The Third Coast Center for AIDS Research (TC CFAR) is pleased to announce the first Directors’ Choice publication selected for 2024, “Analysis of the Contribution of 6-mer Seed Toxicity to HIV-1-Induced Cytopathicity,” recently published in the Journal of Virology. Led by corresponding author Marcus Peter, PhD, the Tom D. Spies Professor of Cancer Metabolism at Northwestern University, this paper explores new avenues by which a novel cell death mechanism could be used to kill latent HIV.

HIV-1 infection results in the gradual depletion of infected and uninfected ‘bystander’ CD4+ T cells from the body, eventually resulting in AIDS in the absence of antiretroviral therapy. Some infected cells, however, can persist in the body for prolonged periods of time, withstanding viral cytotoxicity and forming a latent reservoir.

“Understanding the mechanisms by which HIV-1 kills some cells while enabling long-term persistence in others is critical for the development of new curative therapies aimed at depleting the latent reservoir,” said Judd Hultquist, PhD, a co-author of this paper.

Marcus Peter
Marcus Peter, PhD

Small RNAs in cells can downregulate the expression of genes in a process known as RNA interference. The Peter Lab, located within the Robert H. Lurie Comprehensive Cancer Center at Northwestern, previously identified a cell death pathway that uses small RNAs to downregulate essential genes. These small RNAs contain what are termed ‘toxic seed’ sequences that recognize and bind to these essential gene transcripts.

In this paper, the authors demonstrate that HIV-1 infected cells have changes in their small RNA expression profiles that make infected cells more susceptible to cell death by these toxic RNAs. The HIV genome itself contains a toxic RNA sequence that could contribute to enhanced sensitivity of infected cells to this cell death pathway. When the authors removed some of the protections cells used to prevent toxic RNA mediated death, HIV-1 infected cells died much faster.

“Based on these data, HIV-1 infected cells are much more sensitive to cell death mediated by toxic small RNAs. This sensitivity is even exhibited in cell line models of HIV latency,” said Hultquist. “Therefore, by either boosting toxic RNA levels or inhibiting cellular protections, we could preferentially kill latently infected cells in the body.”

Judd Hultquist, PhD
Judd Hultquist, PhD

Hultquist concluded: “Several other mechanisms regulating HIV-mediated cell death have been described, but these data outline a new mechanism that contributes to our overall understanding of the complex biological processes at work.”

This study was spearheaded by Peter, who became involved in HIV research through connections with the TC CFAR and subsequent Viral Pathogenesis Core services, which led him to secure an independent NIH grant. The labs of Hultquist, Rich D’Aquila, MD, and Tom Hope, PhD, contributed to the work through the VP Core.

Read the entire publication here.