Half-life Of Virus Research Articles

Ganciclovir-Resistant Cytomegalovirus Infections among Lung Transplant Recipients Are Associated with Poor Outcomes despite Treatment with Foscarnet-Containing Regimens

Ganciclovir-resistant cytomegalovirus (CMV) infections are reported infrequently among lung transplant recipients receiving extended valganciclovir prophylaxis. We performed a single-center, retrospective review of ganciclovir-resistant CMV infections in a program that employed valganciclovir prophylaxis for ≥6 months after lung transplant. CMV infections were diagnosed in 28% (170/607) of patients. UL97 mutations were detected in 9.4% (16/170) of CMV-infected patients at a median of 8.5 months posttransplant (range, 5 to 21) and despite prophylaxis for a median of 7 months (range, 4 to 21). UL97 mutations were canonical; 25% (4/16) of strains carried concurrent UL54 mutations. Ganciclovir-resistant CMV was more likely with breakthrough infections (75% [12/16] versus 19% [30/154]; P = 0.00001) and donor positive/recipient negative (D+/R-) serostatus (75% versus 45% [69/154]; P = 0.03). The median whole-blood CMV load was 4.13 log10 copies/cm(3) (range, 2.54 to 5.53), and 93% (14/15) of patients had low-moderate immune responses (Cylex Immunoknow). Antiviral therapy was successful, failed, or eradicated viremia followed by relapse in 12% (2/16), 31% (5/16), and 56% (9/16) of patients, respectively. Eighty-seven percent (14/16) of patients were treated with foscarnet-containing regimens; toxicity developed in 78% (11/14) of these. Median viral load half-life and time to viremia eradication among foscarnet-treated patients were 2.6 and 23 days, respectively, and did not correlate with protection from relapse. Sixty-nine percent (11/16) of patients developed CMV pneumonitis, and 25% (4/16) died of it. Serum viral load was independently associated with death among foscarnet-treated patients (P = 0.04). In conclusion, ganciclovir-resistant CMV infections remained a major cause of morbidity and mortality following lung transplantation. Foscarnet-based regimens often eradicated viremia rapidly but were ineffective in the long term and limited by toxicity.

The hepatitis C virus NS5A inhibitor daclatasvir has a dual mode of action and leads to a new virus half-life estimate

Chronic infection with hepatitis C virus (HCV) affects approximately 160 million people worldwide [1] and is the leading cause of cirrhosis, liver cancer and liver transplantation [2]. Until 2011, ...

Modeling shows that the NS5A inhibitor daclatasvir has two modes of action and yields a shorter estimate of the hepatitis C virus half-life

The nonstructural 5A (NS5A) protein is a target for drug development against hepatitis C virus (HCV). Interestingly, the NS5A inhibitor daclatasvir (BMS-790052) caused a decrease in serum HCV RNA levels by about two orders of magnitude within 6 h of administration. However, NS5A has no known enzymatic functions, making it difficult to understand daclatasvir's mode of action (MOA) and to estimate its antiviral effectiveness. Modeling viral kinetics during therapy has provided important insights into the MOA and effectiveness of a variety of anti-HCV agents. Here, we show that understanding the effects of daclatasvir in vivo requires a multiscale model that incorporates drug effects on the HCV intracellular lifecycle, and we validated this approach with in vitro HCV infection experiments. The model predicts that daclatasvir efficiently blocks two distinct stages of the viral lifecycle, namely viral RNA synthesis and virion assembly/secretion with mean effectiveness of 99% and 99.8%, respectively, and yields a more precise estimate of the serum HCV half-life, 45 min, i.e., around four times shorter than previous estimates. Intracellular HCV RNA in HCV-infected cells treated with daclatasvir and the HCV polymerase inhibitor NM107 showed a similar pattern of decline. However, daclatasvir treatment led to an immediate and rapid decline of extracellular HCV titers compared to a delayed (6-9 h) and slower decline with NM107, confirming an effect of daclatasvir on both viral replication and assembly/secretion. The multiscale modeling approach, validated with in vitro kinetic experiments, brings a unique conceptual framework for understanding the mechanism of action of a variety of agents in development for the treatment of HCV.

