Rate Of Viral Clearance Research Articles

Systematic review and meta-analysis of effectiveness of treatment options against SARS-CoV-2 infection.

Treatment options for severe acute respiratory syndrome‐related coronavirus‐2 (SARS‐CoV‐2) are limited with no clarity on efficacy and safety profiles. We performed a systematic review and meta‐analysis of studies on patients ≥18 years reporting data on therapeutic interventions in SARS‐CoV‐2. Primary outcome was all‐cause mortality and secondary outcomes were rates of mechanical ventilation, viral clearance, adverse events, discharge, and progression to severe disease. Pooled rates and odds ratios (OR) were calculated. Twenty‐nine studies with 5207 patients were included. Pooled all‐cause mortality in intervention arm was 12.8% (95% confidence interval [CI]: 8.1%‐17.4%). Mortality was significantly higher for studies using hydroxychloroquine (HCQ) for intervention (OR: 1.36; 95% CI: 0.97‐1.89). Adverse events were also higher in HCQ subgroup (OR: 3.88; 95% CI: 1.60‐9.45). There was no difference in other secondary outcomes. There is a need for well‐designed randomized clinical trials for further investigation of every therapeutic intervention for further insight into different therapeutic options.

Systematic and Statistical Review of Coronavirus Disease 19 Treatment Trials.

The following systematic review and meta-analysis compile the current data regarding human controlled COVID-19 treatment trials. An electronic search of the literature compiled studies pertaining to human controlled treatment trials with COVID-19. Medications assessed included lopinavir/ritonavir, arbidol, hydroxychloroquine, tocilizumab, favipiravir, heparin, and dexamethasone. Statistical analyses were performed for common viral clearance endpoints whenever possible. Lopinavir/ritonavir showed no significant effect on viral clearance for COVID-19 cases (OR 0.95 [95% CI 0.50–1.83]). Hydroxychloroquine also showed no significant effect on COVID-19 viral clearance rates (OR 2.16 [95% CI 0.80–5.84]). Arbidol showed no 7-day (OR 1.63 [95% CI 0.76–3.50]) or 14-day viral (OR 5.37 [95% CI 0.35–83.30]) clearance difference compared to lopinavir/ritonavir. Review of literature showed no significant clinical improvement with lopinavir/ritonavir, arbidol, hydroxychloroquine, or remdesivir. Tocilizumab showed mixed results regarding survival. Favipiravir showed quicker symptom improvement compared to lopinavir/ritonavir and arbidol. Heparin and dexamethasone showed improvement with severe COVID-19 cases requiring supplemental oxygenation. Current medications do not show significant effect on COVID-19 viral clearance rates. Tocilizumab showed mixed results regarding survival. Favipiravir shows favorable results compared to other tested medications. Heparin and dexamethasone show benefit especially for severe COVID-19 cases.

Finding the Best Antiviral Regimen for COVID-19: A Double-Center Retrospective Cohort Study of 207 Cases in Hunan, China.

Objective:To compare the efficacy of 3/4-drugs’ group with 1-drug’s or 2-drugs’ groups in coronavirus disease 2019 (COVID-19).Methods:We included 207 patients confirmed with COVID-19. We compared the viral clearance rate and discharge rate at day 7, 14, 21 and 28, and median time of viral clearance and length of hospitalization in patients treated with 3/4, 1 or 2 drugs.Results:The viral clearance rates of the 3/4-drugs group at day 7, 14 and 21 were significantly lower than those in the 1-drug’s or 2-drugs’ groups (P < 0.05). The median viral clearance days in 3/4-drugs group (13.5 days) were longer than 1-drug’s or 2-drugs’ groups (both were 9 days) (P < 0.001). The patients’ discharge rates in the 3/4-drugs group at day 14 and 21 were significantly lower than that in the 1-drug’s or 2 drugs’ group (P < 0.05). The median length of hospitalization in the 3/4-drugs group was 17 days, which was significantly longer than 11 days in the 1-drug group and 13 days in the 2-drug group (P < 0.05).Conclusion:The efficacy of 1 or 2 antiviral drugs was similar in COVID-19, and 3/4-drug regimens were not associated with clinical improvement. Corticosteroid treatment and more serious disease were also risk factors for viral clearance and patients’discharge.

