HIV infection and latency induce a unique metabolic signature in human macrophages

Paul Castellano,Silvana Valdebenito,Lisa Prevedel,Eliseo A Eugenin

doi:10.1038/s41598-019-39898-5

Paul Castellano, Silvana Valdebenito + Show 2 more

Open Access

https://doi.org/10.1038/s41598-019-39898-5

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Abstract

Currently, a major barrier to curing HIV infection is the generation of tissue-associated, non-replicating, long-lasting viral reservoirs that are refractory to therapy and can be reactivated upon anti-retroviral therapy interruption. One of these reservoirs are latently HIV-infected macrophages. Here, we show that HIV infection of macrophages results in survival of a small population of infected cells that are metabolically altered and characterized by mitochondrial fusion, lipid accumulation, and reduced mitochondrial ATP production. No changes in glycolysis were detected. Metabolic analysis indicated an essential role of succinate and other TCA metabolites in the tricarboxylic acid (TCA) cycle in mediating lipid accumulation and oxidative phosphorylation (OXPHOS) in the mitochondria. Furthermore, we show that while uninfected and HIV infected macrophages use fatty acids and glucose as primary sources of energy, surviving HIV infected macrophages also use glutamine/glutamate as a major energy source, and blocking these new sources of energy resulted in the killing of latent HIV infected macrophages. Together, our data provide a new understanding of the formation, properties, and potential novel ways to eliminate macrophage viral reservoirs.

Highlights

A key feature of HIV infection that has made it virtually impossible to truly cure this disease is the generation of latent viral reservoirs in different tissues
These results show that HIV reservoirs have a compromised tricarboxylic acid (TCA) cycle and oxidative phosphorylation (OXPHOS) system, with the accumulating lipids possibly serving as an additional source of energy to support the minimal loss in oxygen consumption rate (OCR) function
If we simultaneously inhibited glucose and glutamine oxidation using a cocktail of etomoxir and UK5099, requiring cells to use fatty acids, the OCR change in uninfected cells was negligible (Fig. 6C, fatty acid, UI, black bar). These data indicate that uninfected macrophages can use fatty acids as a fuel source for OXPHOS, and is consistent with our observation that macrophages are dependent on fatty acids more than other fuel types (Fig. 6A, fatty acid compared to glutamine and glucose)

Summary

Introduction

A key feature of HIV infection that has made it virtually impossible to truly cure this disease is the generation of latent viral reservoirs in different tissues. No changes in membrane potential or mitotracker staining were observed among uninfected or HIV infected cells (Supplemental Fig. 4C).

Results

Conclusion