Mathematical Modeling of Triphasic Viral Dynamics in Patients with HBeAg-Positive Chronic Hepatitis B Showing Response to 24-Week Clevudine Therapy

BackgroundModeling of short-term viral dynamics of hepatitis B with traditional biphasic model might be insufficient to explain long-term viral dynamics. The aim was to develop a novel method of mathematical modeling to shed light on the dissociation between early and long-term dynamics in previous studies.MethodsWe investigated the viral decay pattern in 50 patients from the phase III clinical trial of 24-week clevudine therapy, who showed virological response and HBsAg decline. Immune effectors were added as a new compartment in the model equations. We determined some parameter values in the model using the non-linear least square minimization method.ResultsMedian baseline viral load was 8.526 Log10copies/mL, and on-treatment viral load decline was 5.683 Log10copies/mL. The median half-life of free virus was 24.89 hours. The median half-life of infected hepatocytes was 7.39 days. The viral decay patterns were visualized as triphasic curves with decreasing slopes over time: fastest decay in the first phase; slowest in the third phase; the second phase in between.ConclusionsIn the present study, mathematical modeling of hepatitis B in patients with virological response and HBsAg decline during 24-week antiviral therapy showed triphasic viral dynamics with direct introduction of immune effectors as a new compartment, which was thought to reflect the reduction of clearance rate of infected cells over time. This modeling method seems more appropriate to describe long-term viral dynamics compared to the biphasic model, and needs further validation.

A norovirus outbreak in a nursing home: Norovirus shedding time associated with age

BackgroundNorovirus (NoV) GII.4 has been identified as predominant in outbreaks in the long-term health-care facilities. ObjectivesNoV excretion during an outbreak of gastroenteritis affecting 19/42 residents and 12/33 employees was investigated in a Taiwan nursing home. Study designReal-time reverse transcription polymerase chain reaction (RT-PCR) was used to quantify viral RNA from stool samples up to the point of negative detection. ResultsInitial fecal viral loads in affected residents were higher than in affected employees (p=0.024). Viral reduced rate was measured as 0.66/day, with a viral half-life of 1.7 days. A mixed model indicated that time (days post-illness onset), initial virus load and resident status (as opposed to employee status) were the most important determining factors of fecal NoV concentration. According to a univariable accelerated failure time (AFT) model, strong associations existed between virus excretion duration and both age (p=0.005) and resident status (p=0.004). No associations were noted between viral excretion duration and either initial viral load or diarrhea duration. According to a multivariable AFT model, age was the only factor affecting virus excretion duration. ConclusionIn conclusion, outbreaks in nursing homes may have resulted from environmental contamination, the existence of asymptomatic residents and prolonged virus shedding time in the elderly and care providers. This outbreak finished quickly because frequent cleaning of the surface was done and contact precautions were taken for prolonged viral shedding residents.

Bioreducible polymer-conjugated oncolytic adenovirus for hepatoma-specific therapy via systemic administration

Systemic administration of adenovirus (Ad) vectors is complicated by host immune responses and viral accumulation in the liver, resulting in a short circulatory virus half-life, low efficacy, and host side effects. Ad surface modification is thus required to enhance safety and therapeutic efficacy. An arginine-grafted bioreducible polymer (ABP) was chemically conjugated to the Ad surface, generating Ad-ΔE1/GFP-ABP. A hepatocellular carcinoma [HCC]-selective oncolytic Ad complex, YKL-1001-ABP, was also generated. Transduction efficiency of Ad-ΔE1/GFP-ABP was enhanced compared to naked Ad-ΔE1/GFP. YKL-1001-ABP elicited an enhanced and specific killing effect in liver cancer cells (Huh7 and HepG2) expressing α-fetoprotein (AFP). Compared with naked Ad, systemic administration of ABP-conjugated Ad resulted in reduced liver toxicity and interleukin (IL)-6 production in vitro and in vivo. Ad-ΔE1/GFP-ABP was more resistant to the neutralizing effects of human serum compared to naked Ad-ΔE1/GFP. ABP conjugation extended blood circulation time 45-fold and reduced anti-Ad Ab neutralization. Moreover, systemic administration of YKL-1001-ABP markedly suppressed growth of Huh7 hepatocellular carcinoma. These results demonstrate that chemical conjugation of ABP to the Ad surface improves safety and efficacy, indicating that ABP-conjugated Ad is a potentially useful cancer therapeutic agent to target cancer via systemic administration.

