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Department of Medicine

Department of Medicine

   Division of Infectious Diseases

Research

Basic and Translational Research

 

Ambrose Lab

The Ambrose laboratory takes three approaches to studying HIV infection and therapeutics: 1) transmission and prevention of HIV; 2) HIV treatment and drug resistance, including identification of new therapeutic targets; and 3) persistence of viral reservoirs in vivo. Daily oral pre-exposure prophylaxis (PrEP) using two antiretroviral drugs is effective at preventing HIV transmission in high-risk populations. One concern in using antiretroviral drugs for both treatment of HIV-infected individuals and for PrEP is the potential for transmission or development of drug-resistant HIV isolates during PrEP. The Ambrose laboratory is studying the efficacy of long-lasting PrEP in preventing transmission of HIV, including common drug-resistant strains. In addition, we are investigating the mechanisms of novel small molecule inhibitors at preventing HIV infection in vitro and in vivo. The Ambrose laboratory also is investigating the differences of HIV infection of macrophages and CD4+ T cells, both critical cell types infected in the host. The lab hopes by understanding these differences, they can exploit these pathways with novel antiretroviral strategies. Finally, the Ambrose laboratory studies viral diversity and variability, particularly of drug resistance mutations that develop in blood and different tissues before, during, and after therapy to identify the nature and dynamic properties of persistent viral reservoirs both in and outside of the blood.

 

Culyba Lab

Dr. Culyba's laboratory fuses molecular and biochemical methodologies with experimental microbial evolution to study mutational phenomena and bacterial adaptation. Mutation and gene transfer events are the source of heritable variation for evolution. These genome diversifying processes can range from being relatively site-specific in the genome to being nearly random. Furthermore, beyond the mutations themselves, the DNA damage and DNA repair events associated with mutagenesis can also be deleterious to the host and are subject to multiple levels of active regulation by cells. Understanding how microorganisms respond to their environments and control the rate and specificity of mutagenesis is the focus of the laboratory. Ongoing studies are aimed at elucidating the (i) molecular mechanisms which regulate mutational phenomena in bacteria during transitions to new environments, (ii) molecular specificity determinants of enzymes involved in mutational phenomena, and (iii) new methods for tracking and detecting mutations in populations of cells. Research projects in the lab are designed to inform a variety of pressing scientific challenges, including combating the crisis of antimicrobial resistance, improving the specificity and safety of cutting-edge gene editing technologies, and building a comprehensive model of molecular evolution.

 

Doi Lab

The mission of Dr. Doi's laboratory is to identify and investigate antimicrobial resistance of clinical concern among gram-negative bacterial pathogens. The areas of research include: (i) genetic and molecular basis of emerging antimicrobial resistance mechanisms; (ii) rapid diagnosis of resistance using phenotypic, genetic and lipidomic approaches, and (iii) inhibitor-based drug discovery. Current efforts are focused on colistin resistance in Acinetobacter baumannii, a problematic healthcare-associated pathogen, and fosfomycin resistance in Escherichia coli, the predominant cause of urinary tract infection in both healthcare and community settings

 

Harrison Lab

Dr. Harrison's research focuses on the epidemiology and genomic epidemiology of important vaccine-preventable and drug-resistant bacterial pathogens that are transmitted in the community and causes of hospital-associated infections (HAI's). Pathogens studied include Streptococcus pneumoniae, group B Streptococcus, Neisseria meningitidis, Escherichia coli O157:H7, Salmonella enterica, Clostridium difficile, Klebsiella pneumoniae, and Pseudomonas aeruginosa. He is the PI of the Microbial Genomic Epidemiology Laboratory (MiGEL), which conducts research on and provides training in genomic epidemiology and provides outbreak detection support to the Director of Infection Control at the University of Pittsburgh Medical Center (UPMC).  MiGEL uses molecular epidemiologic tools, such as pulsed field gel electrophoresis (PFGE), multilocus sequence typing (MLST), multilocus variable number tandem repeat analysis (MLVA) and whole genome sequencing (WGS) to study emergence and transmission of these bacteria. More recently, Dr. Harrison has been studying the use of WGS and data mining of the electronic medical record (EMR) and machine learning tools for enhanced outbreak detection in the hospital. He is also studying the utility of the peri-rectal microbiome to predict risk of HAI's.

