenes proteins: implications for dominant and subdominant CTL responses.

Summary: Listeria monocytogenes (L. monocytogenes) secretes proteins associated with its virulence into the cytosol of infected cells. These secreted proteins are degraded by host cell proteasomes and processed into peptides that are bound by MHC class I molecules in the endoplasmic reticulum. We have found that the MHC class I antigen‐processing pathway is very efficient at generating the epitopes that are presented to cytolytic T lymphocytes (CTL). Depending on which antigen is investigated, from 3 to 30 % of degraded antigens are processed into nonamer peptides that are bound by MHC class I molecules. Surprisingly, neither the efficiency of epitope generation nor the absolute number of epitopes per infected cell determines the magnitude of the in vivo CTL response. One of the least prevalent epitopes, derived from an antigen that is virtually undetectable in infected cells, primes the immunodominant CTL response in L. monocytogenes‐infected mice. Our studies suggest that immunodominant and subdominant T‐cell responses cannot be predicted by the prevalence of antigens or epitopes alone, and that additional factors, yet to be determined, are involved.

Integrase strand transferase inhibitors: the preferred antiretroviral regimen in HIV-positive renal transplantation.

In the era of antiretroviral therapy, people living with HIV/AIDS live longer and are subject to co-morbidities that affect the general population, such as chronic kidney disease. An increasing number of people living with HIV/AIDS with end-stage renal disease are candidates for renal transplantation. Prior experience demonstrated that HIV-positive renal transplant recipients had acceptable survival but graft survival was decreased and rejection rates were increased, possibly due to suboptimal management of immunosuppressive medications in the face of drug interactions with antiretroviral therapy, particularly protease inhibitors and non-nucleoside reverse transcriptase inhibitors. Integrase strand transferase inhibitors are advantageous since they avoid drug–drug interactions with immunosuppressive drugs such as calcineurin inhibitors. We report clinical outcomes of 12 HIV-positive patients who underwent 13 kidney transplantations at our institution between 2000 and 2015. Cumulative survival was 75%, one-year and three-year survival were 100% and 63%. Integrase strand transferase inhibitor-based regimens were used in nine patients, of which eight survived. In patients on integrase strand transferase inhibitor, there was 100% graft survival and two had allograft rejection. In contrast, graft failure occurred in three patients on non-integrase strand transferase inhibitor-based regimens. Based on our study findings and on previously published data, we conclude that integrase strand transferase inhibitor-based therapy, preferably instituted prior to transplantation, is the preferred antiretroviral regimen in HIV-positive renal transplantation.

Extensive Central Nervous System Cryptococcal Disease Presenting as Immune Reconstitution Syndrome in a Patient with Advanced HIV: Report of a Case and Review of Management Dilemmas and Strategies.

One of the complications of the use of antiretroviral therapy (ART), immune reconstitution inflammatory syndrome (IRIS), is particularly problematic in the management of cryptococcal meningitis. We present the case of a 35-year-old male with acquired immune deficiency syndrome diagnosed with extensive central nervous system (CNS) cryptococcal disease, including meningitis and multiple intracranial cysts, diagnosed eight weeks after the initiation of ART. The patient experienced a relapsing and remitting clinical course despite repeated courses of potent antifungal therapy and aggressive management of raised intracranial pressure. This review highlights therapeutic dilemmas and strategies in the management of CNS cryptococcosis complicated with IRIS and highlights gaps in available treatment guidelines.

Prevention and Treatment of Cryptococcal Meningitis in Patients with AIDS

SummaryPreviously a rare diagnosis, cryptococcal meningitis has emerged as the most common fungal meningitis in the US because of the AIDS epidemic. Due to the profound and prolonged immunosuppression seen in patients with AIDS, the clinical presentation and course of the disease differ from those previously seen in non-HIV-infected patients.Accordingly, previous ‘standard’ treatment strategies have undergone reevaluation in a number of retrospective and prospective clinical studies. In addition, the availability of triazole compounds has changed the management of the disorder. A strategy of aggressive initial treatment with amphotericin B followed by lifelong suppressive therapy with fluconazole has become the accepted approach. Although several clinical studies addressing treatment have been completed. a number of important questions remain about optimal management of this disease.

A rare case of visceral leishmaniasis in an immunocompetent traveler returning to the United States from Europe

A young, healthy traveler returning to the United States presented with fever, night sweats, splenomegaly, and pancytopenia. Bone marrow biopsy revealed leishmaniasis (Leishmania infantum), likely acquired in southern France. Although many cases of endemic visceral leishmaniasis (VL) have been reported in Europe, this is a rare case of imported VL in a healthy traveler returning from Europe to the US. Despite successful initial treatment with liposomal amphotericin B (LamB), relapse occurred. Treatments for VL in immunocompetent individuals are highly effective, but relapse can occur. There is more extensive experience in endemic areas with treating relapse that may be lacking in North America. This case alerts physicians in the US that immunocompetent adults can acquire VL during brief visits to endemic areas in Europe. It is important that travelers be counseled on preventive measures. Patients should be monitored after treatment for relapse.

