UC San Diego

ABSTRACT OF THE THESIS

Trehalose, an mTOR-independent Inducer of Autophagy, Inhibits HIV Infection in Primary Human Macrophages

by

Simson Hon

Master of Science in Biology

University of California, San Diego, 2017

Professor Stephen Spector, Chair

Professor Li-Fan Lu, Co-Chair

While tremendous progress has been made in terms of prevention, detection, and treatment of human immunodeficiency virus type-1 (HIV), the agent that causes acquired immunodeficiency syndrome (AIDS), concerns remain as strains of HIV that are resistant to antiretroviral therapy (ART) have begun to emerge. In the face of this new threat, other methods must be considered in combination with medical treatment. Autophagy, a highly conserved pathway that enable cells to recycle cytoplasmic content to promote survival during periods of stress, has been receiving renewed attention for its role in neurodegenerative diseases and immune response to pathogen challenge. In fact, chemically induced autophagy has been shown to inhibit HIV replication in human primary macrophages. However, autophagy has been classically studied as a pathway regulated by the mammalian target of rapamycin complex 1 (mTORC1), which recently, has been shown to have other modulatory effects beyond autophagy.

As such, we determined if trehalose, small-molecule enhancer of rapamycin 28 (SMER28), and spermidine, which are compounds that have been shown to induce autophagy in an mTOR-independent fashion, are able to inhibit HIV replication in human primary macrophages. Here, I show that all three mTOR-independent inducers of autophagy have an inhibitory effect on HIV replication. Furthermore, I demonstrate that trehalose can induce autophagic flux in human primary macrophages. Yet, perhaps the most striking result was that trehalose downregulates CD4 and chemokine CC receptor 5 (CCR5) expression, both of which are key receptors for HIV entry. In support of this, I observed decreased HIV entry into human primary macrophages following trehalose treatment. Taken together, these results support further investigation into the beneficial effects that trehalose may have as part of standard HIV treatment.