Viral Decay Rates Research Articles

Benthic and Pelagic Viral Decay Experiments: a Model-Based Analysis and Its Applicability

The viral decay in sediments, that is, the decrease in benthic viral concentration over time, was recorded after inhibiting the production of new viruses. Assuming that the viral abundance in an aquatic system remains constant and that viruses from lysed bacterial cells replace viruses lost by decay, the decay of viral particles can be used as a measure of viral production. Decay experiments showed that this approach is a useful tool to assess benthic viral production. However, the time course pattern of the decay experiments makes their interpretation difficult, regardless of whether viral decay is determined in the water column or in sediments. Different curve-fitting approaches (logarithmic function, power function, and linear regression) to describe the time course of decay experiments found in the literature are used in the present study and compared to a proposed "exponential decay" model based on the assumption that at any moment the decay is proportional to the amount of viruses present. Thus, an equation of the form dVA/dt = -k x VA leading to the time-integrated form VAt = VA0 x e(-k x t) was used, where k represents the viral decay rate (h(-1)), VAt is the viral abundance (viral particles ml(-1)) at time t (h), and VA0 is the initial viral abundance (viral particles ml(-1)). This approach represents the best solution for an accurate curve fitting based on a mathematical model for a realistic description of viral decay occurring in aquatic systems. Decay rates ranged from 0.0282 to 0.0696 h(-1) (mean, 0.0464 h(-1)). Additionally, a mathematical model is presented that enables the quantification of the viral control of bacterial production. The viral impact on bacteria based on decay rates calculated from the different mathematical approaches varied widely within one and the same decay experiment. A comparison of the viral control of bacterial production in different aquatic environments is, therefore, improper when different mathematical formulas are used to interpret viral decay experiments.

Effects of freezing and storage temperature on MS2 viability

Monitoring human enteric virus levels in domestic wastewater effluent is crucial to protecting human health. Occasionally, during intensive sampling, wastewater samples must be stored for later viral analysis. Little data exist regarding how enteric viruses survive during storage at different temperatures in secondary treated wastewater. During a field-scale study assessing pathogen removal performance by various onsite treatment technologies, the MS2 bacteriophage, an indicator of enteric viruses, was inoculated into septic tank (STE), sand filter, peat filter and constructed wetland (CW) effluents to determine virus decay at various storage temperatures. Virus stored at temperatures ≥10 °C and at −20 °C decayed nearly twice as fast as those stored at 4 °C or −80 °C. Decreased water quality decreased viral decay rates at 4 °C and −80 °C, with slowest decay occurring in STE and the fastest in sterile PBS and low pH peat effluent. In CW effluent after 8 days, less MS2 was inactivated when stored at 4 °C (20%) compared to −80 °C (58%); however, during extended storage (∼300 days), less MS2 was inactivated at −80 °C (75%) compared) to 4 °C (93%). We recommend that viruses in wastewater be stored in the dark at 4 °C unless storage for >40 days is necessary.

Development of anti-retroviral resistance of HIV-1 infected individuals on therapy: is it inevitable?

Highly active antiretroviral therapy directed against HIV-1 has dramatically modified morbidity and mortality in infected individuals. Enthusiasm for the success of these medications have been tempered by an inability to clear virus from the infected host leaving a virus poised to leverage any advantage into one of productive survival. One mechanism used to accomplish escape from suppression secondary to antiretroviral therapy is by developing mutations. The goal of therapy has been to diminish viral replication, thereby effectively abrogating the development of these resistance-bearing mutations. This strategy has met with significant success but numerous host-viral factors impact on the ability of the clinician to persistently suppress viral load, thereby providing a window of opportunity for the virus to mutate. In particular we review evidence for ongoing viral replication in the face of suppressive antiretroviral therapy and viral replication in tissue compartments. We discuss whether viral resistance can develop during transient elevations in viral load (viral blips) or as a function of the rate of viral load decay while on therapy. Finally, we touch on the therapeutic strategy that diminished viral replication capacity of mutational species can maintain host immunity.

