Clinical Significance of Human Immunodeficiency Virus Type 1 Replication Fitness

Infectious Diseases Division, Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA.
Clinical Microbiology Reviews (Impact Factor: 17.41). 11/2007; 20(4):550-78. DOI: 10.1128/CMR.00017-07
Source: PubMed


The relative fitness of a variant, according to population genetics theory, is that variant's relative contribution to successive generations. Most drug-resistant human immunodeficiency virus type 1 (HIV-1) variants have reduced replication fitness, but at least some of these deficits can be compensated for by the accumulation of second-site mutations. HIV-1 replication fitness also appears to influence the likelihood of a drug-resistant mutant emerging during treatment failure and is postulated to influence clinical outcomes. A variety of assays are available to measure HIV-1 replication fitness in cell culture; however, there is no agreement regarding which assays best correlate with clinical outcomes. A major limitation is that there is no high-throughput assay that incorporates an internal reference strain as a control and utilizes intact virus isolates. Some retrospective studies have demonstrated statistically significant correlations between HIV-1 replication fitness and clinical outcomes in some patient populations. However, different studies disagree as to which clinical outcomes are most closely associated with fitness. This may be in part due to assay design, sample size limitations, and differences in patient populations. In addition, the strength of the correlations between fitness and clinical outcomes is modest, suggesting that, at present, it would be difficult to utilize these assays for clinical management.

