HIV and Aging: Evaluating Metabolic Deficits and Immune Dysfunction
Article Summary
- People are living longer with HIV and face complications related to aging.
- A collaborative Miller School study funded by the National Institute on Aging evaluates metabolic deficits and immune dysfunction in older people with HIV.
- People with HIV often have elevated levels of inflammation, which is related to metabolic abnormalities.
As people with HIV live longer, healthier lives due to advances in medicine, they also face complications related to aging.
A collaborative study at the University of Miami Miller School of Medicine was recently awarded more than $2.9 million from the National Institute on Aging to evaluate metabolic deficits and immune dysfunction in older people with HIV. The study hopes to identify viable therapies to improve immune system function in people with HIV.
Daniela Frasca, Ph.D., and Suresh Pallikkuth, Ph.D., both research associate professors in the Miller School’s Department of Microbiology and Immunology, are the principal investigators on the five-year project. Their interest grew from prior research on immune responses in individuals with inflammation stemming from aging, obesity and type 2 diabetes, leading to metabolic dysfunction.
“In people with HIV, even those on antiretroviral treatment with suppressed viral loads, we still observe high levels of inflammation,” Dr. Pallikkuth said. “This persistent inflammation is linked to aging and correlates with metabolic abnormalities, particularly in immune cells. Ongoing inflammation in virally suppressed people with HIV contributes to metabolic irregularities, which in turn affects overall immune function.”
Exploring Metabolic Pathways
The labs of Drs. Frasca and Pallikkuth focus on immunity at the cellular level, studying key immune cells like T cells, B cells and monocytes. One aspect of their research is examining how immune abnormalities worsen when individuals, both young and elderly, acquire HIV. They also investigate comorbidities like obesity, which can accelerate or worsen pre-existing immune damage. Although this area of research has been studied in other diseases, it remains relatively novel in the context of HIV.
In this study, the researchers hypothesize that metabolic pathways are responsible for the dysfunctional immunity in people of different ages and in conditions such as HIV. Both scientists will investigate the metabolic dysfunctions affecting nutrient uptake in immune cells. These nutrients include glucose and lipids such as cholesterol and fat.
Once absorbed, nutrients can follow two primary pathways: aerobic glycolysis in the mitochondria, which provides most of the energy for cellular function, and anaerobic glycolysis in the cytoplasm, which leads to lactate secretion.
“Both pathways play significant roles in immune cell metabolism and influence how these processes affect the different immune cells in the blood,” Dr. Frasca noted. “The question now is how inflammation, combined with a condition like HIV superimposed on aging, alters these pathways. One of the goals of this project is to investigate not only these pathways but also additional ones, whether associated with the mitochondria or not.”
Team Science Advances HIV Research
Cell samples for the research will come from the Multicenter AIDS Cohort Study/Women’s Interagency HIV Study (MACS/WIHS). The University of Miami is a MACS/WIHS recruitment site and the study features a large cohort of people with and without HIV.
Researchers will collect cells from 400 participants of various ages, with half of the samples from people with HIV and the other half from people without HIV, as healthy controls.
“This combined cohort study provides a platform for investigators to use data and samples collected from people with HIV,” said Maria Alcaide, M.D., UM interim vice provost for research and scholarship and director of the Infectious Diseases Research Unit and professor of medicine at the Miller School. “Researchers can then use this information to answer their scientific questions while saving time and money.”
Identifying Outcomes for HIV Therapeutics
Drs. Frasca and Pallikkuth will first identify the metabolic status of each participant, studying the effects of aging, HIV and obesity. They will then assess how a person’s metabolism affects immune cell function and response. Although studied in vitro, these results are expected to reflect in vivo immune responses to infections or vaccines. Finally, they will focus on identifying key metabolic pathways that can be targeted for therapeutic interventions.
The grant will fund a range of high-throughput technologies to characterize the immune systems in people with HIV, including single-cell RNA sequencing to analyze immune cells in the blood and identify altered transcription factors and metabolic pathways.
Mass spectrometry will be used to evaluate metabolites in the serum, particularly those from the gut. Additionally, Agilent Seahorse technology will assess the metabolic status of immune cells.
“The key is determining if we can use exogenous interventions,” Dr. Frasca said. “We’re looking at metabolic modifiers and senolytic compounds already in clinical trials. We won’t introduce anything new, but rather use FDA-approved substances that have been proven safe. We will test these interventions in vitro and propose novel therapeutic strategies to improve immune system function in people with HIV.”
Tags: aging, Dr. Daniela Frasca, Dr. Suresh Pallikkuth, HIV, HIV/AIDS research, immune system, immunology, metabolics