Howard E Gendelman
University of Nebraska Medical Center, NE·Microbiology & Immunology
HIV can be controlled with daily pills, but it is never fully removed from the body: the virus hides as DNA inserted into the genomes of long-lived immune cells in lymph nodes, gut, spleen and brain. Work in this lab spans three connected goals built around that problem.
- Fields
Microbiology & Immunology
Pharmacology
Neuroscience
- Topics
antiretroviral therapy
long-acting injectable
LASER ART
- Grants
- 3 known grants, through Feb 2030
What they work on
- Scale up and characterize long-acting injectable nanoformulated prodrugs of dolutegravir, emtricitabine and tenofovir (NM2DTG, NPFTC, NPTFV) under cGMP manufacturing, testing toxicology and pharmacokinetics in rhesus macaques for HIV prevention dosing up to once yearly.
- Determine whether esterified and ProTide-modified antiretroviral prodrug formulations sustain plasma and tissue drug levels above 90% inhibitory concentrations for months, while reducing injection volume through slower prodrug hydrolysis.
- Optimize lipid nanoparticle composition carrying CRISPR-Cas9 and multi-exon guide RNAs for lymphoid tissue delivery, decorating particles with CXCR4 and CCR5 ligands to reach latently infected CD4+ T cells and myeloid cells.
- Map where CRISPR-loaded nanoparticles travel in infected animals using radiomagnetic labeling with positron emission tomography and MRI, and test microbubble-enhanced focused ultrasound to move editing cargo into the brain.
- Test whether maximal viral suppression with ultra-long-acting antiretrovirals followed by targeted CRISPR nanoparticle delivery eliminates integrated HIV-1 proviral DNA from lymph nodes, gut, spleen and brain in infected humanized mice.
- Characterize the lab's new humanized mouse model at cell, immune and tissue levels to define how HIV-1 compartmentalization and macrophage-microglia inflammation alter amyloid pathology in the setting of Alzheimer's disease.
- Assess how antiretroviral therapy and other immune-modulating agents shift effector CD4+ T cell responses, and test whether regulatory T cells engineered with an amyloid beta-specific transgenic T-cell receptor or chimeric antigen receptor reduce plaque burden and protect neurons.
More about the research
First, reformulate existing HIV drugs so that a single injection lasts months to a year, which could prevent infection in people who struggle to take a daily pill. Second, combine such long-lasting drugs with gene-editing packages that travel to the tissues where the virus hides, with the aim of cutting the viral DNA out of infected cells. Third, understand how chronic HIV infection and the immune response to it interact with aging brain disease, using a mouse model the lab created that carries both human immune cells and Alzheimer's-like pathology.
Why it matters
Long-acting injectable antiretrovirals could make HIV prevention workable for people who cannot take a daily pill, lowering transmission risk. Targeted gene-editing nanoparticles may offer a route toward removing hidden virus rather than only suppressing it, which would change what a cure attempt looks like. And a mouse carrying both HIV infection and Alzheimer's pathology gives a testbed for treating aging people living with HIV, a group facing both viral persistence and dementia risk.
Known grants
From NIH and NSF research grants. Labs often have other funding we can't see.
Closest labs
Angela Raquel Wahl
University of Alabama at Birmingham, AL·Microbiology & Immunology
Analyze how the HIV reservoir forms in the gastrointestinal tract of BLT humanized mice on antiretroviral therapy, measuring HIV DNA and transcripts in gut CD4+ T cells compared with blood.
Wenhui Hu
Virginia Commonwealth University, VA·Microbiology & Immunology
Show that brain-penetrating AAV can deliver cargo to astrocytes and neurons that then relay it to untouched microglia, using PEG10- and syncytin-A-based endogenous retrovirus-like particles carrying Cre messenger RNA in LoxP-STOP-LoxP tdTomato reporter mice that turn red when edited.
James Whitney
Boston College, MA·Microbiology & Immunology
Determine how early the persistent viral reservoir is established after SIV infection and how initiating antiretroviral therapy early limits seeding and expansion of cellular reservoirs.
The school
University of Nebraska Medical Center: 20 labs on PI Pages, $657M a year on research, 82 research doctorates a year.
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