Strategies for improved stability of Peste des Petits Ruminants Vaccine

The main focus of this work was the improvement of the stability of the current PPRV vaccine. First, new formulations based on the Tris buffer were tested, with and without the addition of sucrose and trehalose and compared with the formulation normally used to stabilize the vaccine, the Weybridge medium. The results show a virus half-life of 21h at 37°C and 1 month at 4°C for the Tris/trehalose liquid formulation and, in the lyophilized form, the formulation was able to maintain the viral titer above the 1×104 TCID50/mL (>10 doses/mL) for at least 21 months at 4°C (0.6log lost), 144h at 37°C (0.6log lost) and 120h at 45°C (1log lost).Secondly, a strategy based on culture medium composition manipulation aiming at improving the intrinsic PPRV vaccine stability was also evaluated. The addition of 25mM fructose resulted in a higher virus production (1log increase) with higher stability (2.6-fold increase compared to glucose 25mM) at 37°C. Increased concentrations of NaCl, improved virus release, reducing the cell-associated fraction of the virus produced. Moreover this harvesting strategy is scalable and more suitable for a larger scale production than the freeze/thaw cycles normally used.The information gathered in this work showed that it is possible for the PPRV vaccine to have adequate short-term stability at non-freezing temperatures to support manufacturing, short-term shipping and storage. The identification of a more stable formulation should significantly enhance the utility of the vaccine in the control of a PPRV outbreak.

Distinct p53, p53:LANA, and LANA Complexes in Kaposi's Sarcoma-Associated Herpesvirus Lymphomas

The role of p53 in primary effusion lymphoma (PEL) is complicated. The latency-associated nuclear antigen (LANA) of Kaposi's sarcoma-associated herpesvirus (KSHV) binds p53. Despite this interaction, we had found that p53 was functional in PEL, i.e., able to induce apoptosis in response to DNA damage (C. E. Petre, S. H. Sin, and D. P. Dittmer, J. Virol. 81:1912-1922, 2007), and that hdm2 was overexpressed. To further elucidate the relationship between LANA, p53, and hdm2, we purified LANA complexes from PEL by column chromatography. This confirmed that LANA bound p53. However, the LANA:p53 complexes were a minority compared to hdm2:p53 and p53:p53 complexes. The half-life of p53 was not extended, which is in contrast to the half-life of simian virus 40 T antigen-transformed cells. p53:p53, LANA:p53, and LANA:LANA complexes coexisted in PEL, and each protein was able to bind to its cognate DNA element. These data suggest that under normal conditions, p53 is inactive in PEL, thus allowing for exponential growth, but that this inactivation is driven by the relative stoichiometries of LANA, hdm2, and p53. If p53 is activated by DNA damage or nutlin-3a, the complex falls apart easily, and p53 exercises its role as guardian of the genome.

Advantage of IFN-β/α2b same-day administration for ribavirin-intolerant patients with chronic hepatitis C

Although interferon (IFN)/ribavirin is the mainstream combination treatment for chronic hepatitis C in patients with a high viral load, ribavirin is problematic for women of childbearing age and patients with anemia. Therefore we needed to establish a new regimen without ribavirin. We devised a new regimen (same-day beta/alpha2b) to administer IFN-beta and alpha2b on the same-day, and compared it with IFN-alpha2b alone and IFN-alpha2b plus ribavirin. The cases were 36 patients (26.1%) in whom ribavirin could not be used (young women, anemia, etc.) among 138 patients who underwent IFN treatment after ribavirin release. The percentages of patients withdrawing due to side-effects were 6.8%, 18.8% and 17.0% in the treatment with same-day beta/alpha2b, IFN-alpha2b alone and IFN-alpha2b plus ribavirin groups, respectively. In genotype 1b, the sustained viral response (SVR) was 28.6% (4/14), 13.6% (3/22) and 25.0% (8/32) with a high viral load, and 91.7% (11/12), 27.3% (3/11) and 57.1% (4/7) with a low viral load for the respective groups. According to a study on viral half-life during the early phase of IFN therapy, there was no difference among the regimens of same-day IFN-beta/alpha2b, beta alone, alpha2b alone and twice-daily treatment with IFN-beta. Same-day beta/alpha2b treatment showed a significantly higher SVR rate in moving type patients with a genotype 1b/high viral load. Same-day beta/alpha2b treatment resulted in few cases where therapy was discontinued and showed a high SVR rate. This regimen is especially appropriate in cases where ribavirin has been deemed unsuitable.

