# HIV immune evasion and escape through T cell virological synapses

> **NIH NIH R56** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2020 · $538,488

## Abstract

HIV-1 establishes a chronic infection that the immune system cannot spontaneously clear. The virus has
a remarkable capacity to evade immune responses and generates a high sequence diversity that defies the
forces of purifying selection. We and others have found that viral dissemination takes place both in vitro and in
vivo through cell-cell contacts, called virological synapses (VS), which mask immune detection of infected
cells, and promote viral quasispecies diversity that enable escape. Our data indicate that HIV Env, the central
viral protein involved in VS formation and viral entry, assumes distinct conformations on viruses versus on the
cell surface. We propose that these conformations can render infected cells as “hypoantigenic” relative to cell-free
virus and further suggest that allosteric sensing mechanisms allow Env to detect whether it is cell-associated
or virion-associated. The studies address the key problem of how Env is recognized differently on
the surface of infected cells and how cell-cell transmission affects viral escape. During VS formation Env
works as a cell adhesion receptor between the infected and uninfected cell, prior to its role as viral membrane
fusion protein. Through the VS HIV exploits cell biology -- polarized receptor recruitment and viral endocytosis
into the target cell -- to enhance cell-to-cell transmission. The T cell VS is critical for viral spread in cell culture
and functions in vivo in lymphoid tissues of humanized mice. VS transmission facilitates potent immune
evasion. Most broadly neutralizing antibodies (bNabs) are less potent at neutralizing cell-to-cell infection than
the same virus in a cell free form. When tested against transmitted founder clones, bNabs incompletely inhibit
cell-to-cell infection at maximum concentration, i.e. display reduced efficacy. We propose to define the cellular
mechanisms underlying the reduced potency and efficacy of neutralizing antibodies against the VS. We will
also test a model for how the multicopy transmission of HIV through VS contributes to maintaining a diverse
swarm of mutated sequences, or quasispecies, that can allow HIV to easily escape immune pressures. We
hypothesize that cell-to-cell HIV-1 transmission is a pivotal immune evasion and escape strategy that drives
viral persistence.

## Key facts

- **NIH application ID:** 10225070
- **Project number:** 9R56AI148064-10A1
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** BENJAMIN K CHEN
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $538,488
- **Award type:** 9
- **Project period:** 2020-09-14 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10225070

## Citation

> US National Institutes of Health, RePORTER application 10225070, HIV immune evasion and escape through T cell virological synapses (9R56AI148064-10A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10225070. Licensed CC0.

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