Heinrich Gottlinger
University of Massachusetts Chan Medical School, MA·Microbiology & Immunology
HIV-1 gets into a new cell using a spike protein on its surface, and anything that damages that spike blunts the virus. This project follows an unexpected finding: HIV-1 particles scoop up large amounts of a host enzyme that then attacks the virus's own spike from the inside out.
- Fields
Microbiology & Immunology
Biochemistry
Biology
- Topics
ectodomain shedding
gp41
membrane-proximal external region
- Grants
- 1 known grant, through Dec 2028
What they work on
- Determine how ADAM10, a membrane-anchored protease incorporated into HIV-1 particles, affects virus infectivity and cell-to-cell transmission, including whether other cellular ADAM10 substrates contribute to the block.
- Test whether protecting the viral transmembrane protein gp41 from ADAM10 cleavage is a core function of the HIV-1 Nef protein, and whether this depends on Nef engaging the clathrin adaptor AP-2.
- Test the hypothesis that a point mutation in the membrane-proximal external region of gp41, which rescued Nef-deficient HIV-1 in the presence of ADAM10, blocks cleavage by altering the N-capping propensity of the mutated residue.
- Determine which TSPANC8 tetraspanins — membrane proteins that complex with ADAM10 and set its substrate preference — direct gp41 cleavage, and whether Nef acts by shifting the repertoire of TSPANC8/ADAM10 complexes.
- Examine whether Nef suppresses gp41 cleavage by reducing exposure of phosphatidylserine, a lipid that activates ADAM10 and is externalized by the Nef targets SERINC3 and SERINC5, which act as lipid scramblases.
More about the research
The enzyme is ADAM10, a protease tethered in the cell membrane that normally snips other membrane proteins just outside the membrane, releasing their outer portions — a process called ectodomain shedding. The lab finds that HIV-1 virions selectively package considerable amounts of the active form of ADAM10, and that ADAM10 cuts the viral transmembrane protein gp41 in a short stretch called the membrane-proximal external region. The cut leaves a stub behind in the membrane and sheds the rest of the spike off the particle.
Why it matters
This work describes a previously unrecognized way HIV-1 can be neutralized: the virus carries along a host protease that destroys its own entry machinery. Identifying the specific tetraspanin–ADAM10 complexes responsible for cutting gp41 could open the prospect of inactivating HIV-1 with agonists that selectively switch those complexes on, a vulnerability distinct from existing antiretroviral targets.
Known grants
From NIH and NSF research grants. Labs often have other funding we can't see.
Closest labs
Yong-Hui Zheng
University of Illinois Chicago, IL·Microbiology & Immunology
Characterize how MARCH8, a membrane-anchored ubiquitin ligase, blocks maturation of the HIV-1 envelope protein gp160 during infection of primary human cells and human T cell lines, using RNA silencing and CRISPR/Cas9 knockout.
Michael McVoy
Virginia Commonwealth University, VA·Microbiology & Immunology
Determine how RL13, an envelope glycoprotein that restrains cytomegalovirus growth, blocks replication by testing whether it interacts with glycoprotein M to impair assembly or release of infectious virions, using genetic and molecular approaches.
Thomas Gallagher
Loyola University Chicago, IL·Microbiology & Immunology
Determine how mutations in the S2 fusion segment of the SARS-CoV-2 spike control the receptor-binding domain and its engagement with receptors, identifying specific variant substitutions that alter receptor reactivity and spike stability.
The school
University of Massachusetts Chan Medical School: 29 labs on PI Pages, $350M a year on research, 55 research doctorates a year.
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