RT-SHIV subpopulation dynamics in infected macaques during anti-HIV therapy

Advanced Biomedical Computing Center, SAIC Frederick, Inc, National Cancer Institute at Frederick, Frederick, MD, USA.
Retrovirology (Impact Factor: 4.19). 11/2009; 6(1):101. DOI: 10.1186/1742-4690-6-101
Source: PubMed


To study the dynamics of wild-type and drug-resistant HIV-1 RT variants, we developed a methodology that follows the fates of individual genomes over time within the viral quasispecies. Single genome sequences were obtained from 3 pigtail macaques infected with a recombinant simian immunodeficiency virus containing the RT coding region from HIV-1 (RT-SHIV) and treated with short-course efavirenz monotherapy 13 weeks post-infection followed by daily combination antiretroviral therapy (ART) beginning at week 17. Bioinformatics tools were constructed to trace individual genomes from the beginning of infection to the end of the treatment.
A well characterized challenge RT-SHIV inoculum was used to infect three monkeys. The RT-SHIV inoculum had 9 variant subpopulations and the dominant subpopulation accounted for 80% of the total genomes. In two of the three monkeys, the inoculated wild-type virus was rapidly replaced by new wild type variants. By week 13, the original dominant subpopulation in the inoculum was replaced by new dominant subpopulations, followed by emergence of variants carrying known NNRTI resistance mutations. However, during ART, virus subpopulations containing resistance mutations did not outgrow the wide-type subpopulations until a minor subpopulation carrying linked drug resistance mutations (K103N/M184I) emerged. We observed that persistent viremia during ART is primarily made up of wild type subpopulations. We also found that subpopulations carrying the V75L mutation, not known to be associated with NNRTI resistance, emerged initially in week 13 in two macaques. Eventually, all subpopulations from these two macaques carried the V75L mutation.
This study quantitatively describes virus evolution and population dynamics patterns in an animal model. The fact that wild type subpopulations remained as dominant subpopulations during ART treatment suggests that the presence or absence of at least some known drug resistant mutations may not greatly affect virus replication capacity in vivo. Additionally, the emergence and prevalence of V75L indicates that this mutation may provide the virus a selective advantage, perhaps escaping the host immure system surveillance. Our new method to quantitatively analyze viral population dynamics enabled us to observe the relative competitiveness and adaption of different viral variants and provided a valuable tool for studying HIV subpopulation emergence, persistence, and decline during ART.

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Available from: Robert M Stephens, Jun 10, 2015
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    • "Due to a low sensitivity of simian immunodeficiency virus (SIV) to non-nucleoside reverse transcriptase inhibitors (NNRTIs) and some nucleoside reverse transcriptase inhibitors (NRTIs), especially for post-exposure prophylaxis (PEP), a number of RT-SHIV strains have been constructed to evaluate the activity of HIV-specific drugs and microbicides both in vitro and in macaques [4-8]. RT-SHIV carry HIV-1 reverse transcriptase (RT) gene, which is the target of NNRTIs and NRTIs, suitable for evaluating the efficacy of HIV RT inhibitors in macaques [1,9]. Up to now, RT-SHIV is commonly used to study the effect of highly active antiretroviral therapy (HAART) and antiviral resistance in India origin rhesus macaques (In RM) [1], pigtailed monkey [9,10], and Chinese-origin rhesus macaques (Ch RM) [11]. "
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    ABSTRACT: The precise efficacy of nucleoside analogue reverse-transcriptase inhibitors (NRTIs) in preventing and inhibiting virus replication remains unknown in RT-SHIV infected Chinese-origin rhesus macaques (Ch RM). Ch RM were inoculated intravenously with 200 TCID50 RT-SHIV and treated by gavage with NRTIs (20 mg AZT and 10 mg 3TC twice per day) for four consecutive weeks beginning at one hour, on day 217 or 297 post inoculation, respectively. Treatment with AZT/3TC inhibited transiently RT-SHIV replication during chronic infection, but did not significantly affect peripheral blood CD4+ T cells in macaques. Treatment with AZT/3TC at 1 hour post infection prevented RT-SHIV infection in two out of four animals during the 120-day observation period. Therefore, the Ch RM model with RT-SHIV infection can be used to evaluate the efficacy of new NRTIs.
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    • "The poor response of the laboratory simian lentiviruses to NNRTIs prompted some to replace the reverse transcriptase (RT) gene of the simian lentivirus with a gene encoding HIV-1 RT [18]. This substitution is extremely useful for studying the occurrence of drug resistance mutations in vivo [19], and for preclinical testing of novel NRTIs. However, an impact of the RT substitution on the natural history of the disease cannot be excluded so far. "
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    ABSTRACT: RNA viruses replicate as complex mutant spectra, also termed ‘mutant clouds’, known as viral quasispecies. While this is a widely observed viral population structure, it is less known that a number of biologically relevant features of this important group of viral pathogens depend on (or are strongly influenced by) the complexity and composition of mutant spectra. Among them, fitness increase or decrease depending on intrapopulation complementation or interference, selection triggered by memory genomes, pathogenic potential of viruses, disease evolution and the response to antiviral treatments. Quasispecies represent the recognition of complex behavior in viruses, and it is an oversimplification to equate such a population structure with the classic polymorphism of population biology. Darwinian principles acting on genome collectivities that replicate with high error rates provide a unique population structure prone to flexible and largely unpredictable behavior.
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