Quinoline antimalarials as investigational drugs for HIV-1/AIDS: in vitro effects on HIV-1 replication, HIV-1 response to antiretroviral drugs, and intracellular antiretroviral drug concentrations

2006 ◽  
Vol 67 (10) ◽  
pp. 806-817 ◽  
Author(s):  
Andrea Savarino ◽  
Mothanje B. Lucia ◽  
Rob ter Heine ◽  
Elena Rastrelli ◽  
Sergio Rutella ◽  
...  
Keyword(s):  
Antiretroviral Drugs ◽  
Drug Concentrations ◽  
Antiretroviral Drug ◽  
Investigational Drugs ◽  
In Vitro Effects ◽  
Hiv 1

scholarly journals Cytotoxicity assessment, inflammatory properties, and cellular uptake of Neutraplex lipid-based nanoparticles in THP-1 monocyte-derived macrophages

2017 ◽  
Vol 4 ◽  
pp. 184954351774625 ◽  
Author(s):  
Eric Berger ◽  
Dalibor Breznan ◽  
Sandra Stals ◽  
Viraj J Jasinghe ◽  
David Gonçalves ◽  
...  
Keyword(s):  
Targeted Delivery ◽  
Small Interfering Rna ◽  
Human Monocyte ◽  
Antiretroviral Drugs ◽  
Small Interfering Rnas ◽  
Lactate Dehydrogenase Release ◽  
Drug Concentrations ◽  
Interfering Rna ◽  
Hiv 1

Current antiretroviral drugs used to prevent or treat human immunodeficiency virus type 1 (HIV-1) infection are not able to eliminate the virus within tissues or cells where HIV establishes reservoirs. Hence, there is an urgent need to develop targeted delivery systems to enhance drug concentrations in these viral sanctuary sites. Macrophages are key players in HIV infection and contribute significantly to the cellular reservoirs of HIV because the virus can survive for prolonged periods in these cells. In the present work, we investigated the potential of the lipid-based Neutraplex nanosystem to deliver anti-HIV therapeutics in human macrophages using the human monocyte/macrophage cell line THP-1. Neutraplex nanoparticles as well as cationic and anionic Neutraplex nanolipoplexes (Neutraplex/small interfering RNA) were prepared and characterized by dynamic light scattering. Neutraplex nanoparticles showed low cytotoxicity in CellTiter-Blue reduction and lactate dehydrogenase release assays and were not found to have pro-inflammatory effects. In addition, confocal studies showed that the Neutraplex nanoparticles and nanolipoplexes are rapidly internalized into THP-1 macrophages and that they can escape the late endosome/lysosome compartment allowing the delivery of small interfering RNAs in the cytoplasm. Furthermore, HIV replication was inhibited in the in vitro TZM-bl infectivity assay when small interfering RNAs targeting CXCR4 co-receptor was delivered by Neutraplex nanoparticles compared to a random small interfering RNA sequence. This study demonstrates that the Neutraplex nanosystem has potential for further development as a delivery strategy to efficiently and safely enhance the transport of therapeutic molecules into human monocyte-derived macrophages in the aim of targeting HIV-1 in this cellular reservoir.

scholarly journals Association between lipodystrophy and length of exposure to ARTs in adult HIV-1 infected patients in Montreal

2019 ◽  
Vol 19 (1) ◽  
Author(s):  
Ahmad Alikhani ◽  
Helene Morin ◽  
Stephanie Matte ◽  
Pouriya Alikhani ◽  
Cécile Tremblay ◽  
...  
Keyword(s):  
Cross Sectional Study ◽  
Continuous Variable ◽  
Antiretroviral Drugs ◽  
Cumulative Exposure ◽  
Sectional Study ◽  
Cross Sectional ◽  
Centre Hospitalier Universitaire ◽  
Antiretroviral Drug ◽  
Trunk Limb ◽  
Hiv 1

Abstract Background The aim of this study was to establish the prevalence of lipodystrophy and its association to cumulative exposure to antiretroviral drugs. Method We conducted a cross sectional study in all HIV- infected patients attending the HIV clinic in the Centre hospitalier universitaire de Montréal (CHUM) with DEXA scan. Lipodystrophy was defined as a trunk/limb fat ratio ≥ 1.5. Association between cumulative exposure to antiretroviral (measured in years of use) with trunk/limb fat ratio (coded as a continuous variable) was assessed using univariate and multivariate linear regression for each antiretroviral drug with at least 40 exposed patients. Results One hundred sixty-six patients were included. Seventy-five percent were male, median age was 56 years, 67% were Caucasian. Overall, prevalence of lipodystrophy was 47%, with a mean trunk/limb fat ratio of 1.87, SD = 1.03, min = 0.6 and max = 5.87. Each 10-year increase in age and HIV infection duration was associated with an average increase of 0.24 and 0.34 for the trunk/limb fat ratio respectively. (p = 0.003, p = 0.002, respectively) Patients classified as lipodystrophic were more likely to be diabetic (50 vs. 28%, p = 0.07) and to have dyslipidemia (47 vs. 19%, p = 0.01). According to viral load at DEXA test, each one log increase was associated with less probability (0.7) of lipodystrophy. (p = 0.01) Among ARV drugs tested, there was an association between years of use of d4T, ritonavir and raltegravir and higher trunk/limb fat ratio (indicating more lipodystrophy) (p < 0.05). Conclusion Lipodystrophy is very common in HIV infected patients and is correlated with duration of some new antiretroviral drugs.

