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Viral decay kinetics in the highly active antiretroviral therapy-treated rhesus macaque model of AIDS.

Deere JD, Higgins J, Cannavo E, Villalobos A, Adamson L, Fromentin E, Schinazi RF, Luciw PA, North TW - PLoS ONE (2010)

Bottom Line: Bi-phasic decay of viral RNA was also observed in these animals with half-lives of 1.8 and 5.8 days.Viral loads in these animals during a third phase ranged from 2-58 RNA copies/mL, with little decay over time.The viral decay kinetics observed in these macaques are similar to those reported for HIV-1 infected humans.

View Article: PubMed Central - PubMed

Affiliation: Center for Comparative Medicine, University of California Davis, Davis, California, United States of America.

ABSTRACT
To prevent progression to AIDS, persons infected with human immunodeficiency virus type 1 (HIV-1) must remain on highly active antiretroviral therapy (HAART) indefinitely since this modality does not eradicate the virus. The mechanisms involved in viral persistence during HAART are poorly understood, but an animal model of HAART could help elucidate these mechanisms and enable studies of HIV-1 eradication strategies. Due to the specificity of non-nucleoside reverse transcriptase (RT) inhibitors (NNRTIs) for HIV-1, we have used RT-SHIV, a chimeric virus of simian immunodeficiency virus with RT from HIV-1. This virus is susceptible to NNRTIs and causes an AIDS-like disease in rhesus macaques. In this study, two groups of HAART-treated, RT-SHIV-infected macaques were analyzed to determine viral decay kinetics. In the first group, viral loads were monitored with a standard TaqMan RT-PCR assay with a limit of detection of 50 viral RNA copies per mL. Upon initiation of HAART, viremia decayed in a bi-phasic manner with half-lives of 1.7 and 8.5 days, respectively. A third phase was observed with little further decay. In the second group, the macaques were followed longitudinally with a more sensitive assay utilizing ultracentrifugation to concentrate virus from plasma. Bi-phasic decay of viral RNA was also observed in these animals with half-lives of 1.8 and 5.8 days. Viral loads in these animals during a third phase ranged from 2-58 RNA copies/mL, with little decay over time. The viral decay kinetics observed in these macaques are similar to those reported for HIV-1 infected humans. These results demonstrate that low-level viremia persists in RT-SHIV-infected macaques despite a HAART regimen commonly used in humans.

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Analysis of suppressed RT-SHIV virus loads during HAART.(A) Comparison of variation in RT-SHIV plasma RNA loads during HAART from weeks 14–34 post-infection of the longitudinal study. Solid circles indicate RT-SHIV RNA copies/mL. Open circles indicate that the sample was below the level of detection of the ultracentrifugation virus load assay (UVLA). Median with the range. (B) Individual data from the nine HAART-treated macaques in the longitudinal study. Plasma samples were analyzed for levels of RT-SHIV RNA using the UVLA from 14–34 weeks post-infection. Solid circles indicate that RNA was detected in the assay. Open circles indicate that RNA levels were below the limit of detection of the UVLA. Mean plus standard error of the mean of single plasma samples analyzed by triplicate TaqMan RT-PCR. Some standard errors were too small to display on the graphs.
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pone-0011640-g004: Analysis of suppressed RT-SHIV virus loads during HAART.(A) Comparison of variation in RT-SHIV plasma RNA loads during HAART from weeks 14–34 post-infection of the longitudinal study. Solid circles indicate RT-SHIV RNA copies/mL. Open circles indicate that the sample was below the level of detection of the ultracentrifugation virus load assay (UVLA). Median with the range. (B) Individual data from the nine HAART-treated macaques in the longitudinal study. Plasma samples were analyzed for levels of RT-SHIV RNA using the UVLA from 14–34 weeks post-infection. Solid circles indicate that RNA was detected in the assay. Open circles indicate that RNA levels were below the limit of detection of the UVLA. Mean plus standard error of the mean of single plasma samples analyzed by triplicate TaqMan RT-PCR. Some standard errors were too small to display on the graphs.

Mentions: The VLs of each macaque from weeks 14 through 34, when viremia was suppressed below the detection limit of the SVLA, were also analyzed (Fig. 4A). A one-way ANOVA determined that the average VLs between the animals were not statistically different (p = 0.16). However, Bartlett's test for equal variances indicated that the standard deviations for the mean VLs of each animal were significantly different (p<0.0001). This result was most apparent with macaque 36348, which more consistently maintained VL suppression during HAART, with many of its plasma samples showing viral RNA levels below the detection limit of even the UVLA (Fig. 4B).