Antiviral Activity and Safety of Darunavir/Cobicistat for the Treatment of COVID-19.

BackgroundWe aimed to evaluate the antiviral activity and safety of darunavir/cobicistat (DRV/c) in treating COVID-19 patients.MethodsIn this single-center, randomized, and open-label trial, mild patients with polymerase chain reaction (PCR)–confirmed COVID-19 were enrolled in Shanghai, China. Participants were randomized to receive DRV/c for 5 days on the top of interferon alpha 2b inhaling or interferon alpha 2b inhaling alone. The primary end point was the virological clearance rate of oropharyngeal swabs at day 7 after randomization in the intention-to-treat population (clinicaltrials.gov: NCT04252274).ResultsFrom January 30, 2020, to February 6, 2020, a total of 30 patients were enrolled, of whom 18 (60%) were male, aged 47.2 ± 2.8 years; 63.3% (19/30) of the participants had fever, and 46.7% (14/30) had cough at enrollment. The participants were randomized (range) at 4 (2–5) days after onset of symptoms. The proportion of negative PCR results at day 7 was 46.7% (7/15) and 60.0% (9/15) in the DRV/c and control groups (P = .72), respectively. The viral clearance rate at day 3 was 20% (3/15) in both study groups, while the number increased to 26.7% (4/15) in the DRV/c group and remained 20% (3/15) in the control group at day 5. Fourteen days after randomization, 1 participant in the DRV/c group progressed to critical illness and discontinued DRV/c, while all the patients in the control group were stable (P = 1.0). The frequencies of adverse events in the 2 groups were comparable.ConclusionsFive days of DRV/c did not increase the proportion of negative conversion vs standard of care alone, although it was well tolerated.

Continuous and discrete modeling of HIV-1 decline on therapy.

Mathematical models have shed light on the dynamics of HIV- 1 infection in vivo. In this paper, we generalize continuous mathematical models of drug therapy for HIV-1 by Perelson et al. (Science 271:1582-1586, 1996) and Perelson and Nelson (SIAM Rev 41:3-44, 1999) on time scales, i.e., a nonempty closed subset of real numbers in order to derive new discrete models that predict the total concentration of plasma virus as a function of time. One of our main goals is to compare discrete mathematical models with the continuous model in Perelson et al. (1996) where HIV infected patients were given protease inhibitors and sampled frequently thereafter. For the comparison, we use experimental data collected in Perelson et al. (1996) and estimate the parameters such as the virion clearance rate and the rate of loss of infected cells by fitting the total concentration of plasma virus to this data set. Our results show that discrete systems describe the best fit. In the previous models of this study, the efficacy of protease inhibitor is assumed to be perfect. Motivated by Perelson and Nelson (1999), we end the paper with a mathematical model of imperfect protease inhibitor and reverse transcriptase (RT) inhibitor combination therapy of HIV-1 infection on time scales with its stability analysis.

Effect of Jinhua Qinggan granules on novel coronavirus pneumonia in patients.

To evaluate the effectiveness and safety of Jinhua Qinggan granules in the treatment of patients with novel coronavirus pneumonia (COVID-19). Eighty cases of COVID-19 diagnosed from January 24 to February 17, 2020 in Beijing YouAn Hospital Affiliated to Capital Medical University were retrospectively analyzed. All 80 patients received symptomatic and supportive treatment. Among them, 44 patients took Jinhua Qinggan granules (treatment group) within 24 h of admission, and the remaining 36 patients either did not take Jinhua Qinggan granules or took the granules for less than 2 d (control group). In this study, we compared the duration of viral nucleic acid detection and of pneumonia absorption improvement between the two groups. Among the 80 cases, 37 were male (46%) and 43 were female (54%) with age ranging from 15 to 86 years, with an average age of 51.19 years. The average duration of viral nucleic acid detection was (7 ± 4) d in the Jinhua Qinggan administration group and (10 ± 4) d for the control group (P = 0.010), following which, nucleic acid tests were negative. Of the two groups, 56.82% in the Jinhua Qinggan treatment group and 27.78% in the control group demonstrated negative nucleic acid tests within 7 d or less. The 7-day viral clearance rate was significantly higher in the Jinhua Qinggan group compared with the control group (P = 0.009). Furthermore, the pneumonia recovery time indicated by chest CT was (8 ± 4) d in the Jinhua Qinggan group, which was significantly shorter than the control group, at (10 ± 5) d (P = 0.021). No adverse reactions were found in the treatment group after taking this medicine. In patients with COVID-19, Jinhua Qinggan granules can effectively shorten the duration of nucleic acid detection and promote the absorption of pneumonia inflammatory exudate without obvious adverse reactions.