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    • "Ordinary differential equation based models have been developed to estimate the replication dynamics of two competing virus variants (Goudsmit et al., 1997; Bonhoeffer et al., 2002; Maré e et al., 2000). Wu et al. (2006) extended the basic framework proposed by previous models to estimate viral kinetic and fitness parameters for the flow cytometry-based growth competition assay developed by Dykes and Demeter (2007). The model was further improved by Miao et al. (2008) by allowing for dual infections of target cells as well as a time-varying target cell population. "
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    ABSTRACT: A common approach to understand and analyze complex biological systems is to describe the dynamics in terms of a system of ordinary differential equations (ODE) depending on numerous biologically meaningful and descriptive parameters that are estimated using observed data. The ODE models are often based on the implicit assumption of well-mixed dynamics, i.e., the delay of interaction due to spatial distribution is not included in the model. In this article, we address the question how the heterogeneity of the underlying system affects the estimated parameter values of the ODE model, and on the other hand, what information about the microscopic system can be drawn from these values. The system we are considering is a pairwise growth competition assay used to quantify ex vivo replicative fitness of different HIV-1 isolates. To overcome the lack of ground truth, we generate data using a detailed microscopic spatially distributed hybrid stochastic-deterministic (HSD) infection model in which the dynamics is controlled by parameters directly related to cell level infection, virus production processes, and diffusion of virus particles. The synthetic data sets are then analyzed using an ODE based well-mixed model, in which the corresponding macroscopic parameter distributions are estimated using Markov chain Monte Carlo (MCMC) methods. This approach provides a comprehensive picture of the statistical dependencies of the model parameter across different scales.
    Bulletin of Mathematical Biology 02/2014; 76(2). DOI:10.1007/s11538-013-9926-2 · 1.39 Impact Factor
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    • "Therefore, viral fitness was assayed in peripheral blood mononuclear cells (PBMCs), in the presence of AZT and tenofovir. The lower nucleotide concentrations found in primary human PBMCs facilitate the detection of minor differences in virus replication efficiencies [40]. Mutants M41L/L210W/T215Y and M41L/L210W/T215Y/R284K grown in PBMCs in the absence of drugs showed decreased replication capacity compared to the WT virus (Figure 2). "
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    ABSTRACT: Background Thymidine analogue resistance mutations (TAMs) selected under treatment with nucleoside analogues generate two distinct genotypic profiles in the HIV-1 reverse transcriptase (RT): (i) TAM1: M41L, L210W and T215Y, and (ii) TAM2: D67N, K70R and K219E/Q, and sometimes T215F. Secondary mutations, including thumb subdomain polymorphisms (e.g. R284K) have been identified in association with TAMs. We have identified mutational clusters associated with virological failure during salvage therapy with tenofovir/emtricitabine-based regimens. In this context, we have studied the role of R284K as a secondary mutation associated with mutations of the TAM1 complex. Results The cross-sectional study carried out with >200 HIV-1 genotypes showed that virological failure to tenofovir/emtricitabine was strongly associated with the presence of M184V (P < 10-10) and TAMs (P < 10-3), while K65R was relatively uncommon in previously-treated patients failing antiretroviral therapy. Clusters of mutations were identified, and among them, the TAM1 complex showed the highest correlation coefficients. Covariation of TAM1 mutations and V118I, V179I, M184V and R284K was observed. Virological studies showed that the combination of R284K with TAM1 mutations confers a fitness advantage in the presence of zidovudine or tenofovir. Studies with recombinant HIV-1 RTs showed that when associated with TAM1 mutations, R284K had a minimal impact on zidovudine or tenofovir inhibition, and in their ability to excise the inhibitors from blocked DNA primers. However, the mutant RT M41L/L210W/T215Y/R284K showed an increased catalytic rate for nucleotide incorporation and a higher RNase H activity in comparison with WT and mutant M41L/L210W/T215Y RTs. These effects were consistent with its enhanced chain-terminated primer rescue on DNA/DNA template-primers, but not on RNA/DNA complexes, and can explain the higher fitness of HIV-1 having TAM1/R284K mutations. Conclusions Our study shows the association of R284K and TAM1 mutations in individuals failing therapy with tenofovir/emtricitabine, and unveils a novel mechanism by which secondary mutations are selected in the context of drug-resistance mutations.
    Retrovirology 08/2012; 9(1):68. DOI:10.1186/1742-4690-9-68 · 4.19 Impact Factor
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    • "The only promoter that dictates the transcription of a reporter gene is the internal promoter CMV. Thus, the expression of GFP protein is a reliable indicator of HIV-1 replication [41]. It is also important to distinguish specific antiretroviral activity from non-specific inhibitor effects or DWE-mediated cytotoxicity. "
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    ABSTRACT: Acquired immunodeficiency syndrome (AIDS), which is caused by the human immunodeficiency virus (HIV), is an immunosuppressive disease that results in life-threatening opportunistic infections. The general problems in current therapy include the constant emergence of drug-resistant HIV strains, adverse side effects and the unavailability of treatments in developing countries. Natural products from herbs with the abilities to inhibit HIV-1 life cycle at different stages, have served as excellent sources of new anti-HIV-1 drugs. In this study, we aimed to investigate the anti-HIV-1 activity of aqueous dandelion extract. The pseudotyped HIV-1 virus has been utilized to explore the anti-HIV-1 activity of dandelion, the level of HIV-1 replication was assessed by the percentage of GFP-positive cells. The inhibitory effect of the dandelion extract on reverse transcriptase activity was assessed by the reverse transcriptase assay kit. Compared to control values obtained from cells infected without treatment, the level of HIV-1 replication and reverse transcriptase activity were decreased in a dose-dependent manner. The data suggest that dandelion extract has a potent inhibitory activity against HIV-1 replication and reverse transcriptase activity. The identification of HIV-1 antiviral compounds from Taraxacum officinale should be pursued. The dandelion extract showed strong activity against HIV-1 RT and inhibited both the HIV-1 vector and the hybrid-MoMuLV/MoMuSV retrovirus replication. These findings provide additional support for the potential therapeutic efficacy of Taraxacum officinale. Extracts from this plant may be regarded as another starting point for the development of an antiretroviral therapy with fewer side effects.
    BMC Complementary and Alternative Medicine 11/2011; 11(1):112. DOI:10.1186/1472-6882-11-112 · 2.02 Impact Factor
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