 

Macatangay Lab

Immunoregulatory mechanisms can influence many aspects of the body's immune responses to different antigens, and can control inflammatory responses thereby preventing pathology caused by persistent immune activation and inflammation. The Macatangay laboratory focuses on various immunoregulatory pathways in different inflammatory states, especially in HIV infection.  Specifically, the lab aims to define the role of different immunoregulatory mechanisms in: (i) the inflammatory state associated with chronic HIV infection; (ii) HIV persistence; (iii) various HIV immunotherapeutic strategies, such as in therapeutic vaccination. By using specimens obtained from the various studies at the Pittsburgh Treatment and Evaluation Unit (PTEU), the AIDS Clinical Trials Group (ACTG), and the Multicenter AIDS Cohort Study (MACS), the Macatangay lab assess the immunophenotype and frequencies of regulatory immune cell subsets, and analyzes specific suppressive functions and components of regulatory pathways in order to further understand the influence of specific immunoregulatory mechanisms in HIV pathogenesis and persistence. In doing so, they aim to improve existing or develop new immunotherapeutic strategies for the control of chronic HIV-associated inflammation and/or for the functional cure of HIV.

 

Mellors Lab

The goals of the Mellors Laboratory are to discover the most effective ways to prevent, treat and cure HIV-1 infection through the discovery, preclinical and clinical evaluation of new preventive and therapeutic strategies. Two large research efforts are under way.  The first includes a multidisciplinary team of laboratory scientists and clinical researchers that is investigating the mechanisms and anatomical reservoirs of HIV that persist in infected individuals despite clinically effective antiretroviral therapy (ART) and that constitute the major barrier to curing HIV infection. A broad range of technologically-advanced approaches are being applied to characterize HIV reservoirs including single cell and single molecule quantification and sequencing as well as traditional methods of virus culture and characterization. Such approaches have elucidated the sources of persistent viremia on ART, the decay of HIV-infected cells and persistent viremia during long-term ART, and the emergence of infected cell clones carrying intact proviruses. The impact of innovative therapies on HIV reservoirs is being studied in Phase I/II trials of histone deacetylase inhibitors, monoclonal antibodies to immune checkpoint ligands, monoclonal antibodies to HIV envelope glycoproteins, and TLR agonists. The second research effort is focused on understanding the emergence of variants of HIV that are resistant to antiretrovirals that are being used to prevent and treat HIV infection. The frequency and type of drug-resistant HIV variants are being characterized in international clinical trials of first-, second-, and third-line ART. Similarly, the transmission and emergence of drug-resistant HIV from the use of antiretrovirals for HIV prevention is being studied and the laboratory has been selected by the United States Agency for International Development (USAID) to be the global Center for Evaluation of Microbicide Sensitivity (GEMS Project).

 

Nguyen and Clancy Labs

Drs. Clancy and Nguyen conduct collaborative laboratory, translational and clinical research on issues relevant to the treatment, diagnosis and prevention of infections in immunosuppressed and other vulnerable patient populations.  Research teams are engaged in four inter-related areas of investigation: a) Medical mycology; b) Extensively-drug resistant (XDR) Gram negative bacterial infections and antimicrobial stewardship; c) Transplant infectious diseases; and d) Legionella control and environmental management.  Medical mycology research includes projects on mechanisms and clinical impact of antifungal drug resistance, molecular pathogenesis of invasive Candida infections, fungal diagnostics, and clinical studies and trials on fungal diseases, treatments and diagnostics.  XDR bacterial and antimicrobial stewardship research includes projects on evolution, and tolerance/resistance and pathogenic mechanisms of carbapenem-resistant Enterobacteriaceae (CRE) and other Gram negative bacteria, development of novel antibiotic treatment strategies based on bacterial genetics and pharmacokinetic-pharmacodynamic (PK-PD) principles, the clinical and economic impact of XDR infections and antimicrobial stewardship interventions, and clinical trials of new antimicrobials and diagnostic tests. Transplant Infectious Diseases research includes projects on the role of the microbiome in infections and outcomes among transplant recipients, the impact of rectal CRE carriage on transplant patients' outcome, and clinical studies and trials on a wide range of opportunistic fungal, bacterial and viral infections. Legionella and environmental management research includes projects on the genomic epidemiology of disease-causing and water system Legionella at the VA Pittsburgh Healthcare System, and environmental remediation and control of potential pathogens.  The Clancy and Nguyen labs employ a range of cutting edge technologies in their research, including molecular biology techniques, animal models of fungal and bacterial infections, genomics, transcriptomics and microbiome profiling, and PK-PD modeling.  Projects are structured on a bedside-to-bench-to-bedside design, and involve clinical and laboratory investigators.     

