HIV targeting of IPS-1/mavs to block type i interferon

The National Institute of Allergy and Infectious Diseases awarded Western University of Health Sciences $144,000 on June 19, 2026, under the Allergy and Infectious Diseases Research program (CFDA 93.855) to investigate how HIV accessory proteins VPU and NEF target the IPS-1 adaptor protein, leading to its degradation and inhibition of type I interferon production. The research examines the mechanism by which HIV manipulates the interferon system to evade immune detection and persist in the host, with specific focus on confirming that this targeting mechanism is consistent across HIV infection of multiple cell types. The project runs through May 31, 2028, with performance at Western University's location in Pomona, California. This R03 Project Grant supports exploratory research aimed at advancing understanding of HIV pathogenesis and immune evasion strategies.

Abstract

Over the course of infection by HIV, a dynamic interplay occurs between the HIV and the human immune system. HIV is an immune cell-tropic virus, infecting both CD4+ t helper cells as well as macrophages which also express CD4 in humans. Infection of these two different, key immune cells sets up a scenario that allows modulation of the immune system coupled with the pathology of the viral infection. In fact, successful replication and pathogenesis of any virus within a human host is dependent on how well the virus is able to manipulate the many defenses of the immune system and in this case, the cells HIV infects. One of the main targets of this manipulation of human immunity by viral infections is the type i interferon system. Our group has focused on modulation of the type i interferons by the accessory proteins of HIV that are used by HIV to promote viral replication within a human. We showed that both NEF and VPU are able to target both the production of and signaling by type i interferon pathways within t cells allowing improved replication of HIV. In this proposal we will investigate how HIV manipulates the interferon (IFN) system to evade immune detection and persist in the host. This R03's specific aim is to determine the mechanism by which HIV accessory proteins VPU and NEF target IPS-1, a key adaptor protein for IFN induction, leading to its degradation and inhibiting IFN production and to confirm that this mechanism is consistent in HIV infection of multiple cell types.