Present and future management of viral hepatitis B and C in children

Having a hepatitis B virus (HBV) or hepatitis C virus (HCV) infection places a child at higher risk for subsequent chronic hepatitis B (CHB) or chronic hepatitis C (CHC) infection. The risk of mother-to-child transmission is higher for HBV (20% to 90%) than for HCV (<5%). Perinatal HBV infection generally causes CHB infection while perinatal HCV infection has a certain rate of spontaneous viral clearance (around 20% to 30%). Of the two, only HBV infection can benefit from passive/active perinatal immunoprophylaxis. The risk of CHB in children with HBV horizontal transmission decreases with age, whereas HCV transmission among teenagers commonly results into a long-life infection and CHC infection. Children with CHB or CHC should be carefully assessed for the need for antiviral treatment. When treatment cannot be deferred, pediatric CHB infection has different first-line treatment options: standard interferon (for children aged≥1 year), pegylated interferon (for children aged≥3 years), and the oral nucleotide analogues entecavir (for children aged≥2 years) and tenofovir (for children aged≥12 years). The choice of treatment depends on the child's age, virus genotypes, previous treatment failure and presence of contraindications. Expected responsiveness rate is 25% of hepatitis B e-antigen clearance, with both standard interferon and nucleotide analogues. Direct antiviral agents are first-line treatment for CHC infection in children aged 3 years or older. Hepatitis C virus sustained virus response is as high as 97%. Therefore, if direct antiviral agents can be proven to be safe and well tolerated in very young children, HCV eradication could be planned after the first screening.

Favorable outcome of retreatment by direct-acting antivirals for hepatitisC patients with daclatasvir plus asunaprevir combination therapy failure.

In patients with hepatitisC virus, treatment failure of daclatasvir plus asunaprevir combination therapy (DCV + ASV) seems to become intractable due to the induction of resistance-associated substitutions. This study aimed to investigate the outcomes of retreatment with direct-acting antivirals (DAAs) in patients with DCV + ASV therapy failure, as well as changes in drug resistance mutations. We retrospectively analyzed 44 patients re-treated with DAAs after DCV + ASV failure between December 2015 and April 2018. All patients were analyzed for amino acid substitutions, and additional treatment regimens were selected based on the results and current treatment guidelines. The sustained virological response rate with second-line treatment was 81.8% (36/44), and relapse occurred in five of 16 patients who received sofosbuvir/ledipasvir and three of seven patients who received DCV/ASV/beclabuvir. Third- and fourth-line treatments were also tried in relapsed cases, and the overall sustained virological response rates were 90.9% (40/44) and 93.2% (41/44), respectively. A high rate of viral clearance was eventually observed. Before second-line treatment, the prevalence of mutations in the NS5A and NS3/4A regions was 100% (44/44) and 86.4% (38/44), respectively. There was no significant increase in the number of amino acid substitutions in patients for whom second-line treatment failed. Amino acid substitutions were frequently observed in patients with DCV + ASV failure, but most patients achieved a sustained virological response after retreatment with DAAs. Although the spread of drug-resistant viruses due to unsuccessful DAA treatment was a matter of concern, most cases of DCV + ASV failure were overcome with additional treatment.

Viral Kinetics and Resistance Development in Children Treated with Neuraminidase Inhibitors: The Influenza Resistance Information Study (IRIS).