Comparison of Linear, Nonlinear and Semiparametric Mixed‐effects Models for Estimating HIV Dynamic Parameters

AbstractThe potency of antiretroviral agents in AIDS clinical trials can be assessed on the basis of an early viral response such as viral decay rate or change in viral load (number of copies of HIV RNA) of the plasma. Linear, parametric nonlinear, and semiparametric nonlinear mixed‐effects models have been proposed to estimate viral decay rates in viral dynamic models. However, before applying these models to clinical data, a critical question that remains to be addressed is whether these models produce coherent estimates of viral decay rates, and if not, which model is appropriate and should be used in practice. In this paper, we applied these models to data from an AIDS clinical trial of potent antiviral treatments and found significant incongruity in the estimated rates of reduction in viral load. Simulation studies indicated that reliable estimates of viral decay rate were obtained by using the parametric and semiparametric nonlinear mixed‐effects models. Our analysis also indicated that the decay rates estimated by using linear mixed‐effects models should be interpreted differently from those estimated by using nonlinear mixed‐effects models. The semiparametric nonlinear mixed‐effects model is preferred to other models because arbitrary data truncation is not needed. Based on real data analysis and simulation studies, we provide guidelines for estimating viral decay rates from clinical data. (© 2004 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)

An open-label assessment of TMC 125--a new, next-generation NNRTI, for 7 days in HIV-1 infected individuals with NNRTI resistance.

The development of resistance to any of the currently licensed non-nucleoside reverse transcriptase inhibitors (NNRTI) invariably leads to cross-resistance to the drugs in that class. New NNRTI, that have the promise of being active even when such 'signature' mutations are present, are in development. Such novel therapies could be effective after current NNRTI failure as there would probably be no cross-resistance. We assessed the short-term efficacy and safety of a next generation NNRTI, TMC 125, a diarylpyrimidine derivative that has in vitro activity against NNRTI resistant HIV-1. TMC 125 was studied in HIV-1 infected patients with high-level phenotypic NNRTI resistance in an open-label phase IIa trial. Sixteen individuals receiving an NNRTI-containing antiretroviral regimen (efavirenz or nevirapine) with an HIV-1 RNA viral load of > 2000 copies/ml and phenotypic resistance to NNRTI, received TMC 125 for 7 days, as a substitute for their current NNRTI in their failing therapy. Full pharmacokinetic profiles were investigated. The primary end point--viral load decay rate per day--was 0.13 log10 RNA copies/ml per day. Over 7 days, we observed a median 0.89 log10 decrease in HIV-1 viral load; seven individuals (44%) had a decrease of > 1 log10. The most significant adverse effects were grade I diarrhoea (31%) and a mild headache (25%). Steady-state drug levels were achieved by day 6. TMC 125, a next generation NNRTI, is well tolerated and demonstrates significant and rapid antiviral activity in patients with high levels of phenotypic NNRTI resistance to current NNRTI.

Missing Time-Dependent Covariates in Human Immunodeficiency Virus Dynamic Models

Summary The study of human immunodeficiency virus dynamics is one of the most important areas in research into acquired immune deficiency syndrome in recent years. Non-linear mixed effects models have been proposed for modelling viral dynamic processes. A challenging problem in the modelling is to identify repeatedly measured (time-dependent), but possibly missing, immunologic or virologic markers (covariates) for viral dynamic parameters. For missing time-dependent covariates in non-linear mixed effects models, the commonly used complete-case, mean imputation and last value carried forward methods may give misleading results. We propose a three-step hierarchical multiple-imputation method, implemented by Gibbs sampling, which imputes the missing data at the individual level but can pool information across individuals. We compare various methods by Monte Carlo simulations and find that the multiple-imputation method proposed performs the best in terms of bias and mean-squared errors in the estimates of covariate coefficients. By applying the favoured multiple-imputation method to clinical data, we conclude that there is a negative correlation between the viral decay rate (a virological response parameter) and CD4 or CD8 cell counts during the treatment; this is counter-intuitive, but biologically interpretable on the basis of findings from other clinical studies. These results may have an important influence on decisions about treatment for acquired immune deficiency syndrome patients.