Viral decay kinetics in the highly active antiretroviral therapy-treated rhesus macaque model of AIDS.

Deere JD, Higgins J, Cannavo E, Villalobos A, Adamson L, Fromentin E, Schinazi RF, Luciw PA, North TW - PLoS ONE (2010)

Analysis of suppressed RT-SHIV virus loads during HAART.(A) Comparison of variation in RT-SHIV plasma RNA loads during HAART from weeks 14–34 post-infection of the longitudinal study. Solid circles indicate RT-SHIV RNA copies/mL. Open circles indicate that the sample was below the level of detection of the ultracentrifugation virus load assay (UVLA). Median with the range. (B) Individual data from the nine HAART-treated macaques in the longitudinal study. Plasma samples were analyzed for levels of RT-SHIV RNA using the UVLA from 14–34 weeks post-infection. Solid circles indicate that RNA was detected in the assay. Open circles indicate that RNA levels were below the limit of detection of the UVLA. Mean plus standard error of the mean of single plasma samples analyzed by triplicate TaqMan RT-PCR. Some standard errors were too small to display on the graphs.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2909142&req=5

pone-0011640-g004: Analysis of suppressed RT-SHIV virus loads during HAART.(A) Comparison of variation in RT-SHIV plasma RNA loads during HAART from weeks 14–34 post-infection of the longitudinal study. Solid circles indicate RT-SHIV RNA copies/mL. Open circles indicate that the sample was below the level of detection of the ultracentrifugation virus load assay (UVLA). Median with the range. (B) Individual data from the nine HAART-treated macaques in the longitudinal study. Plasma samples were analyzed for levels of RT-SHIV RNA using the UVLA from 14–34 weeks post-infection. Solid circles indicate that RNA was detected in the assay. Open circles indicate that RNA levels were below the limit of detection of the UVLA. Mean plus standard error of the mean of single plasma samples analyzed by triplicate TaqMan RT-PCR. Some standard errors were too small to display on the graphs.
Mentions: The VLs of each macaque from weeks 14 through 34, when viremia was suppressed below the detection limit of the SVLA, were also analyzed (Fig. 4A). A one-way ANOVA determined that the average VLs between the animals were not statistically different (p = 0.16). However, Bartlett's test for equal variances indicated that the standard deviations for the mean VLs of each animal were significantly different (p<0.0001). This result was most apparent with macaque 36348, which more consistently maintained VL suppression during HAART, with many of its plasma samples showing viral RNA levels below the detection limit of even the UVLA (Fig. 4B).

Bottom Line: Bi-phasic decay of viral RNA was also observed in these animals with half-lives of 1.8 and 5.8 days.Viral loads in these animals during a third phase ranged from 2-58 RNA copies/mL, with little decay over time.The viral decay kinetics observed in these macaques are similar to those reported for HIV-1 infected humans.

View Article: PubMed Central - PubMed

Affiliation: Center for Comparative Medicine, University of California Davis, Davis, California, United States of America.

ABSTRACT
To prevent progression to AIDS, persons infected with human immunodeficiency virus type 1 (HIV-1) must remain on highly active antiretroviral therapy (HAART) indefinitely since this modality does not eradicate the virus. The mechanisms involved in viral persistence during HAART are poorly understood, but an animal model of HAART could help elucidate these mechanisms and enable studies of HIV-1 eradication strategies. Due to the specificity of non-nucleoside reverse transcriptase (RT) inhibitors (NNRTIs) for HIV-1, we have used RT-SHIV, a chimeric virus of simian immunodeficiency virus with RT from HIV-1. This virus is susceptible to NNRTIs and causes an AIDS-like disease in rhesus macaques. In this study, two groups of HAART-treated, RT-SHIV-infected macaques were analyzed to determine viral decay kinetics. In the first group, viral loads were monitored with a standard TaqMan RT-PCR assay with a limit of detection of 50 viral RNA copies per mL. Upon initiation of HAART, viremia decayed in a bi-phasic manner with half-lives of 1.7 and 8.5 days, respectively. A third phase was observed with little further decay. In the second group, the macaques were followed longitudinally with a more sensitive assay utilizing ultracentrifugation to concentrate virus from plasma. Bi-phasic decay of viral RNA was also observed in these animals with half-lives of 1.8 and 5.8 days. Viral loads in these animals during a third phase ranged from 2-58 RNA copies/mL, with little decay over time. The viral decay kinetics observed in these macaques are similar to those reported for HIV-1 infected humans. These results demonstrate that low-level viremia persists in RT-SHIV-infected macaques despite a HAART regimen commonly used in humans.

Show MeSH
Related in: MedlinePlus