Alterations of redox and iron metabolism accompany development of HIV latency

Abstract

Metabolic alterations, such as oxidative stress, are hallmarks of HIV-1 infection. However, their influence on the development of viral latency, and thus on HIV-1 persistence during antiretroviral therapy (ART), have just begun to be explored. We analyzed omics profiles of in-vitro and in-vivo models of infection by HIV-1 and its simian homolog SIVmac. We found that cells survive retroviral replication by upregulating antioxidant pathways and intertwined iron import pathways. These changes are associated with remodeling of the redox sensitive promyelocytic leukemia protein nuclear bodies (PML NBs), an important constituent of nuclear architecture and a marker of HIV-1 latency. We found that PML is depleted in productively infected cells and restored by ART. Moreover, we identified intracellular iron as a key link between oxidative stress and PML depletion, thus supporting iron metabolism modulators as pharmacological tools to impair latency establishment.

Glycolysis downregulation is a hallmark of HIV-1 latency and sensitizes infected cells to oxidative stress

“…Therefore, nicotinamide consumption may contribute to divert metabolism from glycolysis to the pentose cycle, consistent with a model where glycolysis favors HIV-1 replication while the pentose cycle favors HIV-1 latency as well as antioxidant defenses. The latter phenomenon is in line with the previously described upregulation of antioxidant responses in latently HIV-1 infected cells (Shytaj et al, 2020). Moreover, oxidative stress immediately following HIV-1 infection was shown to induce increased transcription of G6PDH (Shytaj et al 2020), therefore further validating the diversion of glucose 6-phosphate to the pentose cycle.…”

“…Network analysis revealed a likely connection between NADH decrease and redox pathways in latently infected cells ( Figure 2G). Accordingly, increased levels of oxidized glutathione, consistent with higher oxidative stress upon infection, as previously described (Shytaj et al, 2020), were associated with a decrease not only in NADH but also in its precursor NAD + . The HIV-1related NAD + consumption was also associated with altered nicotinamide metabolism (Additional files 5,6) and with a trend towards increased expression of proteins consuming NAD + /NADH ( Figure 2G).…”

“…respectively]. Finally, analysis of a previously published proteomic dataset of the same CD4 + T-cell model (Shytaj et al, 2020) further corroborated the downregulating effect of HIV-1 on glycolysis, confirming significant downmodulation of GPI, PGK1 and TPI1 (Additional file 2).…”

“…To expand these analyses, we explored an RNA-Seq dataset derived from the same primary CD4 + T-cell model, which was previously published elsewhere (Shytaj et al, 2020). In this dataset, the number of donors and time points was higher, allowing the study of the expression of glycolytic enzymes during each infection stage ( Figure 1C).…”

“…Among the most significantly enriched pathways, we further considered metabolism of antioxidants (Additional file 5), due to its well described interconnection with glycolysis and NAD + , via the pentose pathway (Grant, 2008), and its relevance in the establishment and maintenance of HIV-1 latency (Shytaj et al, 2020;Benhar et al, 2016). Network analysis revealed a likely connection between NADH decrease and redox pathways in latently infected cells ( Figure 2G).…”