Uneven growth and different susceptibility to viruses among bacteria increase estimates of virus production in the East Sea based on TEM observation

We developed a theory that uneven distribution of bacterial growth rates and different susceptibility to viral infection in bacterial community could result in higher estimates of virus production based on transmission electron microscopy (TEM) observation (VP TEM ) compared to estimates obtained by neglecting uneven growth and different susceptibilities in the bacterial community. We tested this idea by classifying bacteria into 4 groups based on morphotypes (i.e. rods, cocci, curved shapes, and spirillae) and enumerating the frequency of visibly infected cells (FVIC) and the frequency of dividing cells (FDC; an indirect measure of the growth rates) in the 4 groups in the East Sea samples (n = 15). FVIC and FDC varied between different morphotypes and were highest in cocci. Further, FVIC and estimated growth rates of bacterial morphotypes were significantly correlated. The presence of a fast-growing bacterial group (apparently more susceptible to viral infection) in the bacterial community substantially increased (1.2 to 2.8-fold) the estimates of VP TEM in comparison to those obtained by using the mean growth rate of the bacterial community. Until now the differences between virus production measured by virus decay rates (VP D ) and VP TEM have been thought to be explained by adsorption of viruses to particles, degradation of viruses due to enzymes and inactivation of viruses caused by sunlight. It seems that uneven growth and different susceptibility to viruses in the bacterial community might be another additional explanation for the discrepancy between VP D and VP TEM .

Degree of ultraviolet radiation damage and repair capabilities are related to G+C content in marine vibriophages

A key issue in the ecology of viruses in the marine environment is the rate of viral production and decay. The ultraviolet (UV) radiation in sunlight has been found to cause loss of infec- tivity in marine bacteriophages at rates nearly equal to all other decay mechanisms combined. There are 2 main host-mediated mechanisms that can repair UV-damaged phage DNA: photoreactivation and excision repair. Both these mechanisms were investigated in 2 marine Vibrio parahaemolyticus hosts as they catalyzed the reactivation of 7 phages. Photoreactivation was the dominant repair mode in all but one case. A significant correlation was found between G+C content of the phage DNAs (16 to 70%) and degree of DNA damage (r = 0.955), indicating a strong relationship between the number of thymine dimer targets and the capability to photoreactivate DNA damage. Evolution of high G+C content may be a strategy for protection from UV damage in marine phages.

Viral distribution and activity in Antarctic waters

Abstract Variability in abundance of virus-like particles (VLP), VLP decay rates and prokaryotic mortality due to viral infection were determined in three Antarctic areas: Bellingshausen Sea, Bransfield Strait and Gerlache Strait, during December 1995 and February 1996. VLP abundance showed very small spatial variability in the three areas (7×106–2×107 VLP ml−1). VLP abundance, on the other hand, decreased one order of magnitude from the surface to the bottom, in two stations where deep vertical profiles were sampled. Low seasonal variability in VLP abundance was found when comparing each area separately. Diel VLP variability was also very low. VLP abundance showed the lowest values when solar irradiation was maximal, in two of the three stations where diel cycles were examined. Viral decay rates (VDR) were determined using KCN in two kinds of experiments. Type 1 experiments were performed in 6 stations to determine viral decay. Type 2 experiments were carried out in 2 stations to examine the influence of temperature and organic matter concentration on viral decay. VDR was not influenced by these parameters. Prokaryotic mortality due to viral infection was always higher than that due to bacterivores in the stations where both factors of prokaryotic mortality were measured. Viral infection accounted for all the prokaryotic heterotrophic production in Bellingshausen Sea and Gerlache Strait and for half of the prokaryotic heterotrophic production in Bransfield Strait. These high values of prokaryotic mortality due to viral infection are difficult to reconcile in nature, and more work is necessary to determine the mechanisms involved in the disappearance of viruses.

