HIV-1 replication and latency are balanced by mTOR-driven cell metabolism

Abstract

Human Immunodeficiency virus type 1 (HIV-1) relies on host cell metabolism for all aspects of viral replication. Efficient HIV-1 entry, reverse transcription, and integration occurs in activated T cells because HIV-1 proteins co-opt host metabolic pathways to fuel the anabolic requirements of virion production. The HIV-1 viral life cycle is especially dependent on mTOR, which drives signaling and metabolic pathways required for viral entry, replication, and latency. As a central regulator of host cell metabolism, mTOR and its downstream effectors help to regulate the expression of enzymes within the glycolytic and pentose phosphate pathways along with other metabolic pathways regulating amino acid uptake, lipid metabolism, and autophagy. In HIV-1 pathogenesis, mTOR, in addition to HIF-1α and Myc signaling pathways, alter host cell metabolism to create an optimal environment for viral replication. Increased glycolysis and pentose phosphate pathway activity are required in the early stages of the viral life cycle, such as providing sufficient dNTPs for reverse transcription. In later stages, fatty acid synthesis is required for creating cholesterol and membrane lipids required for viral budding. Epigenetics of the provirus fueled by metabolism and mTOR signaling likewise controls active and latent infection. Acetyl-CoA and methyl group abundance, supplied by the TCA cycle and amino acid uptake respectively, may regulate latent infection and reactivation. Thus, understanding and exploring new connections between cellular metabolism and HIV-1 pathogenesis may yield new insights into the latent viral reservoirs and fuel novel treatments and cure strategies.

Cardiometabolic Differences in People Living with HIV Receiving Integrase Strand Transfer Inhibitors Compared to Non-nucleoside Reverse Transcriptase Inhibitors: Implications for Current ART Strategies

“…Normally, oxidative phosphorylation is upregulated in activated T-cells to produce ATP, which also lead to increases in harmful reactive oxygen species. Alternatively, the pentose phosphate pathway is able to use glucose to produce the antioxidant-enhancing NADPH to prevent this damage to cells [ 21 ]. HIV-infected cells increase their energy usage to form virions and the upregulated pentose phosphate pathway is thought to induce increased protection on these infected cells.…”

“…HIV-infected cells increase their energy usage to form virions and the upregulated pentose phosphate pathway is thought to induce increased protection on these infected cells. In addition, the pentose phosphate pathway produces deoxynucleotide triphosphates (dNTPs) that play a role in reverse transcriptase activation [ 21 ]. Lower levels of dNTPs are associated with impaired HIV transcription [ 22 ].…”

The Dynamic Linkage between Provirus Integration Sites and the Host Functional Genome Property Alongside HIV-1 Infections Associated with Antiretroviral Therapy

“…The gene product of rptor forms a stoichiometric complex with the mammalian target of rapamycin (mTOR) kinase. mTOR signaling largely regulates cell metabolism in activated T cells and is known to be required for HIV-1 replication and latency [ 29 , 30 ], highlighting the importance of immunometabolism involved in HIV-1 pathogenesis [ 31 ]. The gene rapgef2 was found throughout the infection course of HIV-1 in patients ( Figure 3 e and Table S27 ).…”

Retinoic Acid Boosts HIV-1 Replication in MacrophagesviaCCR5/SAMHD1-Dependent and mTOR-Modulated Mechanisms

“…This evidence supports the link between viral replication and host cell metabolism 140 . In this context, mTOR inhibitors, used in clinic for the treatment of diabetes and tested in clinical trials for cancer 141,142 , may also be used in HIV-1 infection. Most recently, our group and others provided evidences pointing to metformin, an indirect mTOR inhibitor, as an efficient therapeutic strategy for the control of residual HIV-1 transcription and premature ageing in ART-treated PLWH 128,143,144 .…”