John Tilton
Case Western Reserve University, OH·Microbiology & Immunology
HIV treatment depends on drugs that keep working, and resistance is how they stop working. One major drug class, protease inhibitors, blocks the viral enzyme protease, which cuts long viral proteins into the finished pieces a new virus needs.
- Fields
Microbiology & Immunology
Biochemistry
Medicine & Clinical Research
- Topics
protease
antiretroviral therapy
drug resistance
- Grants
- 1 known grant, through Dec 2029
What they work on
- Assess how mutations within HIV-1 protease or at its p6*-protease cleavage site influence dimerization, the pairing of two subunits into a functional enzyme, and the activity of both the precursor and mature protease.
- Determine whether protease inhibitor resistance that arises without the canonical resistance mutations in protease instead alters enzyme dimerization or precursor versus mature protease function.
- Perform in vitro viral propagation experiments, growing HIV-1 under drug pressure in culture, to test how the precursor protease contributes to the emergence of protease inhibitor resistance.
- Use techniques that lock protease in its precursor configuration to test whether viruses can mature, fuse with target cells and replicate without forming mature protease, the path proposed for resistance evolution.
More about the research
The enzyme is first made as a precursor, still attached to a neighboring viral protein, before it frees itself to become the mature form. The precursor is far less sensitive to protease inhibitors than the mature enzyme. That difference raises a specific possibility: the virus may survive drug pressure through the relatively drug-resistant precursor, giving resistance mutations room to accumulate.
Why it matters
Protease inhibitors are a mainstay of HIV therapy, and resistance limits how long regimens keep working. If resistance really does evolve through the activity of the drug-insensitive precursor protease, that would change how this drug class is understood and could inform strategies to design inhibitors or regimens that make resistance less likely for people living with HIV.
Known grants
From NIH and NSF research grants. Labs often have other funding we can't see.
Closest labs
Gokul Raghunath
Emory University, GA·Biophysics
Test how specific amino acids in synthetic spacer peptide 2 (SP2), a short conserved HIV-1 peptide, control its binding to the viral matrix protein and its remodeling of lipid membranes, using fluorescence imaging and biophysical assays on liposomes.
Patrick Jackson
University of Virginia, VA·Microbiology & Immunology
Test whether variation in Rev-RRE activity is selected during HIV sexual transmission, by measuring activity in viral quasispecies from longitudinal samples spanning acute to chronic infection in people who acquired HIV through different transmission routes.
Hillel Haim
University of Iowa, IA·Microbiology & Immunology
Build a deep mutational scanning system using replication-defective HIV-1 to measure, safely and at high throughput, how every amino acid substitution at each site of the capsid protein affects viral fitness and resistance to the capsid inhibitor lenacapavir.
The school
Case Western Reserve University: 34 labs on PI Pages, $643M a year on research, 213 research doctorates a year.
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