# Leveraging CTLs targeting highly networked epitopes to suppress the latent HIV-1 reservoir

> **NIH NIH K08** · MASSACHUSETTS GENERAL HOSPITAL · 2020 · $199,800

## Abstract

Project Summary/Abstract
This proposal presents a five year research career development program focused on the study of CTL
responses to highly “networked” epitopes as a new set of invariant targets to include in a therapeutic CTL-
based vaccine for HIV-1. The candidate is currently an Instructor of Medicine at Harvard Medical School and
the Division of Gastroenterology at Massachusetts General Hospital. The outlined proposal builds on the
candidate's previous research experience in HIV-1 immunology and biochemistry where he defined CTL
epitopes that carry structural and functional constraints, and which are preferentially targeted by individuals
who naturally control HIV-1. He is now positioned, under the guidance of his mentor Dr. Bruce Walker at the
Ragon Institute of MGH, MIT and Harvard, to determine whether these epitopes could be valuable CTL targets
in treatment-suppressed individuals. The proposed experiments and didactic work will position the candidate
with a unique set of skills that will enable him transition to independence as a physician-scientist in the field of
prophylactic and therapeutic HIV-1 vaccinology.
The HIV/AIDS epidemic continues to have enormous medical, societal and economic implications worldwide.
While combination anti-retroviral therapy (cART) has helped to greatly reduce the global burden of HIV, the
ability of the virus to establish a persistent latent reservoir requires lifelong treatment for HIV-infected
individuals. As a result, new modalities that can suppress or eliminate the viral reservoir and thereby limit HIV
treatment duration are greatly needed. Recent efforts have been focused on the induction of cytotoxic T cells
as potential targets for therapeutic vaccines. However, the accumulation of CTL escape mutations in
chronically infected cART-suppressed patients limits the ability to successfully prevent viral rebound following
cART cessation. During his postdoctoral fellowship, the candidate developed a new approach known as
structure-based network analysis that identifies specific epitopes, presented by a broad array of HLA alleles,
which are intolerant to mutations. He also demonstrated that the targeting of highly “networked” CTL epitopes
is able to distinguish individuals who spontaneously control HIV-1 from those with progressive disease. The
candidate now hypothesizes that CTL mediated immune responses directed against highly “networked”
epitopes can also suppress viral outgrowth following cART cessation in chronically infected cART-treated
individuals. This hypothesis will be tested through the following aims: 1) Perform deep mutational scanning of
highly networked epitopes in proviral DNA, 2) Assess whether CTLs targeting highly networked epitopes can
suppress viral outgrowth from cART-treated patients and 3) Develop an adenovirus (Ad) vector encoding
multiple highly networked epitopes and assess its ability to induce CTL responses in vivo. Effective CTL-
mediated responses to highly networked epi...

## Key facts

- **NIH application ID:** 9906843
- **Project number:** 5K08AI140960-02
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Gaurav Das Gaiha
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $199,800
- **Award type:** 5
- **Project period:** 2019-04-05 → 2020-09-01

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9906843

## Citation

> US National Institutes of Health, RePORTER application 9906843, Leveraging CTLs targeting highly networked epitopes to suppress the latent HIV-1 reservoir (5K08AI140960-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9906843. Licensed CC0.

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