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. 2017 Sep 28;9(10):277.
doi: 10.3390/v9100277.

Effects of Amprenavir on HIV-1 Maturation, Production and Infectivity Following Drug Withdrawal in Chronically-Infected Monocytes/Macrophages

Ana Borrajo  1   2 , Alessandro Ranazzi  3 , Michela Pollicita  4 , Rosalinda Bruno  5 , Andrea Modesti  6 , Claudia Alteri  7 , Carlo Federico Perno  8 , Valentina Svicher  9 , Stefano Aquaro  10
Affiliations

Effects of Amprenavir on HIV-1 Maturation, Production and Infectivity Following Drug Withdrawal in Chronically-Infected Monocytes/Macrophages

Ana Borrajo et al. Viruses. .

Abstract

A paucity of information is available on the activity of protease inhibitors (PI) in chronically-infected monocyte-derived macrophages (MDM) and on the kinetics of viral-rebound after PI removal in vitro. To fill this gap, the activity of different concentrations of amprenavir (AMP) was evaluated in chronically-infected MDM by measuring p24-production every day up to 12 days after drug administration and up to seven days after drug removal. Clinically-relevant concentrations of AMP (4 and 20 μM) drastically decreased p24 amount released from chronically-infected MDM from Day 2 up to Day 12 after drug administration. The kinetics of viral-rebound after AMP-removal (4 and 20 μM) showed that, despite an initial increase, p24-production over time never reached the level observed for untreated-MDM, suggesting a persistent intracellular drug activity. In line with this, after AMP-removal, human immunodeficiency virus 1 (HIV-1) infectivity and intracellular the p24/p55 ratio (reflecting virion-maturation) were remarkably lower than observed for untreated MDM. Overall, AMP shows high efficacy in blocking HIV-1 replication in chronically-infected MDM, persisting even after drug-removal. This highlights the role of protease inhibitors in preventing the establishment of this important HIV-1 reservoir, thus reducing viral-dissemination in different anatomical compartments.

Keywords: Human immunodeficiency virus; amprenavir; monocytes/macrophages; protease inhibitors.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Kinetics of human immunodeficiency virus 1 (HIV-1) p24 gag Ag production in supernatants from HIV-1 chronically-infected monocyte-derived macrophages (MDM) treated with different doses of amprenavir (AMP). On Day 10 after infection, when HIV-1 infection becomes chronic, the drug was added to chronically-infected MDM. The figure reports data from a single experiment (each time point run at least in triplicate), which is representative of three different experiments.
Figure 2
Figure 2
Photographs of electron microscopy representing: (A) viral particles contained in cytoplasmatic vacuoles in untreated HIV-1-infected macrophage; (B) immature virus particles contained in cytoplasmatic vacuoles in AMP-treated HIV-1-infected MDM.
Figure 3
Figure 3
Kinetics of HIV-1 p24 rebound after AMP removal. HIV-1 p24 was measured in culture supernatants at 12, 24, 48 and 72 h after drug-removal from the supernatants of HIV-1 chronically-infected MDM. TI: treatment-interruption.
Figure 4
Figure 4
(A) Reduction of HIV-1 p24 production at three and seven days after drug removal in chronically-infected MDM. Statistical analysis was performed by the χ2 test. * p < 0.001; (B) HIV-1 titers (expressed as TCID50/mL) determined using supernatants from untreated HIV-1-infected MDM, AMP-treated HIV-1-infected MDM and HIV-1-infected MDM in which the drug was removed. Statistical analysis was performed by the χ2 test. * p < 0.001. DR: drug-removed.
Figure 5
Figure 5
(A) Effects of AMP removal on p24 maturation in HIV-1 BaL chronically-infected MDM. p24 maturation was expressed as the ratio of p24 amount on p55 amount in cell lysates. p24 and p55 amounts were determined by ELISA; (B) western blot analysis showing p24 and p55 amount detected in cell lysates from chronically-infected macrophages. * Indicates the removal of AMP. In (A,B), the following experimental conditions were tested: Group 1, 18th day infection and 7th day treatment; Group 2, 18.5th day infection and 7.5th day treatment; Group 3, 19th day infection and 8th day treatment. HIV-1 BaL refers to an HIV-1 strain isolated from alveolar macrophages by a bronchoalveolar lavage.
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