BackgroundWe studied the effect of age, baseline viral load, vaccination status, antiviral therapy, and emergence of drug resistance on viral shedding in children infected with influenza A or B virus.MethodsSamples from children (aged ≤13 years) enrolled during the 7 years of the prospective Influenza Resistance Information Study were analyzed using polymerase chain reaction to determine the influenza virus (sub-)type, viral load, and resistance mutations. Disease severity was assessed; clinical symptoms were recorded. The association of age with viral load and viral clearance was examined by determining the area under the curve for viral RNA shedding using logistic regression and Kaplan-Meier analyses.ResultsA total of 2131 children infected with influenza (683, A/H1N1pdm09; 825, A/H3N2; 623, influenza B) were investigated. Age did not affect the mean baseline viral load. Children aged 1−5 years had prolonged viral RNA shedding (±1–2 days) compared with older children and up to 1.2-fold higher total viral burden. Besides, in older age (odds ratio [OR], 1.08; confidence interval [CI], 1.05–1.12), prior vaccination status (OR, 1.72; CI, 1.22–2.43) and antiviral treatment (OR, 1.74; CI, 1.43–2.12) increased the rate of viral clearance. Resistance mutations were detected in 49 children infected with influenza A virus (34, A/H1N1pdm09; 15, A/H3N2) treated with oseltamivir, most of whom were aged <5 years (n = 39).ConclusionsChildren aged 1−5 years had a higher total viral burden with prolonged virus shedding and had an increased risk of acquiring resistance mutations following antiviral treatment.Clinical Trials RegistrationNCT00884117.

REBACIN® as a noninvasive clinical intervention for high-risk human papillomavirus persistent infection.

The development of highly sensitive HPV-genotyping tests has opened the possibility of treating HPV-infected women before high-grade lesions appear. The lack of efficient intervention for persistent high-risk HPV infection necessitates the need for development of novel therapeutic strategy. Here we demonstrate that REBACIN®, a proprietary antiviral biologics, has shown potent efficacy in the clearance of persistent HPV infections. Two independent parallel clinical studies were investigated, which a total of 199 patients were enrolled and randomly divided into a REBACIN®-test group and a control group without treatment. The viral clearance rates for the REBACIN® groups were 61.5% (24/39) and 62.5% (35/56), respectively, for the two independent parallel studies. In contrast, the nontreatment groups showed self-clearance rates at 20.0% (8/40) and 12.5% (8/64). We further found that REBACIN® was able to significantly repress the expression of HPV E6 and E7 oncogenes in TC-1 and Hela cells. The two viral genes are well known for the development of high-grade premalignancy lesion and cervical cancer. In a mouse model, REBACIN® was indicated to notably suppress E6/E7-induced tumor growth, suggesting E6 and E7 oncogenes as a potential target of REBACIN®. Taken together, our studies shed light into the development of a novel noninvasive therapeutic intervention for clearance of persistent HPV infection with significant efficacy.

Modeling the Effects of Morphine-Altered Virus Specific Antibody Responses on HIV/SIV Dynamics

Drugs of abuse, such as opiates, have been widely associated with enhancing HIV replication, accelerating disease progression and diminishing host-immune responses, thereby making it harder to effectively manage HIV infection. It is thus important to study the effects of drugs of abuse on HIV-infection and immune responses. Here, we develop mathematical models that incorporate the effects of morphine-altered antibody responses on HIV/SIV dynamics. Based on fitting the model to experimental data from simian immunodeficiency virus (SIV) infections in control and morphine-addicted macaques, we found that two of the most significant effects of virus specific antibodies are neutralizing viral particles and enhancing viral clearance. Using our model, we quantified how morphine alters virus-specific antibody responses, and how this alteration affects the key components of virus dynamics such as infection rate, virus clearance, viral load, CD4+ T cell count, and CD4+ T cell loss in SIV-infected macaques under conditioning with morphine. We found that in a subpopulation of SIV-infected morphine addicted macaques, the presence of drugs of abuse may cause significantly diminished antibody responses, resulting in more severe infection with increased SIV infectivity, a decreased viral clearance rate, increased viral load, and higher CD4+ T cell loss.

