# Short-term and long-term effects of methamphetamine exposure on residual viral transcription during treated HIV disease

> **NIH NIH R61** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2021 · $943,730

## Abstract

Sulggi Lee
PROJECT SUMMARY/ ABSTRACT
The most commonly used illicit stimulant in HIV-infected individuals is methamphetamine (MA), and prior
studies demonstrate strong evidence that MA promotes increased HIV transcription as well as immune
dysregulation. HIV cure has emerged as an important clinical and research priority given evidence of ongoing
immune dysfunction in HIV-infected individuals despite effective antiretroviral therapy (ART). A challenge in
achieving worldwide HIV eradication is targeting specific vulnerable populations who are most likely to benefit
from an HIV cure but possess poorer immune responses as a result of residual viral replication due to
suboptimal ART adherence and/or direct immune dysfunction from illicit substance use. Prior non-human
studies demonstrate that MA directly induces HIV production and promotes immune activation and
inflammation. These preclinical findings suggest that HIV+ individuals who use MA may experience greater
immune dysfunction and face additional challenges for future HIV eradication. The experiments of this
R61/R33 proposal will investigate the effects of long-term and short-term MA exposure in HIV+ ART-
suppressed individuals with a history of MA use. In Aim 1, HIV+ ART-suppressed participants with current MA
use will be enrolled in a longitudinal cohort study to determine the effects of long-term MA exposure on
residual virus production, gene expression, inflammation, and trace amine-associated 1 (TAAR1, a promising
drug target for psychostimulant addiction) signaling. In Aim 2, HIV+ infected ART-suppressed individuals with a
prior history of non-dependent MA use will be enrolled in an interventional study where they will be
administered oral methamphetamine to determine the effects of short-term MA exposure on residual virus
production, gene expression, inflammation, and TAAR1 signaling. MA exposure will be quantified in Aim 1 with
hair samples, and in Aim 2 with multiple plasma samples collected over a 24-hour monitoring period. Measures
of MA exposure will then be associated with residual virus production (HIV-1 cell-associated unspliced and
multiply spliced RNA, and, as a marker of recent production – episomal 2-LTR DNA), gene expression
(validated by flow cytometry for protein expression), TAAR1 signaling (urinary β-PEA levels), and inflammation
(plasma interleukin-6, interleukin-10, tumor necrosis factor-α, and transforming growth factor-β). Using this
approach, we will then functionally validate the top 60 genes identified in Aims 1 and 2 using a powerful gene
editing technique (CRISPR-Cas9) using primary HIV+ CD4+ T cells. The proposed study will be the first
human genetic study to directly evaluate the effect of MA exposure on residual viral transcription during
effective ART. The overall goals of the study are to integrate a rigorous clinical study designs with high
throughput `omics data to identify novel targets for reversing HIV latency, reducing inflammation, and
personalizing ...

## Key facts

- **NIH application ID:** 9932963
- **Project number:** 5R61DA047024-03
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Sulggi Angela Lee
- **Activity code:** R61 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $943,730
- **Award type:** 5
- **Project period:** 2018-08-01 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9932963

## Citation

> US National Institutes of Health, RePORTER application 9932963, Short-term and long-term effects of methamphetamine exposure on residual viral transcription during treated HIV disease (5R61DA047024-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9932963. Licensed CC0.

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