# Mechanisms of CMV Replication on HIV Persistence

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2021 · $801,604

## Abstract

Abstract
HIV cure efforts will likely continue to be futile if we ignore the inflammatory mechanisms sustaining the
persistence of HIV.
Scientific Premise: A common driver of inflammation for persons with HIV (PWH) is Cytomegalovirus (CMV),
which almost universally co-infects PWH. During this coinfection, subclinical CMV replication is frequent and
profoundly impacts the immune system, including several CMV-driven mechanisms that promote HIV
persistence, even during antiretroviral therapy (ART). Some of these mechanisms could skew the HIV provirus
towards preferentially integrating into CMV specific CD4+ T cells. Also, as CMV specific CD4+ T cells comprise
a large proportion of all CD4+ T cells, so understanding how they contribute to HIV persistence would be essential
for HIV cure efforts.
Strengths of the proposed research are that it will use state-of-the-art methods and will leverage prior NIH-
investments to collect appropriate biospecimens and data as part of an ACTG-funded, randomized placebo-
controlled trial of the anti-CMV drug letermovir (A5383, Co-chairs: Gianella, Hunt). Merck will provide study drug
for this trial to assess mucosal CMV shedding and biomarkers of systemic inflammation at multiple timepoints.
Study Design: Our project is designed to carefully and rigorously elucidate the CMV-driven mechanisms that
impact HIV persistence. Aim 1 will determine how various viral antigens (CMV, Influenza, EBV and HIV) directly
induce clonal expansion of HIV-infected CD4+ T cells ex vivo. Aim 2 will assess the indirect effect of treating
CMV with letermovir on HIV reservoirs and T cell repertoire in vivo. To clarify mechanistic pathways of ex vivo
and in vivo observations in Aims 1 and 2, we will characterize specific immunologic mechanisms associated with
clonal expansion and inflammation in association with CMV and HIV persistence.
Overall Objective: HIV cure efforts will likely be futile if we ignore the inflammatory mechanisms that sustain the
HIV reservoir. This project is in line with NIH OAR priorities because it will assess the mechanisms by which viral
antigens (CMV, EBV, Influenza and HIV) influence HIV persistence through expansion of CD4+ T cells that carry
HIV DNA (Aim 1). Further, we will determine the benefits of suppressing CMV to decrease immune dysfunction
and HIV cell reservoirs (Aims 2 and 3).
Impact: The proposed project will have meaningful impact by determining how suppressing CMV with letermovir
may influence inflammation, immune dysfunction and HIV reservoirs. Generated results will advance both the
HIV cure and PWH health agendas.

## Key facts

- **NIH application ID:** 10241944
- **Project number:** 5R01AI147821-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Sara Gianella Weibel
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $801,604
- **Award type:** 5
- **Project period:** 2020-08-19 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10241944

## Citation

> US National Institutes of Health, RePORTER application 10241944, Mechanisms of CMV Replication on HIV Persistence (5R01AI147821-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10241944. Licensed CC0.

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