Correlation between reduction in plasma HIV-1 RNA concentration 1 week after start of antiretroviral treatment and longer-term efficacy

Early assessment of antiretroviral drug efficacy is important for prevention of the emergence of drug-resistant virus and unnecessary exposure to ineffective drug regimens. Current US guidelines for changing therapy are based on measurements of plasma HIV-1 RNA concentrations 4 or 8 weeks after the start of treatment with cut-off points of 0.75 or 1.00 log, respectively. We investigated the possibility of assessing drug efficacy from measurements of plasma HIV-1 concentrations made during the first week on therapy. The kinetics of virus decay in plasma during the first 12 weeks of treatment was analysed for 124 HIV-1-infected patients being treated for the first time with a protease inhibitor. Patients with a continuous decline of HIV-1 concentrations and in whom HIV-1 was either undetectable or declined by more than 1.5 log at 12 weeks were defined as good responders; the rest were poor responders. The individual virus decay rate constants (k) at day 6 correlated significantly (r>0.66, p<0.0001) with changes in HIV-1 concentrations at 4, 8, and 12 weeks, and correctly predicted 84% of the responses with a cut-off value of k=0.21 per day (in log scale). Reduction in plasma HIV-1 of less than 0.72 log by day 6 after initiation of therapy predicted poor long-term responses in more than 99% of patients. These results suggest that changes in HIV-1 concentration at day 6 after treatment initiation are major correlates of longer-term virological responses. They offer a very early measure of individual long-term responses, suggesting that treatment could be optimised after only a few days of therapy.

Assessing antiviral potency of anti-HIV therapies in vivo by comparing viral decay rates in viral dynamic models.

A virologic marker, the number of HIV RNA copies or viral load, is currently used to evaluate anti-HIV therapies in AIDS clinical trials. This marker can be used to assess the antiviral potency of therapies, but is easily affected by noncompliance, drug resistance, toxicities, and other factors during the long-term treatment evaluation process. Recently it has been suggested to use viral dynamics to assess the potency of antiviral drugs and therapies, since viral decay rates in viral dynamic models have been shown to be related to the antiviral drug potency directly, and they need a shorter evaluation time. In this paper we first review the two statistical approaches for characterizing HIV dynamics and estimating viral decay rates: the individual nonlinear least squares regression (INLS) method and the population nonlinear mixed-effect model (PMEM) approach. To compare the viral decay rates between two treatment arms, parametric and nonparametric tests, based on the estimates of viral decay rates (the derived variables) from both the INLS and PMEM methods, are proposed and studied. We show, using the concept of exchangeability, that the test based on the empirical Bayes' estimates from the PMEM is valid, powerful and robust. This proposed method is very useful in most practical cases where the INLS-based tests and the general likelihood ratio test may not apply. We validate and compare various tests for finite samples using Monte Carlo simulations. Finally, we apply the proposed tests to an AIDS clinical trial to compare the antiviral potency between a 3-drug combination regimen and a 4-drug combination regimen. The proposed tests provide some significant evidence that the 4-drug regimen is more potent than the 3-drug regimen, while the naive methods fail to give a significant result.*To whom correspondence should be addressed.

Reservoirs for HIV-1: Mechanisms for Viral Persistence in the Presence of Antiviral Immune Responses and Antiretroviral Therapy

