Treatment With Non-Nucleoside Reverse Transcriptase Inhibitor Efavirenz Leads to Increase of Carotid Intima-Media Thickness in Mice

2013 ◽  
Author(s):  
Alexander W. Caulk ◽  
Rudolph L. Gleason
Keyword(s):  
Highly Active Antiretroviral Therapy ◽  
Intima Media Thickness ◽  
Carotid Intima Media Thickness ◽  
Transcriptase Inhibitor ◽  
Media Thickness ◽  
Highly Active ◽  
Atherosclerotic Lesions ◽  
Immunodeficiency Virus ◽  
Reverse Transcriptase Inhibitor ◽  
Hiv 1

Since the advent of highly active antiretroviral therapy (HAART), patients infected with human immunodeficiency virus-1 (HIV-1) are living longer lives. However, HIV-1-positive (HIV-1+) patients are now experiencing many non-AIDS related comorbidities including myocardial infarction, atherosclerotic lesions, and other preclinical markers of atherosclerosis including increased carotid intima-media thickness (cIMT), arterial stiffness, and impaired flow-mediated dilation (FMD). Studies have implicated the virus, the treatment, or both in the progression of these co-morbidities, causing the exact mechanisms of cardiovascular disease progression to remain unclear.

scholarly journals The HEPT Analogue WPR-6 Is Active against a Broad Spectrum of Nonnucleoside Reverse Transcriptase Drug-Resistant HIV-1 Strains of Different Serotypes

2015 ◽  
Vol 59 (8) ◽  
pp. 4882-4888 ◽  
Author(s):  
Weisi Xu ◽  
Jianxiong Zhao ◽  
Jianping Sun ◽  
Qianqian Yin ◽  
Yan Wang ◽  
...  
Keyword(s):  
Reverse Transcriptase ◽  
Highly Active Antiretroviral Therapy ◽  
Therapeutic Index ◽  
Transcriptase Inhibitor ◽  
Resistance Mutations ◽  
Highly Active ◽  
Hiv Drugs ◽  
Reverse Transcriptase Inhibitor ◽  
Hiv 1

ABSTRACTNonnucleoside reverse transcriptase inhibitors (NNRTIs) are important components of the highly active antiretroviral therapy (HAART) used to treat human immunodeficiency type 1 virus (HIV-1). However, because of the emergence of drug resistance and the adverse effects of current anti-HIV drugs, it is essential to develop novel NNRTIs with an excellent safety profile, improved activity against NNRTI-resistant viruses, and enhanced activity against clinical isolates of different subtypes. Here, we have identified 1-[(benzyloxy)methyl]-6-(3,5-dimethylbenzyl)-5-iodopyrimidine-2,4(1H,3H)-dione (WPR-6), a novel NNRTI with a 50% effective concentration (EC50) of 2 to 4 nM against laboratory-adapted HIV-1 strain SF33 and an EC50of 7 to 14 nM against nucleoside reverse transcriptase inhibitor-resistant HIV-1 strain 7391 with a therapeutic index of >1 × 104. A panel of five representative clinical virus isolates of different subtypes circulating predominantly in China was highly sensitive to WPR-6, with EC50s ranging from 1 to 6 nM. In addition, WPR-6 showed excellent antiviral potency against the most prevalent NNRTI-resistant viruses containing the K103N and Y181C mutations. To determine whether WPR-6 selects for novel resistant mutants,in vitroresistance selection was conducted with laboratory-adapted HIV-1 strain SF33 on MT-4 cells. The results demonstrated that V106I and Y188L were the two dominant NNRTI-associated resistance mutations detected in the breakthrough viruses. Taken together, thesein vitrodata indicate that WPR-6 has greater efficacy than the reference HEPT analogue TNK651 and the marketed drug nevirapine against HIV-1. However, to develop it as a new NNRTI, further improvement of its pharmacological properties is warranted.

scholarly journals Lersivirine, a Nonnucleoside Reverse Transcriptase Inhibitor with Activity against Drug-Resistant Human Immunodeficiency Virus Type 1