Role of Type I Interferon (IFN) in the Respiratory Syncytial Virus (RSV) Immune Response and Disease Severity.

Respiratory syncytial virus (RSV) is the most common cause of lower respiratory tract disease in children <2 years of age. Increased morbidity and mortality have been reported in high-risk patients, such as premature infants, patients with cardiac disease, and severely immune compromised patients. Severe disease is associated with the virulence of the virus as well as host factors specifically including the innate immune response. The role of type I interferons (IFNs) in the response to RSV infection is important in regulating the rate of virus clearance and in directing the character of the immune response, which is normally associated with protection and less severe disease. Two RSV non-structural proteins, NS1 and NS2, as well as the envelope G glycoprotein are known to suppress type I IFN production and a robust type I IFN response to RSV does not occur in human infants or neonatal mouse models of RSV infection. Additionally, presence of type I IFNs are associated with mild symptoms in infants and administration of IFN-α prior to infection of neonatal mice with RSV reduces immunopathology. This evidence has driven RSV prophylaxis and therapeutic efforts to consider strategies for enhancing type I IFN production.

Should Hepatitis C Donors Be Used in Naïve Urgent Status Patients on the Heart Transplant Waitlist?

The aim of this commentary is to review contemporary data on the use of hearts from hepatitis C positive donors. There continues to be a critical shortage of suitable heart donors available for patients with advanced heart failure requiring transplantation. Historically, donors with chronic hepatitis C virus were not utilized for heart transplantation due to concern about poor post-transplant outcomes. This was due, in part, to concerns about successfully treating chronic hepatitis C after transmitting the infection from donor to recipient. The availability of direct-acting anti-viral therapies is changing this paradigm. These therapies are generally well-tolerated and have excellent rates of viral clearance. We believe that heart donors with chronic hepatitis C should be routinely utilized for patients listed for urgent heart transplantation.

HCV-Associated Nephropathies in the Era of Direct Acting Antiviral Agents.

Hepatitis C virus (HCV) infection is a systemic disorder that frequently associates with extrahepatic manifestations, including nephropathies. Cryoglobulinemia is a typical extrahepatic manifestation of HCV infection that often involves kidneys with a histological pattern of membranoproliferative glomerulonephritis. Other, less common renal diseases related to HCV infection include membranous nephropathy, focal segmental glomerulosclerosis, IgA nephropathy, fibrillary and immunotactoid glomerulopathy. Over the last decades, the advent of direct-acting antiviral therapies has revolutionized treatment of HCV infection, dramatically increasing the rates of viral clearance. In patients where antiviral therapy alone fails to induce renal disease remission add-on B-cell depleting agents represent an alternative to counteract the synthesis of pathogenic antibodies. Immunosuppressive therapies, such as steroids, alkylating agents, and plasma exchanges, may still represent an effective option to inhibit immune-complex driven inflammatory response, but the potentially associated increase of HCV replication and worsening of liver disease represent a serious limitation to their use.

Abstract # 3084 Rat model of Prenatal Zika Virus infection

Zika virus (ZIKV), a mosquito-borne flavivirus, has been associated with microcephaly and other neurological disorders in infants born to infected mothers. Despite being declared an international emergency by the World Health Organization, comparatively very little is known about the pathogenesis, mechanisms, or behavioral consequences of maternal ZIKV infection in the offspring. Our lab is interested in developing a working animal model to answer some of these questions. Here, we use a rat model of prenatal ZIKV infection to measure the level of infectivity, as well as the rate of viral clearance in both the mother and her pups. We examine various aspects of brain development in pups, including cortical thickness, microglia morphology, apoptosis, and neurogenesis. Given that pregnancy is associated with significant immunomodulation, we are also interested in the role that pregnancy has on the impact of ZIKV infection, therefore we compare viral infectivity between both pregnant and non-pregnant female rats. In this study, we show that prenatal ZIKV infection results in an increase in cell death and reduces hippocampal and cortical volumes in the neonatal rat brain. For the first time, we demonstrate the efficacy and validity of a rat model for maternal ZIKV infection with vertical transmission to the fetus.