Fatal cryptococcal meningitis in an AIDS patient complicated with immune reconstitution syndrome refractory to prolonged amphotericin B treatment

Cryptococcus neoformans is a ubiquitous encapsulated environmental yeast that can cause severe central nervous system disease, primarily in immune compromised hosts. In patients with AIDS, the spectrum of cryptococcal central nervous system disease includes meningitis, cystic lesions, and mass-like cryptococcomas. We report a fatal case of meningitis and cerebritis caused by C. neoformans in an AIDS patient refractory to multiple courses of liposomal amphotericin B despite immune recovery with antiretroviral therapy. This case highlights ongoing diagnostic and therapeutic challenges in the face of treatment failure for cryptococcal meningitis and reinforces the need for improved treatment approaches.

Paradoxical Reaction in a Patient with Co-Occurring Tuberculous Meningitis and Pott’s Disease

Patient: Male, 36 Final Diagnosis: TB paradoxical reaction Symptoms: Back pain • diplopia • Headache Medication: — Clinical Procedure: — Specialty: Infectious Diseases Objective: Unusual clinical course Background: Paradoxical reactions to tuberculosis (TB) are clinical or radiological worsening of prior tuberculous lesions or the development of new lesions upon treatment with appropriate anti-tuberculosis therapy (ATT). This phenomenon has been described in both HIV-seropositive and HIV-seronegative patients. Although historically estimated to occur in 6–30% of HIV-seronegative patients with TB, the phenomenon is often under-recognized in the current era, particularly in countries of low TB prevalence. We describe a case of a TB paradoxical reaction affecting the CNS and spine in an HIV-seronegative individual who received clinical care in the U.S. Case Report: A 36-year-old HIV-seronegative refugee from Eritrea presented to the hospital with fever, back pain, and headache shortly after arriving to the U.S. He was diagnosed with TB meningitis and Pott’s disease and was started on ATT. He developed worsening clinical symptoms, including headaches, transient diplopia, and mood disturbances, as well as new radiologic abnormalities in the brain (tuberculomas) and spine (abnormal enhancement) despite appropriate ATT. He received prolonged 4-drug ATT and steroids as well as changes in his ATT regimen, and multiple attempts were made to biopsy the brain and spine to address concerns for radiologic changes. Eventually, he was discharged 1 year later with clinical improvement and full neurologic recovery. Conclusions: Radiologic and clinical findings due to paradoxical reactions may be unfamiliar to clinicians in countries with low TB prevalence and inadvertently lead to either inadequate management such as the underappreciation of the clinical signs and symptoms indicating potential severity of CNS paradoxical reaction, or conversely overly invasive approaches in a patient who is otherwise clinically improving. Increasing awareness about extrapulmonary paradoxical reactions in such patients is crucial for ensuring appropriate diagnostic approaches and timely clinical management.

Efficacy of an 8-week course of sofosbuvir and ledipasvir for the treatment of HCV infection in selected HIV-infected patients

Background: With the availability of direct acting antiviral treatment for hepatitis C (HCV), HIV and HCV co-infected patients show comparable treatment responses to HCV-monoinfected patients. An 8-week course of sofosbuvir/ledipasvir (SOF/LDV) is highly effective for the treatment of HCV genotype 1 infection in treatment-naïve mono-infected patients with HCV viral loads <6 million IU/ml. There is limited data on the efficacy of this 8-week HCV treatment regimen in HIV-infected individuals with similar viral loads. Methods: The study was a retrospective review of HIV-infected adults coinfected with HCV genotype 1 for whom an 8-week course of SOF/LDV was prescribed by providers at two clinics in the Yale-New Haven Health system from November 1, 2014 until April 30, 2016. Treatment efficacy was assessed as the proportion of treatment initiators who achieved a sustained virologic response 12 weeks after completion of therapy (SVR 12). Results: Nineteen patients met study eligibility criteria and included 14 men (74%); and 12 African-Americans (63%). All patients were on antiretroviral therapy with fully suppressed HIV viral loads and were HCV treatment-naïve. All patients had pre-treatment HCV viral loads <6 million IU/mL. Eighteen patients (95%) completed HCV treatment. Overall, SVR 12 was 95%, with 1 treament failure occurring due to suboptimal adherence. Conclusion: Among our HIV-infected patient cohort with HCV genotype 1 infection, 95% of those treated with an 8 week course of SOF/LDV achieved SVR 12. This is comparable to the efficacy of the same treatment regimen in patients without HIV infection. This study lends proof of concept to the use of shorter course SOF/LDV treatment for HIV-HCV genotype 1 coinfected patients with viral loads <6 million IU/ml. Larger studies are indicated to validate our findings.

A 33-year-old Haitian immigrant with 7 months of abdominal pain and progressive distension

We report a case of a 33-year-old previously healthy Haitian immigrant with a 7-month history of abdominal pain, fever and ascites. He had a history of positive tuberculin skin test but never underwent treatment for latent tuberculosis (TB) infection. Initial examination showed abdominal distension. Abdominal CT scan showed mild ascites, abnormal soft tissue in the greater omentum and small bowel mesentery, retroperitoneal adenopathy, peritoneal thickening and dilated loops of small bowel. Paracentesis and thoracentesis were initially non-diagnostic. HIV testing was negative. The differential diagnosis included lymphoma and TB peritonitis. The omental mass was biopsied under ultrasound guidance, and histopathology revealed non-necrotising granulomas. Sputum cultures and omental biopsy cultures subsequently grew Mycobacterium tuberculosis, and a diagnosis was made of pulmonary TB with TB peritonitis. The patient responded well to the initiation of anti-TB treatment.