2010 ◽  
Vol 54 (10) ◽  
pp. 4451-4463 ◽  
Author(s):  
Romuald Corbau ◽  
Julie Mori ◽  
Chris Phillips ◽  
Lesley Fishburn ◽  
Alex Martin ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Reverse Transcriptase ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Highly Active Antiretroviral Therapy ◽  
Transcriptase Inhibitor ◽  
Highly Active ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT The nonnucleoside reverse transcriptase inhibitors (NNRTIs) are key components of highly active antiretroviral therapy (HAART) for the treatment of human immunodeficiency virus type 1 (HIV-1). A major problem with the first approved NNRTIs was the emergence of mutations in the HIV-1 reverse transcriptase (RT), in particular K103N and Y181C, which led to resistance to the entire class. We adopted an iterative strategy to synthesize and test small molecule inhibitors from a chemical series of pyrazoles against wild-type (wt) RT and the most prevalent NNRTI-resistant mutants. The emerging candidate, lersivirine (UK-453,061), binds the RT enzyme in a novel way (resulting in a unique resistance profile), inhibits over 60% of viruses bearing key RT mutations, with 50% effective concentrations (EC50s) within 10-fold of those for wt viruses, and has excellent selectivity against a range of human targets. Altogether lersivirine is a highly potent and selective NNRTI, with excellent efficacy against NNRTI-resistant viruses.

The Mechanical and Structural Effects of HIV Proteins on Murine Carotid Arteries

2011 ◽  
Author(s):  
Laura Hansen ◽  
Manu Platt ◽  
Roy L. Sutliff ◽  
Rudolph L. Gleason
Keyword(s):  
Cardiovascular Disease ◽  
Highly Active Antiretroviral Therapy ◽  
Intima Media Thickness ◽  
Biomechanical Properties ◽  
Cardiovascular Complications ◽  
Global Epidemic ◽  
Highly Active ◽  
Atherosclerotic Lesions ◽  
Immunodeficiency Syndrome ◽  
Hiv 1

Acquired immunodeficiency syndrome (AIDS) is considered a global epidemic with over 65 million people worldwide infected with the HIV-1 virus, the causative agent [1]. The development of highly active antiretroviral therapy (HAART) has significantly increased the life expectancy of people infected with the virus by slowing the progression to the development of AIDS. However, the treatment has also led to the emergence of early onset cardiovascular complications including myocardial infarction [2] and atherosclerotic lesions [3], as well as subclinical markers of atherosclerosis including increased carotid artery intima-media thickness [4], increased arterial stiffness [5–6], and endothelial dysfunction [6]. It appears that HAART and HIV-1-infection are independent risk factors for the development of atherosclerosis in adults [7]; however, the mechanism of disease progression remains unclear. There is a pressing need to identify mechanisms of early on-set cardiovascular disease associated with HIV-1 infection and HAART and to identify therapeutic strategies to reduce cardiovascular disease in HIV patients. The overall goal of this study is to test the hypothesis that over-expression of HIV proteins will lead to alterations in the biomechanical properties of large arteries.

Future Antiretrovirals, Immune-Based Strategies, and Therapeutic Vaccines

2017 ◽  
Author(s):  
Adrian Majid ◽  
Bruce L. Gilliam
Keyword(s):  
Clinical Trials ◽  
Highly Active Antiretroviral Therapy ◽  
Transcriptase Inhibitor ◽  
Hiv Treatment ◽  
Therapeutic Vaccines ◽  
Highly Active ◽  
Immature Virion ◽  
Tenofovir Alafenamide ◽  
Reverse Transcriptase Inhibitor ◽  
Hiv 1

Highly active antiretroviral therapy remains the mainstay of treatment for patients chronically infected with HIV. Novel drugs, both within existing classes and new ones, are in various stages of development and testing. New medications within existing classes of antiretroviral agents are in clinical trials and will likely offer activity against resistant HIV-1 strains and provide alternatives for combination pill therapy. Novel therapeutics including oral attachment inhibitors and monoclonal antibody treatments continue to show efficacy against HIV-1 and progress in clinical trials. Tenofovir alafenamide is a prodrug that produces higher intracellular levels of tenofovir diphosphate with likely less renal and bone toxicity. Among traditional classes of HIV treatment, both doravirine (a non-nucleoside reverse transcriptase inhibitor) and cabotegravir (an integrase strand inhibitor) are newer agents with activity against resistant virus. Maturation inhibitors are a new class of treatment that block protease cleavage, leading to the release of an immature virion.

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