Graham Simmons, PhD
Download a scientific summary [pdf file]
Download a curriculum vitae [pdf file]
Download a BSRI press release_NAbs inhibit CHIKV entry and release [pdf file]
Link to The 5th Annual Bay Area Symposium on Viruses - Graham Simmons (BSRI)
Link to my UCSF my profiles page
Training / Appointments:
Over the preceding 30 years many new infectious agents have entered the sphere of human diseases, while others have reemerged, or have geographically shifted into previously unaffected areas. Many of these agents pose a threat to the nation’s blood supply, particularly during the initial transition into the population, before routine testing becomes available. In partnership with blood banking and diagnostic colleagues, we are using serological and molecular techniques to study the prevalence and threat that emerging infectious diseases pose to distinct populations. Particular focus has been on enveloped RNA viruses, including Ebola and related filoviruses, and the newly described potential hemorrhagic fever agent, Bas-Congo virus. In order to conduct such studies of pathogenic viruses, as well as newly identified viruses of unknown etiology, we first develop novel reagents and high-throughput screening assays for rapid surveillance.
An example of the threat emerging and reemerging viruses can pose is the current chikungunya virus (CHIKV) outbreak sweeping through the Caribbean and the Americas. CHIKV, an alphavirus spread by mosquito vectors, causes acute infections often followed by chronic complications, including long-term joint pain. Continued instances of local CHIKV transmission within the US now appear likely, given the presence of competent mosquito vectors through large areas of the US. To directly assess the threat that CHIKV poses to the blood supply, we conducted viral nucleic acid and serological surveys of blood donors in Puerto Rico. A sizable proportion of blood donors with detectable CHIKV RNA were detected during the 2014 epidemic in Puerto Rico, demonstrating the rapidity and explosiveness of such epidemics. Indeed, serosurveys flanking the peak epidemic months demonstrated in one short season in 2014, 25% of blood donors in Puerto Rico acquired CHIKV. A number of the CHIKV positive donations had high viral loads and were IgM and IgG negative, suggesting they were in the peak phase of acute infection - highlighting the risk of blood transfusion transmission.
Current treatments or vaccines for many emerging/reemerging viruses are lacking. Therefore, we are building and performing screening assays targeting two critical aspects of viral lifecycles – entry and egress. We are currently focused on the identification of candidate inhibitors for a number of viruses, including CHIKV, SARS-CoV and Ebola, and have screened small molecule inhibitor libraries, leading to the identification of inhibitors of late stages of viral entry for SARS-CoV. These inhibitors have been shown to be active in mouse models.
We have also identified a number of highly potent human monoclonal antibodies (mAbs) directed against CHIKV. The most potent of these mAbs demonstrated previously undescribed mechanisms of action – including cross-linking individual subunits within envelope spikes and the inhibition of viral release – likely by preventing membrane curvature formation. Identification of potent neutralizing mAbs targeting different stages of the viral lifecycle will provide prophylactic and therapeutic treatment options for CHIKV infection and disease – with a focus on vulnerable populations during epidemics.