Modelling and analysis of HFMD with the effects of vaccination, contaminated environments and quarantine in mainland China.

Currently, hand, foot, and mouth disease (HFMD) is widespread in mainland China and seriously endangers the health of infants and young children. Recently in mainland China, preventing the spread of the disease has entailed vaccination, isolation measures, and virus clean-up in the contaminated environment. However, quantifying and evaluating the efficacy of these strategies on HFMD remains challenging, especially because relatively little research analyses the impact of EV71 vaccination for this disease. To assess the effectiveness of these strategies, we propose a new mathematical model that considers vaccination, contaminated environment, and quarantine simultaneously. Unlike the previous studies for HFMD, in which the basic reproduction number R₀ is the only threshold to decide whether the disease is extinct or not, our results show that another threshold value is needed:R̂₀ < 1 (R₀ <= R̂₀ < 1) such that disease is extinct; i.e., the disease-free equilibrium is globally asymptotically stable. Moreover, numerical experiments show that our model may have positive equilibriums even if the basic reproduction number R₀ is less than 1. In designing a new algorithm based on a BP network to estimate the unknown parameters, this proposed model is put forward to individually fit the HFMD reported cases annually in mainland China from 2015 to 2017. At last, the sensitivity analyses and numerical experiments show that increasing the rate of virus clearance, the vaccinated rate of infants and young children, and the quarantined rate of infectious individuals can effectively control the spread of HFMD in mainland China. Nevertheless, it remains difficult to eliminate the disease. Specifically, our results show that the current vaccine measures starting in 2016 have reduced the total number of patients in 2016 and 2017 by 17% and 22%, respectively.

Treatment with direct-acting antivirals improves the clinical outcome in patients with HCV-related decompensated cirrhosis: results from an Italian real-life cohort (Liver Network Activity-LINA cohort).

Direct-acting antivirals (DAAs) are safe and effective for the treatment of HCV infection. However, data regarding their efficacy in patients with Child-Pugh B cirrhosis are scarce and their capability in improving liver function is debated. The aim of our study was to assess the clinical benefits of treatment with DAA in subjects with Child-Pugh B cirrhosis. We conducted a prospective multicentre study among patients with Child-Pugh B cirrhosis of an Italian real-life HCV cohort (LINA cohort) who received treatment with DAAs. Among 89 patients enrolled, the rate of sustained virologic response 12 was 95.5%. No discontinuation occurred, no patient died during treatment. Most patients had Genotype 1 (1b 61.8%, 1a 11.2%). Conversely, 22.5%, 1.1% and 3.4% of patients had Genotype 2, 3 and 4, respectively. At last observation, 61.8% of patients switched to a Class A cirrhosis, 33.7% remained in Class B and 4.5 worsened to Child C (p < 0.001). Liver parameters significantly improved from baseline to 12weeks after the end of treatment. Previous anti-HCV treatments and the presence of decompensated cirrhosis at 1month of treatment were significantly associated with a decompensated cirrhosis at the last observation. Treatment with DAA in patients with Child-Pugh B cirrhosis is safe and leads to a very high rate of viral clearance, a significant rate of re-compensation and an improvement in liver function. Further studies are needed to assess the impact of treatment on survival and quality of life in long-term follow-up.

Progress in the elimination of hepatitis C virus infection: A population-based cohort study in Spain.

