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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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RT-SHIV viral decay kinetics of HAART-treated macaques.The average plasma virus load of 9 RT-SHIV-infected, HAART-treated macaques using the standard virus load assay (SVLA). Colored lines indicate linear regression analysis. Error bars indicate standard error of the mean. The dashed line indicates the limit of detection of the SVLA (50 RNA copies/mL).
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pone-0011640-g001: RT-SHIV viral decay kinetics of HAART-treated macaques.The average plasma virus load of 9 RT-SHIV-infected, HAART-treated macaques using the standard virus load assay (SVLA). Colored lines indicate linear regression analysis. Error bars indicate standard error of the mean. The dashed line indicates the limit of detection of the SVLA (50 RNA copies/mL).

Mentions: In the first study, VLs were monitored throughout treatment using the SVLA. Upon initiation of HAART, the average VL decayed to the limit of detection of the SVLA (Fig. 1). The value of 50 RNA copies/mL was used to calculate the average when RNA was not detected using the SVLA. All nine treated animals eventually achieved a VL below the limit of detection of the SVLA, with occasional positive samples. Linear regression analysis of the average VL over the duration of HAART was performed (Fig.1). The best fit model divided the average VL upon initiation of HAART (6 through 33 weeks post-infection) into three distinct phases represented by lines with slopes of −0.40 (95% Confidence Interval, CI, −0.30 to −0.50), −0.082 (95% CI −0.06 to −0.11), and −0.004 (95% CI −0.0009 to −0.009; p = 0.02). Due to the exponential nature of the viral decay, as described by Ho et al. for HIV-1 [14], the viral half-lives based upon these slopes were estimated to be 1.7 (95% CI 1.4 to 2.3), 8.5 (95% CI 6.3 to 11.6), and 170 (95% CI 77 to 170) days, respectively (Table 1). These data demonstrate that upon initiation of HAART, viremia decays in a bi-phasic manner to the limit of detection of the SVLA. However, the third phase of viral decay is only an estimate because most of the samples during the third phase were below the limit of detection of the SVLA and were assigned the value of 50 RNA copies/mL for the purpose of calculations.


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)

RT-SHIV viral decay kinetics of HAART-treated macaques.The average plasma virus load of 9 RT-SHIV-infected, HAART-treated macaques using the standard virus load assay (SVLA). Colored lines indicate linear regression analysis. Error bars indicate standard error of the mean. The dashed line indicates the limit of detection of the SVLA (50 RNA copies/mL).
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2909142&req=5

pone-0011640-g001: RT-SHIV viral decay kinetics of HAART-treated macaques.The average plasma virus load of 9 RT-SHIV-infected, HAART-treated macaques using the standard virus load assay (SVLA). Colored lines indicate linear regression analysis. Error bars indicate standard error of the mean. The dashed line indicates the limit of detection of the SVLA (50 RNA copies/mL).
Mentions: In the first study, VLs were monitored throughout treatment using the SVLA. Upon initiation of HAART, the average VL decayed to the limit of detection of the SVLA (Fig. 1). The value of 50 RNA copies/mL was used to calculate the average when RNA was not detected using the SVLA. All nine treated animals eventually achieved a VL below the limit of detection of the SVLA, with occasional positive samples. Linear regression analysis of the average VL over the duration of HAART was performed (Fig.1). The best fit model divided the average VL upon initiation of HAART (6 through 33 weeks post-infection) into three distinct phases represented by lines with slopes of −0.40 (95% Confidence Interval, CI, −0.30 to −0.50), −0.082 (95% CI −0.06 to −0.11), and −0.004 (95% CI −0.0009 to −0.009; p = 0.02). Due to the exponential nature of the viral decay, as described by Ho et al. for HIV-1 [14], the viral half-lives based upon these slopes were estimated to be 1.7 (95% CI 1.4 to 2.3), 8.5 (95% CI 6.3 to 11.6), and 170 (95% CI 77 to 170) days, respectively (Table 1). These data demonstrate that upon initiation of HAART, viremia decays in a bi-phasic manner to the limit of detection of the SVLA. However, the third phase of viral decay is only an estimate because most of the samples during the third phase were below the limit of detection of the SVLA and were assigned the value of 50 RNA copies/mL for the purpose of calculations.

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