The success of combination antiretroviral therapy for HIV-1 infection has generated interest in mechanisms by which the virus can persist in the body despite the presence of drugs that effectively inhibit key steps in the virus life cycle. It is becoming clear that viral reservoirs established early in the infection not only prevent sterilizing immunity but also represent a major obstacle to curing the infection with the potent antiretroviral drugs currently in use. Mechanisms of viral persistence are best considered in the context of the dynamics of viral replication in vivo. Virus production in infected individuals is largely the result of a dynamic process involving continuous rounds of de novo infection of and replication in activated CD4(+) T cells with rapid turnover of both free virus and virus-producing cells. This process is largely, but not completely, interrupted by effective antiretroviral therapy. After a few months of therapy, plasma virus levels become undetectable in many patients. Analysis of viral decay rates initially suggested that eradication of the infection might be possible. However, there are several potential cellular and anatomical reservoirs for HIV-1 that may contribute to long-term persistence of HIV-1. These include infected cell in the central nervous system and the male urogenital tract. However, the most worrisome reservoir consists of latently infected resting memory CD4(+) T cells carrying integrated HIV-1 DNA. Definitive demonstration of the presence of this form of latency required development of methods for isolating extremely pure populations of resting CD4(+) T cells and for demonstrating that a small fraction of these cells contain integrated HIV-1 DNA that is competent for replication if the cells undergo antigen-driven activation. Most of the latent virus in resting CD4(+) T cells is found in cells of the memory phenotype. The half-life of this latent reservoir is extremely long (44 months). At this rate, eradication of this reservoir would require over 60 years of treatment. Thus, latently infected resting CD4(+) T cells provide a mechanism for life-long persistence of replication-competent forms of HIV-1, rendering unrealistic hopes of virus eradication with current antiretroviral regimens. The extraordinary stability of the reservoir may reflect gradual reseeding by a very low level of ongoing viral replication and/or mechanisms that contribute to the intrinsic stability of the memory T cell compartment. Given the substantial long-term toxicities of current combination therapy regimens, novel approaches to eradicating this latent reservoir are urgently needed.

Viral dynamics of acute HIV-1 infection.

Viral dynamics were intensively investigated in eight patients with acute HIV infection to define the earliest rates of change in plasma HIV RNA before and after the start of antiretroviral therapy. We report the first estimates of the basic reproductive number (R(0)), the number of cells infected by the progeny of an infected cell during its lifetime when target cells are not depleted. The mean initial viral doubling time was 10 h, and the peak of viremia occurred 21 d after reported HIV exposure. The spontaneous rate of decline (alpha) was highly variable among individuals. The phase 1 viral decay rate (delta(I) = 0.3/day) in subjects initiating potent antiretroviral therapy during acute HIV infection was similar to estimates from treated subjects with chronic HIV infection. The doubling time in two subjects who discontinued antiretroviral therapy was almost five times slower than during acute infection. The mean basic reproductive number (R(0)) of 19.3 during the logarithmic growth phase of primary HIV infection suggested that a vaccine or postexposure prophylaxis of at least 95% efficacy would be needed to extinguish productive viral infection in the absence of drug resistance or viral latency. These measurements provide a basis for comparison of vaccine and other strategies and support the validity of the simian immunodeficiency virus macaque model of acute HIV infection.

Inappropriate Model-Fitting Methods May Lead to Significant Underestimates of Viral Decay Rates in HIV Dynamic Studies

Wu, Hulin*†; Ruan, Ping*†; Ding, A. Adam‡; Sullivan, John L.§; Luzuriaga, Katherine§ Author Information

Inappropriate Model-Fitting Methods May Lead to Significant Underestimates of Viral Decay Rates in HIV Dynamic Studies

Inappropriate Model-Fitting Methods May Lead to Significant Underestimates of Viral Decay Rates in HIV Dynamic Studies

Relationships between antiviral treatment effects and biphasic viral decay rates in modeling HIV dynamics

Recently, potent combination antiviral therapies consisting of reverse transcriptase inhibitor (RTI) drugs and protease inhibitor (PI) drugs, have been developed which can rapidly suppress HIV below the limit of detection. Two phases of plasma viral decay after initiation of treatment have been observed in clinical studies. Some researchers have suggested that the viral decay rates may reflect the potency (efficacy) of antiviral therapies. In this paper we model the effect of RTI drugs and PI drugs as inhibition rates of cell infection and infectious virus production, respectively, based on the biological mechanisms of these two different types of drugs. Through rigorous mathematical derivation, we show that the two viral decay rates are monotone functions of the treatment effects of these antiviral therapies. We derive approximation formulas for the relationships between viral decay rates and treatment effects. Computer simulations show that the approximation formulas approximate the true values very well. These formulas may be used to study what factors really affect the viral decay rates. The results in this paper provide a theoretical justification for using both viral decay rates for evaluation of the treatment efficacy of antiviral therapies.

