Despite repeated exposure to HIV-1, certain individuals remain uninfected. In the mid-90’s, this decreased susceptibility to infection was shown to be, at least partly, explained by homozygosity for a 32 base pair deletion in the gene for the HIV-1 coreceptor CCR51,2.

This deletion is relatively common in northern Europeans, however, is extremely rare in Asians and Africans where HIV-1 seronegativity, despite multiple exposure, has also been documented suggesting the existence of additional genetic susceptibility factors to HIV-1 infection in other human populations.  

Previously, as part of a larger project, the Ireland-Vietnam Blood-Borne Virus Initiative (IVVI), investigators at the UCD Centre for Research in Infectious Disease (CRID) have identified a number of novel mutations in the HIV-1 coreceptor gene CCR5 in exposed, HIV-1 seronegative individuals in Vietnam which were intriguingly associated with HIV-1 gp120 loop motifs indicative of binding to the alternative HIV-1 coreceptor, CXCR43. This project will functionally characterise these novel CCR5 mutants and their effect on surface expression in cultured cells and the impact on HIV-1 infection in vitro. 

This research is led by Prof William W Hall, Dr Virginie Gautier and Dr Michael Carr (National Virus Reference Laboratory).

• Cannon P, June C. Chemokine receptor 5 knockout strategies. Curr Opin HIV AIDS. 2011; 6:74-9.
• Didigu CA, Doms RW. Novel approaches to inhibit HIV entry. Viruses. 2012; 4:309-24.
• Luu QP et al. HIV Type 1 Coreceptor Tropism, CCR5 Genotype, and Integrase Inhibitor Resistance Profiles in Vietnam: Implications for the Introduction of New Antiretroviral Regimens. AIDS Res Hum Retroviruses. 2012 (in press). 

Combine the two narratives below into a single tighter piece....

For the 2,000 HIV patients being treated in Irish hospitals and the approximately 400 new patients who are diagnosed each year, this finding is profoundly important, specifically for those who require immediate therapy. Advances in medical research such as Professor Powderly’s, ultimately mean fewer side effects, fewer pills and more effective long term treatment.

Professor Powderly is Principal Investigator for the Dublin HIV Cohort, a project funded by the Health Research Board to study the natural history and complications of HIV in a diverse population of patients infected with the virus.  This study currently includes over 1,000 patients from major Dublin hospitals. His research areas are infections in immuno-compromised hosts especially HIV infection; clinical trials of new antiretroviral agents and of therapies of opportunistic infection; complications of antiretroviral therapy

Led by Prof William Powderly, our clinical researchers participate in the Dublin HIV Cohort study, a multicentre collaboration with St James' and Beaumont Hospitals. The study aims to provide valuable information on the natural history of HIV and on the emergence of new problems in treated and untreated populations.

The data from this cohort may provide insights into issues such as viral evolution and development of resistance in differing populations, development of adverse events in different patient populations of different ethnic and genetic backgrounds and pharmacogenetics of adverse events with an increased understanding of genetic control of drug metabolism.

Research involving Professor Powderly has led to a breakthrough in identifying the most effective initial treatment for HIV. The study, which was documented in the New England Journal of Medicine, confirmed that one of the most frequently prescribed triple-drug combinations for initial HIV-1 infection is the most effective at suppressing HIV. The study also found that a two-drug regimen performed comparably for patients susceptible to severe side effects from nucleoside reverse transcriptase inhibitors (NRTIs) that form part of the three-drug regimen. This is leading to a better evaluation of the treatments currently on the market and a better understanding of their effectiveness and side effectives.

Innate immune cells are the first line of defense in the fight against invading pathogens. Prof Ulla Knaus' group focuses on understanding molecular mechanisms that innate and mucosal immune host defense use to protect the host from microbial insult, and how some responses wind up damaging the host. For example, second messengers such as reactive oxygen species (ROS) or nitric oxide that are produced during infection can have beneficial as well as detrimental effects. The overall outcome depends on precise spatial and temporal regulation of these second messengers by the affected cell populations. The intracellular signaling pathways that regulate the production of these molecules constitute an ideal target for intervention in disease.

Almost all of the processes connected to pathogen up-take, pathogen elimination, or sustained inflammation are governed by small GTPases of the Rho family. Research in our laboratory centers on Rac, Cdc42, and RhoA, which control various leukocyte functions ranging from ROS production to chemotaxis and phagocytosis. Superoxide generation is accomplished by the Rac-dependent NADPH oxidase Nox2 upon stimulation with chemotactic factors or phagocytic stimuli. GTPases of the Rho family are also involved in signaling cascades, which originate from PAMP-activated Toll-like receptors (TLR) and lead to gene transcription. Prof Knaus' laboratory studies different aspects of TLR signaling in innate immune cells as well as in genetically altered mouse models to discern the impact of GTPases and their targets on innate immune cell functions such as up-regulation of pro-inflammatory cytokines, chemokines, and type I interferon.

A related area of research is the interaction and communication between innate immune cells and the pulmonary epithelium. Prof Knaus' team use an ex vivo differentiated model of human lung epithelium to investigate signaling mechanisms initiated by pathogens. This mucociliary airway epithelial model is also used to study the influence of bacterial-derived ligands and toxins on lung barrier function, and how ROS generation may alter these processes.  ROS-generating NADPH oxidases are expressed in pulmonary epithelium and in lung fibroblasts, and current work investigates the molecular basis for ROS generation by these enzymes. Nox/Duox proteins may serve as compartmentalized signaling modules, thereby activating or inhibiting signaling cascades, as host defense mechanism, or as pro-inflammatory stimulus. Due to their tissue-specific distribution and distinct localization patterns Nox proteins may exert highly specialized functions and undergo isoform-dependent regulation. Elucidating physiological stimuli and control mechanisms for these Nox/Duox enzymes combined with structure-function studies will help defining the biological functions of oxidases in health and disease, and constitutes a prerequisite for drug development and therapeutic intervention in oxidant-induced stress and tissue injury.

Prof Billy Bourke's main research interest is in infectious diarrhoeal diseases of childhood focusing in particular on Campylobacter jejuni, a major human intestinal pathogen and the most common cause of bacterial gastroenteritis.

Together with collaborators Dr Marguerite Clyne, Dr Tadhg O'Croinin and Prof Ulla Knaus, UCD and National Children's Research Centre have developed an internationally competitive infection biology research programme with ties to leading national and international scientists in the area of Campylobacter pathogenesis. Their research has formed the basis for an SFI funded multi-disciplinary, multi-institutional research collaboration aimed at understanding the glycobiology of human intestinal infections (Alimentary Glycosciences Research Cluster).