Polyanionic carbosilane dendrimers as a new adjuvant in combination with latency reversal agents for HIV treatment

Abstract

Background The major obstacle impeding human immunodeficiency virus-1 (HIV-1) eradication in antiretroviral treatment (ART) treated HIV-1 subjects is the establishment of long-lived latently infected resting CD4 + T cells. Due to the fact that no drug has been effective, the search for new drugs and combinations are a priority in the HIV cure. Treatments based on nanotechnology have emerged as an innovative and promising alternative to current and conventional therapies. In this respect, nanotechnology opens up a new door for eliminating latent HIV infection. We studied the role of G1-S4, G2-S16 and G3-S16 polyanionic carbosilane dendrimers in the context of latent HIV-1 persistence. Moreover, we study the efficiency of these dendrimers in combination with latency reversal agents (LRAs) against HIV-1 infection. Methods J89GFP lymphocyte and THP89GFP monocyte derived cell lines latently infected with HIV-1 p89GFP were used as an in vitro model of latency for our study. Viability assays by 3-(4-5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and lactate dehydrogenase (LDH) were performed to determine the working concentrations of dendrimers and LRAs. Both cell lines were treated with G1-S4, G2-S16 and G3-S16 either alone or in combination with bryostatin (BRY), romidepsin (RMD) or panobinostat (PNB) for 24 and 48 h. The expression pattern of GFP was measured by flow cytometry and referred as measure of viral reactivation. Results and discussion The combination treatment of the dendrimers with the protein kinase C (PKC) agonist did not modify the antilatency activity in J89GFP lymphocyte cell line. Interestingly enough, G3-S16 dendrimer alone and its combination with BRY, RMD or PNB showed a significant increased expression of GFP in the THP89GFP monocyte cell line. Conclusion We showed for the first time that nanoparticles, in this case, G3-S16 anionic carbosilan dendrimer may play an important role in new treatments against HIV-1 infection.

Diversity of small molecule HIV‐1 latency reversing agents identified in low‐ and high‐throughput small molecule screens

“…Importantly however, all of the clinical trials performed to date have involved drugs that had been repurposed from treatment of other conditions; and consequently, the full capability of LRAs with respect to the “shock and kill” strategy in general may not be realized until trials with compounds specifically designed and optimized for this purpose. Furthermore, application of recent developments in drug delivery involving nanocarriers, such as polymeric nanoparticles, liposomes, lipid nanoparticles, and dendrimers, to encapsulate LRAs, could increase their circulation or tissue retention time, solubility and bioavailability, enhance drug potency, and reduce cellular toxicity and thereby improve overall success of this approach.…”

Applications and Limitations of Dendrimers in Biomedicine

“…In antiviral therapy, numerous studies have been performed for the development of dendrimeric conjugates with active substances, which offer multiple advantages, such as increased specificity and bioavailability, prolonged half-life, and the reduced toxicity of the drug [ 204 ]. In the last decade, in anti-HIV therapy, nanotechnology using polyanionic carbosilane dendrimers (PCD) has been a promising approach in improving the characteristics of antiretroviral drugs, using dendrimeric nanoparticles with dimensions between 1 and 40 nm [ 205 ] and different generations G1-S4, G2-S16 and G3-S16 [ 206 ]. These compounds are characterized by the sulfonate groups in the peripheral structures, as follows: G1-S4 PCDs have four peripheral sulfonate groups, and G2-S16 and G3-S16 have 16 groups [ 207 , 208 ].…”

“… The structures of PCDs used for conjugation with different anti-HIV agents: ( a ) G1-S4, ( b ) G2-S16, ( c ) G3-S16. Adapted from [ 206 ], published by J. Nanobiotechnol. 2019.…”

Peptides and Dendrimers: How to Combat Viral and Bacterial Infections

“…Poly-anionic dendrimers are able to inhibit HIV, HSV, and many other viruses that target the viral life cycle, and can prevent virus binding to the host cell [ 118 ]. Polyanionic carbosilane dendrimers showed in vitro and in vivo activity against HSV and HIV [ 119 , 120 ]. The polysulfated galactose derivatized poly(propyleneimine) dendrimers inhibited the infection of laboratory-isolated HIV-1 as efficiently as dextran sulfate ( Figure 5 B) [ 121 ].…”