     

photoParikh Lab

Dr. Parikh's translational research laboratory uses novel technical approaches to solve public health problems in the research areas of HIV prevention and drug resistance.  Dr. Parikh leads the USAID/PEPFAR-funded Global Evaluation of Microbicide Sensitivity (GEMS) Project whose goals are to characterize resistance risk from pre-exposure prophylaxis (PrEP) trials and demonstration projects, identify the most effective and efficient HIV testing and resistance monitoring strategies, generate evidence-based policy recommendations for HIV diagnostic testing frequency and ARV resistance monitoring, and monitor seroconverters from PrEP roll-out programs for ARV resistance in selected clinics in South Africa, Zimbabwe, and Kenya.  The GEMS project brings together a diverse team of laboratory scientists, mathematical modelers, policy experts, health economists, in-country stakeholders, demonstration project teams and others towards the common public health goal of minimizing resistance risk during PrEP roll-out.  Her laboratory also serves as the Virology Core for the Microbicides Trial Network (MTN), with the aim of confirming virologic endpoints for all MTN studies, assessing population and low-frequency resistance in seroconverters from HIV prevention trials, developing new assays and addressing research questions relevant to the field of HIV prevention, and providing virology support to MTN protocols, international clinical research sites, and community working groups.  In addition to these major projects, Dr. Parikh's lab is investigating the detection of Y chromosome DNA in genital tract specimens using quantitative real-time PCR as a biomarker for unprotected sex and evaluating new HIV diagnostic algorithms using antigen-based rapid tests for identifying seroconverters.

 

Sluis-Cremer Lab

Dr. Sluis-Cremer's laboratory implements a multi-disciplinary approach that includes biophysics, biochemistry, virology and analysis of clinical samples to gain insight into: (i) the mechanisms of action of antiretroviral drugs; (ii) antiviral and antimicrobial drug resistance; and (iii) understanding how HIV-1 persists in infected individuals despite potent antiretroviral therapy. To elucidate how antiviral drugs inhibit virus replication, the lab uses state-of-the-art biophysical methods, including transient kinetic and single-molecule fluorescence approaches, to define how small molecules affect retroviral enzyme function, the intramolecular protein conformational dynamics, and the intermolecular enzyme-substrate interactions. The knowledge gained from this work is critical for the development of new inhibitors, and for understanding how mutations in the viral enzyme confer drug resistance. For HIV-1, the resistance research is focused on the identification of drug resistance mutations that are selected in infected-individuals failing therapy, defining the mechanisms by which these mutations decrease drug susceptibility using biochemical and virology approaches, and to predict how acquired or transmitted drug resistance mutations impact future treatment options. The Sluis-Cremer laboratory has also recently expanded their resistance portfolio to characterize bacterial resistance to the antibiotic fosfomycin, and to explore novel therapeutic approaches to reverse fosfomycin resistance. In regard to HIV-1 persistence, they are focused on characterizing the latent pool of HIV-1 infection that resides in resting CD4+ T cells, in particular the naïve and central memory subsets, using novel primary cell models of HIV-1 latency and by studying purified subsets of the resting CD4+ T cell population from HIV-infected individuals on suppressive antiretroviral therapy.