Kinetics of retrovirus production and decay

There has been only limited success in using recombinant retroviruses to transfer genes for the purposes of human gene therapy, in part because the average number of genes delivered to the target cells (transduction efficiency) is often too low to achieve the desired therapeutic effect [Miller, AD. 1990. Blood 76:271–278; Mulligan RC. 1993. Science 260:926–932; Orkin SH, Mo- tulsky AG. 1995. Report and recommendations of the panel to assess the NIH investment in research on gene therapy. Bethesda, MD: National Institutes of Health.]. One strategy to improve transduction efficiency is to focus on understanding and improving the processes used to produce recombinant retroviruses. In this report, we characterized the dynamics of retrovirus production and decay in batch cultures of virus producer cells using a simple mathematical model, a recombinant retrovirus encoding the Escherichia coli lacZ gene, and quantitative assays for virus activity and number. We found that the rate at which recombinant retroviruses spontaneously lose their activity (decay) is a strong function of temperature, decreasing roughly 2-fold for every 5°C reduction in temperature, whereas the rate at which retroviruses are produced is only weakly affected by temperature, decreasing about 10% for every 5°C reduction in temperature. In addition, we developed a simple mathematical model of virus production and decay that predicted that the virus titer in batch cultures of virus producer cells would reach a maximum steady-state at a rate that is inversely proportional to the virus decay rate and to a level that is proportional to the ratio of the virus production rate to the virus decay rate. Consistent with the model, we observed that the steady-state levels of virus titer increased more than 3-fold when the cell culture temperature was reduced from 37 to 28°C. Despite their higher titers, virus stocks produced at 28°C, when used in undiluted form so as to mimic human gene transfer protocols, did not transduce substantially more cells than virus stocks produced at 37°C. The implications of our findings on the production of retroviruses for use in human gene therapy protocols are discussed. © 1999 John Wiley & Sons, Inc. Biotechnol Bioeng 63: 654–662, 1999.

Kinetics of retrovirus production and decay

There has been only limited success in using recombinant retroviruses to transfer genes for the purposes of human gene therapy, in part because the average number of genes delivered to the target cells (transduction efficiency) is often too low to achieve the desired therapeutic effect [Miller, AD. 1990. Blood 76:271-278; Mulligan RC. 1993. Science 260:926-932; Orkin SH, Motulsky AG. 1995. Report and recommendations of the panel to assess the NIH investment in research on gene therapy. Bethesda, MD: National Institutes of Health.]. One strategy to improve transduction efficiency is to focus on understanding and improving the processes used to produce recombinant retroviruses. In this report, we characterized the dynamics of retrovirus production and decay in batch cultures of virus producer cells using a simple mathematical model, a recombinant retrovirus encoding the Escherichia coli lacZ gene, and quantitative assays for virus activity and number. We found that the rate at which recombinant retroviruses spontaneously lose their activity (decay) is a strong function of temperature, decreasing roughly 2-fold for every 5 degrees C reduction in temperature, whereas the rate at which retroviruses are produced is only weakly affected by temperature, decreasing about 10% for every 5 degrees C reduction in temperature. In addition, we developed a simple mathematical model of virus production and decay that predicted that the virus titer in batch cultures of virus producer cells would reach a maximum steady-state at a rate that is inversely proportional to the virus decay rate and to a level that is proportional to the ratio of the virus production rate to the virus decay rate. Consistent with the model, we observed that the steady-state levels of virus titer increased more than 3-fold when the cell culture temperature was reduced from 37 to 28 degrees C. Despite their higher titers, virus stocks produced at 28 degrees C, when used in undiluted form so as to mimic human gene transfer protocols, did not transduce substantially more cells than virus stocks produced at 37 degrees C. The implications of our findings on the production of retroviruses for use in human gene therapy protocols are discussed.

