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. 2012 Oct;86(20):11368-72.
doi: 10.1128/JVI.01563-12. Epub 2012 Aug 8.

A Quantitative Measurement of Antiviral Activity of Anti-Human Immunodeficiency Virus Type 1 Drugs Against Simian Immunodeficiency Virus Infection: Dose-Response Curve Slope Strongly Influences Class-Specific Inhibitory Potential

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A Quantitative Measurement of Antiviral Activity of Anti-Human Immunodeficiency Virus Type 1 Drugs Against Simian Immunodeficiency Virus Infection: Dose-Response Curve Slope Strongly Influences Class-Specific Inhibitory Potential

Kai Deng et al. J Virol. .
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Abstract

Simian immunodeficiency virus (SIV) infection in macaques is so far the best animal model for human immunodeficiency virus type 1 (HIV-1) studies, but suppressing viral replication in infected animals remains challenging. Using a novel single-round infectivity assay, we quantitated the antiviral activities of antiretroviral drugs against SIV. Our results emphasize the importance of the dose-response curve slope in determining the inhibitory potential of antiretroviral drugs and provide useful information for regimen selection in treating SIV-infected animals in models of therapy and virus eradication.

Figures

Fig 1
Fig 1
A single-round SIV infectivity assay for quantitation of antiviral activity in vitro. (A) Proviral construct used to generate pseudotyped SIV for infections. The GFP coding sequence was inserted into the nef gene. Stop codons were introduced into the N-terminal region of the env gene (at nucleotide position 171 or 272), to render the viruses capable of only a single round of infection. (B) Detection of gp160 and gp120 in concentrated virions by Western blot analysis. The indicated proviral constructs were transfected alone or with an env expression plasmid into HEK293T cells. Concentrated virion preparations were made by ultracentrifugation of the supernatant from transfected cells. The envelope protein (gp160/gp120) was detected by blotting with a polyclonal antibody (Abcam). (C) Expression of GFP by infected CD4+ T cells. Concentrated virions were used to infect primary rhesus macaque CD4+ T cells. Representative dot plots of GFP expression are shown for virions made by transfecting a proviral construct alone (left) or together with an env expression plasmid (right). PerCP, peridinin chlorophyll protein.
Fig 2
Fig 2
Measurement of IC50 and m using single-round infectivity assay. (A) Log-log dose-response curve for the integrase inhibitor L870812. Each point represents the mean from more than three experiments. The IC50 of L870812 is shown by the arrow. (B) Linearized dose-response curve for L870812 based on median effect model. The IC50 of L870812 is shown by the arrow. (C) Representative flow cytometry plots showing detection of cells that were infected in the absence (left) or presence (right) of 1 μM L870812. (D) Log-log dose-response curve for the protease inhibitor ATV. Each point represents the mean from more than three experiments. The IC50 of ATV is shown by the arrow. (E) Linearized dose-response curve for ATV based on median effect model. The IC50 of ATV is shown by the arrow. (F) Representative flow cytometry plots showing detection of cells that were infected with virions generated in the absence (left) or presence (right) of 1 μM ATV.
Fig 3
Fig 3
IC50 and m values of anti-HIV-1 drugs against SIV infection in vitro. (A) The IC50s of anti-HIV drugs from different classes. Values for the NNRTIs were all greater than 100 μM, the highest concentration tested, and are not shown. (B) m values for antiretroviral drugs from different classes. Definitions for drug name abbreviations are as follows: 3TC, lamivudine; ABC, abacavir; AZT, zidovudine; d4T, stavudine; ddI, didanosine; FTC, emtricitabine; TDF, tenofovir disoproxil fumarate; ATV, atazanavir; APV, amprenavir; DRV, darunavir; IDV, indinavir; LPV, lopinavir; NFV, nelfinavir; SQV, saquinavir; TPV, tipranavir; T20, enfuvirtide; RAL, raltegravir; EFV, efavirenz; NVP, nevirapine; TMC125, etravirine.
Fig 4
Fig 4
Estimated IIPmax values ± standard deviations for five representative drugs against SIV infection in rhesus macaques. The values were calculated using equation 3. Here D is the maximum concentration of the drug in plasma at the doses used to treat experimental SIV infection.

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