In vitro selection of HIV-1 resistance of ddI is not as efficient as for other antiretroviral drugs and yields virus which shows reduced cytophatic activity

1995 ◽  
Vol 26 (3) ◽  
pp. A268
Author(s):  
F. Dianzani ◽  
G. Antonelli ◽  
D. Bellarosa ◽  
F. Bambacioni ◽  
E. Riva ◽  
...  
Keyword(s):  
In Vitro Selection ◽  
Antiretroviral Drugs ◽  
Hiv 1 ◽  
Selection Of

scholarly journals Antiviral Activity of Bictegravir and Cabotegravir against Integrase Inhibitor-Resistant SIVmac239 and HIV-1

2017 ◽  
Vol 61 (12) ◽  
Author(s):  
Said A. Hassounah ◽  
Ahmad Alikhani ◽  
Maureen Oliveira ◽  
Simrat Bharaj ◽  
Ruxandra-Ilinca Ibanescu ◽  
...  
Keyword(s):  
Treatment Strategies ◽  
Fold Increase ◽  
Integrase Inhibitor ◽  
Antiretroviral Drugs ◽  
Strand Transfer ◽  
Single Cycle ◽  
Genetic Barrier ◽  
Hiv 1

ABSTRACT Animal models are essential to study novel antiretroviral drugs, resistance-associated mutations (RAMs), and treatment strategies. Bictegravir (BIC) is a novel potent integrase strand transfer inhibitor (INSTI) that has shown promising results against HIV-1 infection in vitro and in vivo and against clinical isolates with resistance against INSTIs. BIC has a higher genetic barrier to the development of resistance than two clinically approved INSTIs, termed raltegravir and elvitegravir. Another clinically approved INSTI, dolutegravir (DTG) also possesses a high genetic barrier to resistance, while a fourth compound, termed cabotegravir (CAB), is currently in late phases of clinical development. Here we report the susceptibilities of simian immunodeficiency virus (SIV) and HIV-1 integrase (IN) mutants containing various RAMs to BIC, CAB, and DTG. BIC potently inhibited SIV and HIV-1 in single cycle infection with 50% effective concentrations (EC50s) in the low nM range. In single cycle SIV infections, none of the E92Q, T97A, Y143R, or N155H substitutions had a significant effect on susceptibility to BIC (≤4-fold increase in EC50), whereas G118R and R263K conferred ∼14-fold and ∼6-fold increases in EC50, respectively. In both single and multiple rounds of HIV-1 infections, BIC remained active against the Y143R, N155H, R263K, R263K/M50I, and R263K/E138K mutants (≤4-fold increase in EC50). In multiple rounds of infection, the G140S/Q148H combination of substitutions decreased HIV-1 susceptibility to BIC 4.8-fold compared to 16.8- and 7.4-fold for CAB and DTG, respectively. BIC possesses an excellent resistance profile in regard to HIV and SIV and could be useful in nonhuman primate models of HIV infection.

scholarly journals Novel Acylguanidine-Based Inhibitor of HIV-1

2016 ◽  
Vol 90 (20) ◽  
pp. 9495-9508 ◽  
Author(s):  
Philip Mwimanzi ◽  
Ian Tietjen ◽  
Scott C. Miller ◽  
Aniqa Shahid ◽  
Kyle Cobarrubias ◽  
...  
Keyword(s):  
Protein Interactions ◽  
Antiretroviral Drugs ◽  
Virion Release ◽  
Viral Egress ◽  
Pharmacological Studies ◽  
Infected Cells ◽  
New Treatments ◽  
Hiv 1

ABSTRACTThe emergence of transmissible HIV-1 strains with resistance to antiretroviral drugs highlights a continual need for new therapies. Here we describe a novel acylguanidine-containing compound, 1-(2-(azepan-1-yl)nicotinoyl)guanidine (or SM111), that inhibitsin vitroreplication of HIV-1, including strains resistant to licensed protease, reverse transcriptase, and integrase inhibitors, without major cellular toxicity. At inhibitory concentrations, intracellular p24Gagproduction was unaffected, but virion release (measured as extracellular p24Gag) was reduced and virion infectivity was substantially impaired, suggesting that SM111 acts at a late stage of viral replication. SM111-mediated inhibition of HIV-1 was partially overcome by a Vpu I17R mutation alone or a Vpu W22* truncation in combination with Env N136Y. These mutations enhanced virion infectivity and Env expression on the surface of infected cells in the absence and presence of SM111 but also impaired Vpu's ability to downregulate CD4 and BST2/tetherin. Taken together, our results support acylguanidines as a class of HIV-1 inhibitors with a distinct mechanism of action compared to that of licensed antiretrovirals. Further research on SM111 and similar compounds may help to elucidate knowledge gaps related to Vpu's role in promoting viral egress and infectivity.IMPORTANCENew inhibitors of HIV-1 replication may be useful as therapeutics to counteract drug resistance and as reagents to perform more detailed studies of viral pathogenesis. SM111 is a small molecule that blocks the replication of wild-type and drug-resistant HIV-1 strains by impairing viral release and substantially reducing virion infectivity, most likely through its ability to prevent Env expression at the infected cell surface. Partial resistance to SM111 is mediated by mutations in Vpu and/or Env, suggesting that the compound affects host/viral protein interactions that are important during viral egress. Further characterization of SM111 and similar compounds may allow more detailed pharmacological studies of HIV-1 egress and provide opportunities to develop new treatments for HIV-1.