Viral lysis and bacterivory during a phytoplankton bloom in a coastal water microcosm

The relative importance of viral lysis and bacterivory as causes of bacterial mortality were estimated. A laboratory experiment was carried out to check the kind of control that viruses could exert over the bacterial assemblage in a non-steady-state situation. Virus-like particles (VLP) were determined by using three methods of counting (DAPI [4',6-diamidino-2-phenylindole] staining, YOPRO staining, and transmission electron microscopy). Virus counts increased from the beginning until the end of the experiment. However, different methods produced significantly different results. DAPI-stained VLP yielded the lowest numbers, while YOPRO-stained VLP yielded the highest numbers. Bacteria reached the maximal abundance at 122 h (3 x 10(7) bacteria ml-1), after the peak of chlorophyll a (80 μg liter-1). Phototrophic nanoflagellates followed the same pattern as for chlorophyll a. Heterotrophic nanoflagellates showed oscillations in abundance throughout the experiment. The specific bacterial growth rate increased until 168 h (2.6 day-1). The bacterivory rate reached the maximal value at 96 hours (0.9 day-1). Bacterial mortality due to viral infection was measured by using two approaches: measuring the percentage of visibly infected bacteria (%VIB) and measuring the viral decay rates (VDR), which were estimated with cyanide. The %VIB was always lower than 1% during the experiment. VDR were used to estimate viral production. Viral production increased 1 order of magnitude during the experiment (from 10(6) to 10(7) VLP ml-1 h-1). The percentage of heterotrophic bacterial production consumed by bacterivores was higher than 60% during the first 4 days of the experiment; afterwards, this percentage was lower than 10%. The percentage of heterotrophic bacterial production lysed by viruses as assessed by the VDR reached the highest values at the beginning (100%) and at the end (50%) of the experiment. Comparing both sources of mortality at each stage of the bloom, bacterivory was found to be higher than viral lysis at days 2 and 4, and viral lysis was higher than bacterivory at days 7 and 9. A balance between bacterial losses and bacterial production was calculated for each sampling interval. At intervals of 0 to 2 and 2 to 4 days, viral lysis and bacterivory accounted for all the bacterial losses. At intervals of 4 to 7 and 7 to 9 days, bacterial losses were not balanced by the sources of mortality measured. At these time points, bacterial abundance was about 20 times higher than the expected value if viral lysis and bacterivory had been the only factors causing bacterial mortality. In conclusion, mortality caused by viruses can be more important than bacterivory under non-steady-state conditions.

Characterization of viral dynamics in human immunodeficiency virus type 1-infected patients treated with combination antiretroviral therapy: relationships to host factors, cellular restoration, and virologic end points.

Biphasic plasma viral decays were modeled in 48 patients treated with ritonavir, zidovudine, and lamivudine. Estimated first- and second-phase decay rates were d1 as 0.47/day and d2 as 0.04/day. Interpatient differences in both decay rates were significant. The d1 was directly correlated with baseline CD4+, CD4+CD28+, and CD8+CD28+ T lymphocyte counts (P<.05) and inversely correlated with baseline virus load (P=.044) and the magnitude of CD4+ and CD8+ T lymphocyte recovery (P<.01). The d2 was directly correlated with baseline percentage of CD8+ T lymphocytes (P=.023), the CD8+CD38+ cell number (P=.024), and the level of IgG that binds to human immunodeficiency virus (HIV) type 1 gp120 (P=.02). Viral decay rates were not predictive of treatment failure or durability of viral suppression. These exploratory findings are consistent with a model in which immunologic factors contribute to elimination of HIV-infected cells and suggest a dynamic interplay between regulation of HIV expression and lymphocyte activation and recovery.