BackgroundThe World Health Organization set targets to eliminate hepatitis C virus (HCV) infection through detection and treatment of all cases by 2030. This study aimed to describe the progress and difficulties in the elimination of HCV infection in Navarra, Spain.MethodsUsing electronic healthcare databases, we performed a population-based prospective cohort study to describe changes in the prevalence of diagnosed active HCV infection at the beginning of 2015 and the end of 2017, the rate of new diagnoses and the rate of post-treatment viral clearance (PTVC) during this period.ResultsAt the beginning of 2015 there were 1503 patients diagnosed with positive HCV-RNA, 2.4 per 1000 inhabitants, and at the end of 2017 the prevalence had decreased by 47%. In the study period, 333 (18 per 100,000 person-years) new positive HCV-RNA cases were detected, but only 76 (23%; 4.2 per 100,000 person-years) did not have anti-HCV antibodies previously detected. Prevalent cases and new diagnoses of active infection were more frequent in men, people born in 1950–1979, HIV-infected patients and in those with lower income levels. Among patients with HCV-RNA, 984 achieved PTVC (22.7 per 100 person-years). PTVC was less frequent in patients born before 1940, in immigrants and in patients with lower income levels.ConclusionsThe prevalence of diagnosed active HCV infection has dropped by almost half over three years, because the number of patients with PTVC was much higher than the number of new diagnoses. Interventions specifically targeted at population groups with less favourable trends may be necessary.

Identification of factors associated with virus level in tonsils of pigs experimentally infected with porcine reproductive and respiratory syndrome virus.

Porcine reproductive and respiratory syndrome (PRRS) is one of the most important global swine diseases from both an economic and animal welfare standpoint. PRRS has plagued the US swine industry for over 25 yr, and containment of PRRS virus (PRRSV) has been unsuccessful to date. The primary phase of PRRS, tracked by serum viremia, typically clears between 21 and 42 d postinfection (dpi) but tonsils are a main site of PRRSV persistence and PRRSV can be detected in tonsils in excess of 150 dpi. Measuring tonsil virus (TV) levels at late stages of infection (6 to 7 wk postinfection) can be used to assess tonsil persistence, as levels of virus in tonsil at this time likely influence how long the virus will remain in the tissue. TV levels were measured on pigs experimentally infected with either the NVSL-97-7895 (NVSL; n = 524) or KS-2006-72109 (KS06; n = 328) PRRSV type 2 isolates across five trials. The objectives of this study were to (i) estimate the heritability of TV levels at 35 or 42 dpi; (ii) identify factors the affect TV level, including serum viremia; (iii) identify genomic regions associated with TV level; and (iv) compare results for the two PRRSV isolates. TV level was lowly heritable for both isolates (NVSL: 0.05 ± 0.06; KS06: 0.11 ± 0.10). Level of TV was phenotypically associated with traits related to viral clearance from serum: pigs with low TV levels had an earlier and faster rate of maximal serum viral clearance, lower total serum viral load, and lower viremia level at 35 or 42 dpi. Although no genomic regions with major effects on TV level were identified, several showed some association (>0.1% of total genetic variance in the NVSL-infected dataset, the KS06-infected dataset, and the combined dataset). These regions contained the genes CCL1, CCL2, CCL8, HS3ST3B1, GALNT10, TCF7, C1QA/B/C, HPSE, G0S2, and CD34, which are involved in viral infiltration or replication, immune cell migration, and viral clearance from tissue. Results were similar between the two PRRSV isolates. In conclusion, selection for viral clearance traits in serum may reduce PRRSV persistence in the tonsil across PRRSV isolates. However, genetic correlations need to be estimated to determine whether this will be successful.

Analysis of an HIV Model with Immune Responses and Cell-to-Cell Transmission

In this paper, a mathematical model is formulated to investigate the dynamics of HIV infection. The model incorporates two routes of infection (namely cell-to-cell transmission and virus-to-cell infection), two types of adaptive immune responses (i.e., cellular and antibody immune response) and two intracellular delays (viz., the eclipse phase and virus production period). By constructing Lyapunov functionals, we show that the global dynamics of the model can be explicitly determined by five reproduction numbers. Using the uncertainty and sensitivity analyses, we obtain the mean values and standard deviation of the five reproduction numbers and find that the reproduction numbers are most sensitive to the death rate of infected cells, viral clearance rate and immune parameters. We further compare four related HIV models and show that cell-to-cell transmission, immune responses and time delays can substantially affect the dynamical behavior of the system. Specifically, cell-to-cell transmission increases the concentration of infected cells. Inclusion of cytotoxic T lymphocyte and virus production delay can significantly reduce the viral load and infected cell concentration, and generate a higher level of uninfected CD4+ T cells. The analytical and numerical results may help to improve the understanding of HIV dynamics.