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Gregory Melikian, PhD

Gregory Melikian, PhD headshot

Professor
Division of Infectious Disease
Department of Pediatrics
Emory University School of Medicine

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PHONE: 404-727-4652
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2015 Uppergate Drive
Room 546
Atlanta, GA, 30322

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Biography

Our laboratory studies the molecular mechanisms of enveloped virus entry into cells. When activated by binding to cellular receptors and/or by acidic pH in endosomes, viral fusion proteins undergo extensive conformational changes resulting in membrane merger. Current projects in the lab involve function studies of fusion proteins of influenza A virus, Human Immunodeficiency Virus (HIV) and other retroviruses, such as Avian Sarcoma and Leukosis Virus (ASLV). By imaging individual virions co-labeled with fluorescent membrane and content markers, we visualize the lipid mixing (hemifusion) and the fusion pore formation steps in live cells. Moreover, we developed methodologies to simultaneously visualize the pH changes around single internalized viruses and their subsequent fusion with acidic endosomes.


We found that HIV, which has long been thought to infect host cells by direct fusion with the plasma membrane, enters permissive cells via endocytosis and pH-independent fusion with endosomes. These findings provide a new paradigm for HIV entry and suggest alternative strategies to block infection. We have also delineated the entry and trafficking pathways of ASLV pseudoviruses. The two-step mechanism of ASLV entry which involves priming by cognate receptor and triggering with acidic pH, as well as the virus’ ability to utilize two naturally occurring isoforms of the cognate receptor, enable dissection of the virus entry pathways. Our work on the mechanism of the hepatitis C virus (HCV) fusion utilized soluble receptor fragments and low pH to trap transient states of the HCV E1E2 glycoproteins en route to fusion with acidic endosomes. We have shown that one of the four essential receptors, CD81, renders HCV competent for low pH-mediated fusion with endosomes. Finally, we have reconstituted single Vesicular stomatitis virus (VSV) fusion in a supported lipid bilayer system and investigated the lipid-dependence of this process.


Another small project in the lab involves studies of the mechanism of anti-viral activity of human alpha-defensins, small cationic peptides capable of blocking entry of HIV and other viruses. We continue to apply quantitative imaging and spectroscopy methods to better understand virus trafficking and fusion, as well as to delineate the role of receptor signaling in infection.


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Research

Our laboratory studies the molecular mechanisms of enveloped virus entry into cells. When activated by binding to cellular receptors and/or by acidic pH in endosomes, viral fusion proteins undergo extensive conformational changes resulting in membrane merger. Current projects involve function studies of fusion proteins of influenza virus, Human Immunodeficiency Virus (HIV) and other retroviruses, as well as Hepatitis C Virus (HCV). By imaging individual virions co-labeled with fluorescent membrane and content markers, we visualize the lipid mixing (hemifusion) and the fusion pore formation steps in live cells.

We have recently showed that HIV, which has long been thought to infect host cells by direct fusion with the plasma membrane, enters permissive cells via endocytosis and pH-independent fusion with endosomes. These findings provide a new paradigm for HIV entry and suggest alternative strategies to block infection. We also study the entry mechanisms of low pH-dependent viruses, influenza and Avian Sarcoma and Leukosis Virus (ASLV). ASLV Env glycoprotein is first primed by interactions with a cognate receptor at the cell surface, which renders Env competent for low pH-induced conformational changes and fusion with acidic endosomes. Sequential priming and triggering of ASLV fusion and the virus’ ability to utilize two naturally occurring isoforms of the cognate receptor is essential for dissecting the virus entry pathways. Our work on the mechanism of HCV fusion involves the usage of soluble receptor fragments and low pH to trap transient states of the HCV E1E2 glycoproteins en route to fusion with acidic endosomes. We have shown that one of the four essential receptors, CD81, renders HCV competent for low pH-mediated fusion within endosomes. Another project in the laboratory is aimed at understanding the anti-viral activity of human defensins, highly charged cationic peptides capable of blocking entry of HIV and other viruses.

We are currently applying quantitative imaging and spectroscopy methods to better understand virus trafficking and fusion, as well as to delineate the role of receptor signaling in infection. We are also interested in reconstituting viral fusion in a supported lipid bilayer system and carrying out mechanistic studies of this process on a single-molecule level.

 

Link to my lab page.

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