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.
Highlights
Active antiretroviral therapy (HAART) is a combination of drugs, usually three or more from two or more classes, which serves as a means to long-term control of replication of the lentivirus, human immunodeficiency virus type 1 (HIV-1) [1,2,3]
The best fit model divided the average virus loads (VLs) upon initiation of Highly active antiretroviral therapy (HAART) (6 through 33 weeks post-infection) into three distinct phases represented by lines with slopes of 20.40 (95% Confidence Interval, CI, 20.30 to 20.50), 20.082, and 20.004
The results presented in this study demonstrate that low-level viremia persists in reverse transcriptase (RT)-SHIV-infected macaques despite treatment with a first-line HAART regimen for 28 weeks
Summary
Active antiretroviral therapy (HAART) is a combination of drugs, usually three or more from two or more classes, which serves as a means to long-term control of replication of the lentivirus, human immunodeficiency virus type 1 (HIV-1) [1,2,3]. The development of more sensitive assays has demonstrated that continued low-level viremia persists in most subjects despite many years of viral suppression by HAART [4,5,6,7]. Several hypotheses have been proposed recently to explain the persistence of HIV-1 despite suppressive HAART [10,11]. These hypotheses are not mutually exclusive, and the mechanisms of persistence might vary between individuals [12,13]. Occasional immune activation of these cells might allow for complete viral transcription and lead to assembly and release of virus, accounting for the observed low-level viremia. The observed residual viremia might continue to reseed reservoirs thereby prohibiting their decay
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