Wei Li
University of Pittsburgh, PA·Microbiology & Immunology
Antiretroviral therapy keeps HIV in check but does not cure it, because the virus hides in long-lived reservoirs of infected cells. Broadly neutralizing antibodies can help the immune system control the virus after treatment stops, but each antibody covers only part of the diversity of circulating HIV, and the virus mutates to escape, so several antibodies must be combined.
- Fields
Microbiology & Immunology
Biochemistry
Pharmacology
- Topics
soluble CD4
sCD4-D1
CD4-induced epitopes
- Grants
- 1 known grant, through Jul 2031
What they work on
- Engineer soluble CD4 D1-domain variants with improved binding kinetics and isolate single-domain VH binders against CD4-induced epitopes on HIV envelope, combining computational structure design, phage display and time-resolved cryo-electron microscopy.
- Build multivalent and bifunctional sCD4-D1–CD4i fusion molecules using structure-guided and generative AI design, increasing avidity and breadth, with structures validated by cryo-EM.
- Engineer IgG1 Fc domains into lead constructs and test whether they drive Fc-mediated effector functions that eliminate HIV-infected cells in vitro and ex vivo.
- Evaluate lead sCD4-D1–CD4i bispecifics for antiviral activity and reservoir clearance in humanized mice with functional human NK and T cells, during acute infection and under antiretroviral suppression.
- Test whether the engineered constructs avoid the enhancement of infection of CD4-negative, CCR5-positive cells and the rapid clearance that limited earlier soluble CD4 biologics.
More about the research
This project pursues a different strategy that exploits something HIV cannot change: to enter a cell, the virus must grab CD4, a protein on the surface of human immune cells. A soluble version of CD4 (sCD4) acts as a decoy, binding the virus broadly and leaving it little room to develop resistance. As a bonus, when sCD4 latches onto the viral envelope protein (Env), it forces the protein open and exposes hidden surfaces called CD4-induced (CD4i) epitopes, which other binders can then attack, and the construct can recruit immune cells to kill infected cells through its antibody tail (Fc) region.
Why it matters
Current HIV drugs suppress the virus but leave infected cells in place, so treatment is lifelong. A molecule that blocks entry broadly and also flags infected cells for destruction by the immune system could move the field toward durable remission without continuous antiretroviral therapy. Because the approach targets HIV's unavoidable dependence on CD4, it may also be harder for the virus to escape than antibody-based regimens.
Known grants
From NIH and NSF research grants. Labs often have other funding we can't see.
Closest labs
Matthew Gardner
Emory University, GA·Microbiology & Immunology
Test whether co-delivering an AAV vector encoding rhesus macaque PD-L1, a protein that engages the T-cell brake receptor PD-1, sustains blood levels of the HIV broadly neutralizing antibody 10-1074 high enough to protect macaques from repeated low-dose SHIV challenge.
Ashley Nelson
Weill Medical College of Cornell University, NY·Microbiology & Immunology
Compare giving germline-targeting HIV envelope immunogens one after another versus all at once for waking up precursor B cells of two broadly neutralizing antibody classes: those binding the CD4 binding site and those binding the V2 apex of the viral spike.
David Veesler
University of Washington, WA·Microbiology & Immunology
Characterize how broadly serum antibodies from nonhuman primates immunized with nanoparticle vaccines co-displaying multiple receptor-binding-domain and spike antigens bind and neutralize betacoronaviruses.
The school
University of Pittsburgh: 83 labs on PI Pages, $1.5B a year on research, 403 research doctorates a year.
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