Hepatitis B virus clearance rate estimates

We read the study by Dandri et al.1 with much interest. The authors sought to estimate hepatitis B virus (HBV) half-life based on several baseline serum and intrahepatic parameters measured from 80 untreated patients with chronic HBV, including intrahepatic HBV-DNA–containing capsids and serum HBV DNA levels. A mathematical model2 that couples baseline viremia and intracellular virion productivity was applied by Dandri et al. and showed a strong inverse correlation between baseline viremia and HBV half-life. In addition, they estimated that virion clearance is very fast (median half-life [t1/2] 46 minutes [interquartile range, 4 minutes to 3.7 hours] in patients positive for hepatitis B e antigen (HBeAg) and 2.5 minutes [interquartile range, 24 seconds to 13 minutes] in HBeAg-negative patients). More striking is their finding (shown in their figure 2) that the HBV t1/2 varies more than 6 orders of magnitude among patients, with t1/2 being about 0.01 minutes when HBV DNA levels are 103 copies/mL or lower. For simian immunodeficiency virus, the rate of clearance in the presence and absence of high titer neutralizing antibodies differs by a factor of about four,3 leaving unexplained how a 6 order of magnitude increase in HBV clearance could occur in infected patients with low baseline viral loads. Further, when infection is initiated, HBV DNA levels should be low and clearance with a t1/2 of the order of seconds might preclude infection from taking hold. Estimated HBV half-life versus baseline HBV DNA. Free HBV half-life was estimated via mathematical modeling from the first phase HBV DNA decline during therapy in HBeAg-positive patients (circles or triangles) and HBeAg-negative patients (squares). Values were copied from Lewin et al.,7 Colombatto et al.,8 Mihm et al.,9 and Wolters et al.10 Patient 13 from Lewin et al.,7 with HBV DNA = 5.7 × 10 5 copies/mL and HBV half-life = 91 hours, is not shown but was included in the statistical analysis that shows no significant correlation (P = 0.5) between baseline HBV DNA and virion half-life (SPSS version 15; SPSS Inc., Chicago, IL). A number of previous studies have analyzed the rate of HBV virion clearance by using antiviral drugs to inhibit viral production and have come to decidedly different conclusions. Drug perturbation analysis showed no correlation between virion half-life and baseline viremia (Fig. 1), and estimated significantly slower virion clearance (median t1/2 ≈21 hours and ≈9 hours in treated HBeAg-positive and HBeAg-negative patients, respectively (Fig. 1) with less than one order of magnitude variation among patients; see also table 3 by Sypsa et al.4). The discrepancy between the findings of Dandri et al.1 and drug perturbation analysis (Fig. 1) is striking. To resolve the discrepancy, we suggest other approaches such as (1) infusion of viral particles5 and (2) plasma apheresis.6 For simian immunodeficiency virus the clearance rate was estimated from the disappearance of viral particles from plasma after intravenous bolus injection (or constant rate infusion) into rhesus macaques.5 This approach seems feasible to apply in chimpanzees. For both human immunodeficiency virus (type 1) and hepatitis C virus clearance rates were measured using plasma apheresis in which viral clearance was temporarily increased while viral production was unaffected.6 Interestingly, estimates of the hepatitis C virus half-life of 2-3 hours from plasma apheresis6 is similar to drug pertubation analysis estimates.11 This approach seems feasible to apply in patients with chronic HBV as well. This research was performed under the auspices of the U.S. Department of Energy under contract DE-AC52-06NA25396 and supported by National Institutes of Health (NIH) grants RR06555, AI28433, and AI065256 (to A.S.P.). H.D. is supported by the University of Illinois Gastrointestinal and Liver Disease (GILD) Association. Harel Dahari*, Scott J. Cotler*, Thomas J. Layden*, Alan S. Perelson , * Department of Medicine, University of Illinois at Chicago, Chicago, IL, Theoretical Biology and Biophysics, Los Alamos National Laboratory, Los Alamos, NM.

Artesunate as a Potent Antiviral Agent in a Patient with Late Drug‐Resistant Cytomegalovirus Infection after Hematopoietic Stem Cell Transplantation

This is the first report of treatment of cytomegalovirus infection with artesunate, for a stem cell transplant recipient with a newly identified foscarnet-resistant and ganciclovir-resistant DNA polymerase L776M mutation. Artesunate treatment resulted in a 1.7-2.1-log reduction in viral load by treatment day 7, with a viral half-life of 0.9-1.9 days, indicating a highly effective block in viral replication.

Norovirus Excretion in an Aged-Care Setting

Norovirus genogroup II excretion during an outbreak of gastroenteritis was investigated in an aged-care facility. Viral shedding peaked in the acute stage of illness and continued for an average of 28.7 days. The viral decay rate was 0.76 per day, which corresponds to a viral half-life of 2.5 days.

