HIV immune evasion and escape through T cell virological synapses

Icahn School Of Medicine At Mount Sinai, New York NY

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Abstract

Summary Understanding the conformational states of the HIV Envelope (Env) protein that bNAbs target is critical because these are most effective at blocking infection. Env is Translated as a 160 kD precursor, cleaved, and glycosylated in the Golgi before being trafficked to the cell surface, where it is incorporated into virus particles and participates in cell-cell infection. During its production Env is cleaved by furin-like proteases from an initial metastable gp160 precursor trimer, into a mature, cleaved gp120-41 protein. Cleavage is inefficient; thus, both cleaved and uncleaved Env can be found on the cell surface. Fully cleaved Env, which assumes a stable conformation (called State 1), is selectively incorporated onto viral particles. In addition, bNAbs primarily target state 1 Env. Studies have not been able to isolate mixed Env, which have both cleaved and uncleaved protomers. These Env are asymmetric in conformational state and we study them here. We speculate that incompletely processed Env trimers are sent to the endocytic recycling compartment and back to the Golgi for further processing and that only fully processed forms of Env are routed to the nascent virus particle. Understanding the mechanisms that enable recognition of only processed Env for incorporation into the virus particle can help us understand how cell-to-cell infection resists neutralizing antibodies. In this project, we will characterize the mechanism for sorting cleaved Env onto viral particles, by generating asymmetric and homogenous Env trimers and study the conformational changes and trafficking of Env engaged in cell-free and cell-to-cell infection. We hypothesize that the partial cleavage of Env results in asymmetry of Env trimers, providing a signal recognized by host machinery that “marks” Env as not “ready” to be packaged onto virus particles; thus, forcing Env to undergo further processing through endocytic recycling. Establishing cleavage state as a selection marker will help us understand the difference between viral and cell surface Env; therefore, enabling the development of bNAbs that can recognize these differences.