# AAV-delivered HIV inhibitors for SHIV therapy

> **NIH NIH R01** · EMORY UNIVERSITY · 2024 · $808,489

## Abstract

PROJECT SUMMARY
More 10% of the new infections in the United States were from contaminated needle sharing among
people who inject drugs (PWID). Importantly, only about 50% of men and 57% of women of the PWID
group had suppressed viremia. Despite the lack of a sterilizing HIV-1 cure, antiretroviral drug therapies
(ART) effectively suppress viral replication in people living with HIV-1. One limitation of ART is that
these small molecule drugs cannot eliminate the viral reservoir. Broadly neutralizing antibodies
(bNAbs) could supplement ART and be used to reduce the viral reservoir. Several studies have shown
that a single dose of a bNAb can decrease viremia in HIV-1 infected individuals, with viral rebound
occurring as the bNAb concentration decreases. Adeno-associated virus (AAV) vectors may provide
the means for long-term expression of bNAbs at concentrations capable of maintaining viral
suppression via intramuscular inoculations. However, we and others have shown that the emergence of
anti-drug antibodies (ADA) to bNAbs limits their overall expression. Here, we show that we have made
significant strides overcome this host immune response. First is through utilizing immune checkpoints
that regulate immune system pathways. We observed a 21-fold increase in concentrations of the HIV-1
bNAb 10-1074 in rhesus macaques when macaques were co-inoculated with an AAV vector encoding
rhesus macaque PD-L1. Second, we have developed a novel, HIV-1 entry inhibitor, eCD4-Ig, which
tends to be more tolerated in rhesus macaques when expressed from AAV vectors. Unlike bNAbs, we
have shown that AAV vectors encoding eCD4-Ig can express the inhibitor in macaques for over a year
and the ADA response against eCD4-Ig decreases over time. Because eCD4-Ig neutralizes all HIV-1,
HIV-2, and SIV isolates and is difficult to escape, it may be useful when included in a therapy strategy.
Our pilot studies show that low concentrations AAV-expressed eCD4-Ig can suppress SHIV infection in
rhesus macaques for two years, yet viremia is still detectable. This proposal combines our AAV
advancements into a single strategy to determine whether AAV-expressed inhibitors can suppress a
SHIV infection and reduce the viral reservoir. In Aim 1, we will assess the therapeutic efficacy of the
combination of AAV-delivered eCD4-Ig and 10-1074 after ART is lifted in SHIV-infected rhesus
macaques. In Aim 2, we will determine whether suppressing an established SHIV infection with AAV-
delivered eCD4-Ig and 10-1074 results in a quantitatively different viral reservoir compared to ART. In
Aim 3, we will improve the safety of AAV gene therapy by developing an irreversible “kill-switch” to turn
off transgene expression.

## Key facts

- **NIH application ID:** 10854876
- **Project number:** 5R01DA056770-03
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Matthew Ryan Gardner
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $808,489
- **Award type:** 5
- **Project period:** 2022-08-15 → 2027-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10854876

## Citation

> US National Institutes of Health, RePORTER application 10854876, AAV-delivered HIV inhibitors for SHIV therapy (5R01DA056770-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10854876. Licensed CC0.

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