Virion half-life in chronic hepatitis B virus infection is strongly correlated with viral load

Little is known about the mechanisms determining clearance rates of hepatitis B virus (HBV) in chronically infected individuals. Mathematical modeling of viral kinetics may reveal new aspects of this disease. During chronic infection, the rates of viral production and clearance are in balance and determine virion half-life. Methods: Using the relationship between intracellular relaxed circular DNA (rcDNA) and extracellular virions in blood, we performed viral dynamic analysis by quantifying viral loads in serum and in the liver of both treatment naïve chronically HBV-infected patients (N=80), and immunodeficient uPA mice (N=7) repopulated with tupaia hepatocytes and infected with woolly monkey (WM) HBV. Results: We show that free virion clearance in chronic HBV infection can be very rapid and is strongly correlated with viral load (p<0.0001, r=0,83): median half-life was 46 minutes for HBeAg-positive individuals harboring median 4,5×107 HBV-DNA copies/ml serum and a remarkably short 150 seconds for HBeAg-negative individuals with significantly lower median serum HBV-DNA levels (6,5×104 HBV-DNA/ml). Virion half-life in high viremic (4,6×108 WMHBV-DNA copies/ml) immunodeficient uPA mice was similar (90 min) to estimates determined in patients with comparable high titers, suggesting that the fast clearance rates of free virions in high viremic chronic carriers are determined by common non-immune specific mechanisms. However, virion half-life in mice was less dependent on viral load, suggesting that immune components can significantly reduce free virion half-life in chronically HBV-infected individuals with low viral loads.

The woodchuck hepatitis virus post-transcriptional regulatory element reduces readthrough transcription from retroviral vectors

The woodchuck hepatitis virus post-transcriptional regulatory element (WPRE) increases transgene expression from a variety of viral vectors, although the precise mechanism is not known. WPRE is most effective when placed downstream of the transgene, proximal to the polyadenylation signal. We hypothesized that WPRE likely reduces viral mRNA readthrough transcription by improving transcript termination, which in turn would increase viral titers and expression. Using a Cre-lox-mediated plasmid-based assay, we found significant readthrough transcription from gamma-retroviral vector (RV) long terminal repeat (wt RV-LTR) and RV LTR with a self-inactivating deletion (SIN RV-LTR). WPRE, when placed upstream of the RV LTRs, significantly reduced readthrough transcription. Readthrough, present at much lower levels with the SIN HIV-1 LV-LTR, was also reduced with WPRE. When placed in RV vectors, WPRE increased total RV genomic mRNA; and increased viral titers from transiently transfected 293T cells and stable PG13 producer cells by 7- to 15-fold. The mechanism of increased titers and expression was not due to increased nuclear mRNA export, increased rate of viral transcription or a significant increase in viral mRNA half-life. Our results showed that WPRE improved vector genomic transcript termination to increase titers and expression from RVs.

An Intracellular Delay-Differential Equation Model of the HIV Infection and Immune Control

Previous work has shown that intracellular delay needs to be taken into account to accurately determine the half-life of free virus from drug perturbation experiments (1). The delay also effects the estimated value for the infected T-cell loss rate when we assume that the drug is not completely effective (19). Models of virus infection that include intracellular delay are more accurate representations of the biological data. We analyze a non-linear model of the human immunodeficiency virus (HIV) infection that considers the interaction between a replicating virus, CD4+ T-cell and the cytotoxic-lymphocytes (CTL). We then investigate the intracellular delay effect on the stability of the endemically infected steady state. Criteria are given to ensure that the infected steady state is asymptotically stable for all delays. Model analysis also allows the prediction of a critical delay ?c below which the effector CTL can play a significant role in the immune control mechanism even when the basic reproduction number is high.

HIV replication and evolution in patients on highly active antiretroviral therapy