scholarly journals The Roles of HIV-1 Proteins and Antiretroviral Drug Therapy in HIV-1-Associated Endothelial Dysfunction

2008 ◽  
Vol 56 (5) ◽  
pp. 752-769 ◽  
Author(s):  
Erik R. Kline ◽  
Roy L. Sutliff
Keyword(s):  
Cardiovascular Disease ◽  
Endothelial Dysfunction ◽  
Highly Active Antiretroviral Therapy ◽  
Clinical Studies ◽  
Molecular Mechanisms ◽  
Opportunistic Infections ◽  
Antiretroviral Drugs ◽  
Hiv 1

Since the emergence of highly active antiretroviral therapy (HAART), human immunodeficiency virus-1 (HIV-1)-infected patients have demonstrated dramatic decreases in viral burden and opportunistic infections, and an overall increase in life expectancy. Despite these positive HAART-associated outcomes, it has become increasingly clear that HIV-1 patients have an enhanced risk of developing cardiovascular disease over time. Clinical studies are instrumental in our understanding of vascular dysfunction in the context of HIV-1 infection. However, most clinical studies often do not distinguish whether HIV-1 proteins, HAART, or a combination of these 2 factors cause cardiovascular complications. This review seeks to address the roles of both HIV-1 proteins and antiretroviral drugs in the development of endothelial dysfunction because endothelial dysfunction is the hallmark initial step of many cardiovascular diseases. We analyze recentin vitroandin vivostudies examining endothelial toxicity in response to HIV-1 proteins or in response to the various classes of antiretroviral drugs. Furthermore, we discuss the multiple mechanisms by which HIV-1 proteins and HAART injure the vascular endothelium in HIV-1 patients. By understanding the molecular mechanisms of HIV-1 protein- and antiretroviral-induced cardiovascular disease, we may ultimately improve the quality of life of HIV-1 patients through better drug design and the discovery of new pharmacological targets.

scholarly journals Biochemical Reconstitution of HIV-1 Assembly and Maturation

2019 ◽  
Vol 94 (5) ◽  
Author(s):  
Iga Kucharska ◽  
Pengfei Ding ◽  
Kaneil K. Zadrozny ◽  
Robert A. Dick ◽  
Michael F. Summers ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Rna Binding ◽  
Experimental System ◽  
Antiretroviral Drugs ◽  
Gag Protein ◽  
Rate Limiting Step ◽  
Lattice Formation ◽  
Immature Virus ◽  
Hiv 1

ABSTRACT The assembly of an orthoretrovirus such as HIV-1 requires the coordinated functioning of multiple biochemical activities of the viral Gag protein. These activities include membrane targeting, lattice formation, packaging of the RNA genome, and recruitment of cellular cofactors that modulate assembly. In most previous studies, these Gag activities have been investigated individually, which provided somewhat limited insight into how they functionally integrate during the assembly process. Here, we report the development of a biochemical reconstitution system that allowed us to investigate how Gag lattice formation, RNA binding, and the assembly cofactor inositol hexakisphosphate (IP6) synergize to generate immature virus particles in vitro. The results identify an important rate-limiting step in assembly and reveal new insights into how RNA and IP6 promote immature Gag lattice formation. The immature virus-like particles can be converted into mature capsid-like particles by the simple addition of viral protease, suggesting that it is possible in principle to fully biochemically reconstitute the sequential processes of HIV-1 assembly and maturation from purified components. IMPORTANCE Assembly and maturation are essential steps in the replication of orthoretroviruses such as HIV-1 and are proven therapeutic targets. These processes require the coordinated functioning of the viral Gag protein’s multiple biochemical activities. We describe here the development of an experimental system that allows an integrative analysis of how Gag’s multiple functionalities cooperate to generate a retrovirus particle. Our current studies help to illuminate how Gag synergizes the formation of the virus compartment with RNA binding and how these activities are modulated by the small molecule IP6. Further development and use of this system should lead to a more comprehensive understanding of the molecular mechanisms of HIV-1 assembly and maturation and may provide new insights for the development of antiretroviral drugs.

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