Counteracting Akt Activation by HIV Protease Inhibitors in Monocytes/Macrophages

Abstract

Akt signaling plays a central role in many biological processes that are key players in human immunodeficiency virus 1 (HIV-1) pathogenesis. The persistence of latent reservoirs in successfully treated patients, mainly located in macrophages and latently infected resting CD4+ T cells, remains a major obstacle in HIV-1 eradication. We assessed the in vitro effects of an HIV protease inhibitor (PI) and a non-nucleoside reverse transcriptase inhibitor (NNRTI) on HIV-1 Nef-induced Akt activation in macrophages and on HIV-1 reactivation in U1 monocytoid cells. Ex vivo, we investigated the impact of combination antiretroviral therapy (cART) on Akt activation, as measured by flow cytometry, and on the viral reservoir size, quantified by qPCR, in monocytes and autologous resting CD4+ T cells from HIV-infected individuals (Trial registration: NCT02858414). We found that, in myeloid cells, both Akt activation and HIV-1 reactivation were inhibited by PI but not by NNRTI in vitro. Our results indicate that cART decreases Akt activation and reduces the size of the HIV reservoir in both monocytes and resting CD4+ T cells. Our study indicates that Akt activation could play a role in HIV reservoir formation, indicating that drugs which target Akt could be efficient for limiting its size in aviremic chronically infected patients.

The Impact of Matrix Metalloproteinase-9 on the Sequential Steps of the Metastatic Process

“…Probably one of the most relevant anticancer activities of HIV-protease inhibitors is their ability to hamper the AKT signaling pathway [ 183 , 184 , 185 , 186 , 187 , 188 , 189 , 190 , 191 ]. In this respect, HIV-protease inhibitors may resemble novel AKT inhibitors such as IDELALISIB and COPANLISIB, which were recently approved for clinical use in various types of cancer [ 233 ].…”

“…It is worthy of note that HIV protease inhibitors such as ritonavir, saquinavir, indinavir and lopinavir strongly reduce MMP-9 expression and/or activity in normal or cancer cells and in treated patients [ 20 , 169 , 170 , 171 , 172 , 173 , 174 ]. This is because HIV protease inhibitors repress the MAPK/ERK and/or PI3K/AKT signaling pathways, thereby functionally impairing transcription factors targeting the mmp-9 gene, including NF-kB, Specificity protein-1 or the Fra-1 element of the Activator Protein-1 transcriptional complex [ 164 , 169 , 175 , 176 , 177 , 178 , 179 , 180 , 181 , 182 , 183 , 184 , 185 , 186 , 187 , 188 , 189 , 190 , 191 , 192 , 193 , 194 , 195 , 196 ]. It should be noted that the AKT activation process starts when PI3K promotes the production of phosphatidylinositol-3,4,5-trisphosphate (PIP3); this is followed by AKT recruitment to the cell membrane and AKT phosphorylation on Thr308 and Ser473 by the phosphoinosotide-dependent kinase-1 and the mammalian target of rapamycin, respectively [ 191 ].…”

Comparison of miRNA Expression Profiles between HIV-1 and HIV-2 Infected Monocyte-Derived Macrophages (MDMs) and Peripheral Blood Mononuclear Cells (PBMCs)

“…This indicates that PI3K-Akt signaling pathway-related genes are downregulated during HIV-2 infection. On the contrary, reports indicate that PI3K-Akt signaling pathway-related genes are activated in both T cells [95] and macrophages [96] during HIV-1 activation. The delayed disease progression observed in HIV-2-infected individuals could be due to the differences in the activation state of signaling pathway-related genes like the PI3K-Akt signaling pathway.…”

Heparanase, cell signaling, and viral infections

“…It is, therefore, in the interest of a virus to prolong the survival of the host cell. Accordingly, multiple types of viruses have been shown to stimulate Akt phosphorylation, including adenoviruses, poxviruses, HIV, papilloma viruses, herpesviruses, and influenza A [24][25][26][27]. There appears to be a trend of mammalian DNA viruses utilizing the Akt pathway for their own benefit, leveraging its role as a master regulator of signaling [21].…”

“…Thus, even if the host cell successfully inhibits the PI3K-Akt axis, HSV-1 can still translate proteins necessary for its survival. However, the inhibition of Akt results in a reduction of viral load in certain viruses, highlighting the importance of the pathway in a productive infection [25]. Viruses have been shown to modify the PI3K pathway at nearly every point from PI3K to eukaryotic initiation factor 4F (EIF4F) [21].…”