Treatment of HIV-1 infection with highly active antiretroviral therapy (HAART) reduces viremia to below the detection limit of ultrasensitive clinical assays. However, HIV-1 persists in resting CD4+ T cells and possibly other reservoirs. In patients on HAART, HIV-1 persistence is evidenced not only by the latent reservoir in resting CD4+ T cells but also by free virus in the plasma. Given the short half-life of free virus, this residual viremia indicates active virus production. This virus production may reflect low-level ongoing replication that continues despite HAART and/or release of virus from latently infected cells that become activated or from other stable cellular reservoirs. With respect to the issue of drug resistance, it is of particular importance to determine whether ongoing replication continues on HAART because the evolution of resistance can only take place if there are new cycles of replication. The direct characterization of residual viremia provides a window into this state of virologic suppression and a means for determining the importance of different mechanisms of viral persistence. Characterization of this residual viremia has been limited because of the technical difficulties involved in the analysis of extremely low numbers of viral RNA templates. To obtain sufficient numbers of independent viral clones from the plasma of patients on HAART, we have carried out intensive sampling in a series of patients and analyzed plasma virus genotypes with a sensitive RT-PCR method. Viral variants in the plasma were compared to viruses in the latent reservoir. The results provided evidence that in some patients on HAART, much of the residual viremia is due to continued production of a small number of viral clones over prolonged periods without evident sequence change by cells that are not well represented in the circulation. The static nature of the residual viremia is not consistent with ongoing viral replication. These results have implications for understanding HIV-1 persistence and treatment failure.

The half-life of hepatitis B virions

The virion half-life of hepatitis B virus (HBV) is currently estimated at approximately 1 day. This estimate has been obtained from drug perturbation experiments with reverse transcriptase inhibitors. However, the analyses of those experiments have not considered the export of virions produced from preformed mature DNA-containing HBV capsids in infected cells. Data from 3 acutely infected chimpanzees indicates that there is approximately 10-fold more total intracellular HBV DNA than HBV DNA in blood, and therefore the half-life of virions for chimpanzees during acute infection is 10-fold shorter at 3.8 hours than the half-life associated with export of total intracellular HBV DNA. Mathematical model simulations duplicating the viral dynamics observed in drug perturbation experiments suggest a half-life of at most 4.4 hours for HBV virions in chronically infected humans, significantly shorter than current estimates, but consistent with the half-lives of virions for hepatitis C virus and HIV. This faster turnover of HBV in blood indicates a correspondingly higher replication rate and risk of mutation against hepatitis B antiviral therapy. In conclusion, we find the half-life of HBV virions is approximately 4 hours, significantly shorter than current estimates of 1 day. This new value is consistent with virion half-life estimates for HIV and hepatitis C virus.

Perioperative viral kinetics: New insights or the Emperor's new clothes?

Perioperative viral kinetics: New insights or the Emperor's new clothes?

Rapid Dynamics of Polyomavirus Type BK in Renal Transplant Recipients

Polyomavirus type BK-associated nephropathy (PVAN) is an emerging cause of early renal transplant failure. No specific antiviral treatment has been established. Current interventions rely on improving immune functions by reducing immunosuppression. In patients with PVAN, a high BK virus (BKV) load is detectable in plasma. However, the relationship between BKV replication and disease is not well understood. In a retrospective analysis of BKV plasma load in renal transplant recipients undergoing allograft nephrectomy (n = 3) or changes in immunosuppressive regimen (n = 12), we calculated viral clearance rates and generation times and estimated the loss of BKV-infected renal cells. After nephrectomy, BKV clearance was fast (viral half-life [t(1/2)], 1-2 h) or moderately fast (t(1/2), 20-38 h), depending on the sampling density, but it was independent of continued immunosuppressive regimens. After changing immunosuppressive regimens, BKV was cleared with a t(1/2) of 6 h-17 days. Using the basic reproductive ratio, the efficacies of intervention ranged from 7% to 83% (mean, 28%; median, 22%). The results emphasize that high-level BKV replication is a major pathogenetic factor that may have implications for genome rearrangements, immune evasion, and antiviral resistance.

Evidence for a relation between the viral load and genotype and hepatitis C virus-specific T cell responses*1

Background/Aims The reason why patients with hepatitis C virus (HCV) genotype non-1 infection respond better to antiviral therapy than patients with genotype 1 infection is not known. The aim of this study is to explore the relation between the viral genotype, viral load, and the endogenous T cell response. Methods The viral genotype, the viral load, and the endogenous proliferative T cell response to the non-structural 3 protein (NS3) was analysed using serum and peripheral blood mononuclear cells from 103 patients with chronic HCV infection. Results Among 71 nontreated patients a T cell response was more common among those infected by genotype 3, as compared to those infected with genotype 1 (P<0.05). Among 32 patients undergoing antiviral therapy, presence of a T cell response was more common in genotype non-1 infected patients than in those infected by genotype 1 (P<0.01). Presence of a T cell response was related to a more rapid viral clearance (P<0,05), a negative HCV RNA test at week 12 (P<0.05), and a shorter viral half-life (P<0.05). Conclusions The presence of an NS3-specific T cell response is related to the viral genotype and to a more rapid clearance of HCV RNA during antiviral therapy.