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Rapid Screening of HIV Reverse Transcriptase and Integrase Inhibitors
Published on: April 9, 2014
Host factors and efficacy of antiretroviral treatment
1Department of Experimental Medicine and Pathology, Virology Section, University La Sapienza, Rome, Italy.
Abstract:
It has been proposed that some host factors may affect the intracellular drug concentration leading to the inability of drug regimens to inhibit human immunodeficiency virus (HIV) replication in cells. Among them, two factors, whose description is the main aim of this review, have been considered during the last years with particular emphasis. They are: i) altered uptake and reduced activation of nucleoside reverse transcriptase inhibitors (NRTIs) in target cells, and ii) efflux of NRTIs and protease inhibitors (PIs) by cellular transporter molecules. In fact, several authors have shown that: changes in the activity of various purine and pyrimidine biosynthetic enzymes may occur in lymphocytes of HIV-infected patients; HIV-infected patients on prolonged treatment with nucleoside analogs, such as zidovudine, show significantly decreased activity of thymidine kinase compared to untreated HIV-infected persons; NRTI and PIs are substrates for the so-called multidrug membrane transporters. With regard to the latter issue, it is known that the ATP-binding cassette transporter proteins such as the P glycoprotein, and the newly discovered family of multidrug resistance-associated proteins (MRP 1-9) promote the active extracellular efflux of a wide variety of therapeutics and overexpression of some of them lowers intracellular concentration of PIs. In the very near future such mechanisms, called by most authors "cellular drug-resistance", might be taken into account, together with other immunological, virological and behavioral factors, to explain "drug failure" and/or the variability of response in HIV patients undergoing an antiretroviral treatment.
Insights
Host factors like altered drug uptake and efflux by transporters can reduce intracellular drug concentrations, impacting human immunodeficiency virus (HIV) treatment efficacy. Understanding these cellular drug resistance mechanisms is key to addressing antiretroviral treatment variability in HIV patients.
Area of Science:
- Pharmacology
- Virology
- Cell Biology
Background:
- Host factors can influence intracellular antiretroviral drug concentrations, potentially leading to treatment failure in human immunodeficiency virus (HIV) replication.
- Two primary host factors are implicated: altered uptake and activation of nucleoside reverse transcriptase inhibitors (NRTIs) and efflux of NRTIs and protease inhibitors (PIs) by cellular transporters.
- Changes in purine/pyrimidine biosynthetic enzymes and decreased thymidine kinase activity are observed in HIV-infected patients, particularly those on long-term NRTI therapy.
Purpose of the Study:
- To review the role of host factors, specifically altered NRTI uptake/activation and transporter-mediated drug efflux, in HIV treatment outcomes.
- To highlight the significance of cellular drug resistance mechanisms in explaining variable responses to antiretroviral therapy.
- To emphasize the potential impact of these factors on the efficacy of NRTI and PI drug regimens.
Main Methods:
- Literature review focusing on studies investigating host factors affecting intracellular drug concentrations in HIV-infected individuals.
- Analysis of research on nucleoside reverse transcriptase inhibitors (NRTIs) and protease inhibitors (PIs) metabolism and transport.
- Examination of the role of ATP-binding cassette transporters, including P-glycoprotein and multidrug resistance-associated proteins (MRPs), in drug efflux.
Main Results:
- Altered uptake and reduced activation of NRTIs can decrease intracellular drug levels necessary for inhibiting HIV replication.
- NRTI and PIs are substrates for multidrug membrane transporters, such as P-glycoprotein and MRPs.
- Overexpression of certain transporters can lead to lower intracellular concentrations of PIs, contributing to cellular drug resistance.
Conclusions:
- Cellular drug resistance mechanisms, including altered drug uptake/activation and active efflux by transporters, are critical factors in HIV treatment failure.
- These host-mediated mechanisms, alongside immunological, virological, and behavioral factors, are essential for understanding antiretroviral treatment variability.
- Future HIV treatment strategies may need to account for these cellular drug resistance mechanisms to optimize therapeutic outcomes.
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