Dengue is the most prevalent arboviral disease of humans. The host and virus variables associated with dengue virus (DENV) transmission from symptomatic dengue cases (n = 208) to Aedes aegypti mosquitoes during 407 independent exposure events was defined. The 50% mosquito infectious dose for each of DENV-1-4 ranged from 6.29 to 7.52 log10 RNA copies/mL of plasma. Increasing day of illness, declining viremia, and rising antibody titers were independently associated with reduced risk of DENV transmission. High early DENV plasma viremia levels in patients were a marker of the duration of human infectiousness, and blood meals containing high concentrations of DENV were positively associated with the prevalence of infectious mosquitoes 14 d after blood feeding. Ambulatory dengue cases had lower viremia levels compared with hospitalized dengue cases but nonetheless at levels predicted to be infectious to mosquitoes. These data define serotype-specific viremia levels that vaccines or drugs must inhibit to prevent DENV transmission.engue is globally the most important mosquito-borne viral disease of humans, with a global burden of ∼100 million cases per annum (1, 2). Aedes aegypti mosquitoes are the primary mosquito vectors of dengue viruses (DENV), of which there are four virus types (DENV-1-4). Multiple factors influence the likelihood of infection and dissemination of DENV in Ae. aegypti and include the amplitude of daily temperature fluctuations (3), mean temperature (4), and the genotype of mosquito and virus (5), among others (6). The extrinsic incubation period (EIP), a critical determinant of vector competence (7,8), is widely accepted to be 7-14 d for DENV in Ae. aegypti, although a recent modeling analysis of historical DENV transmission data has suggested a wider range of 2-15 d at 30°C (9). A major caveat to many of these observations is that they stem from laboratory experiments with artificially generated virus-spiked blood meals and often in-bred colony mosquitoes.The temporal and virological variables associated with the transmission of DENV from a naturally infected human to a biting Ae. aegypti mosquito are poorly understood. Natural history studies of experimental DENV infection of small cohorts of human volunteers in the 1920s by Siler et al. (10,11), likely using DENV-4 (12), and subsequent studies by Simmons et al. (13), likely using DENV-1 (12), suggested that the window of time before the onset of clinical symptoms that DENV-1 or DENV-4 could be transmitted to Ae. aegypti mosquitoes was 6-18 h or 2 d, respectively (14). After fever onset, the duration of infectiousness was 4-5 d for DENV-1 and up to 2 d for DENV-4, with an EIP in the mosquito of 10 d or more. Consistent with this, mosquitobiting studies by Gubler et al. in the 1960s (15-18) collectively estimated that dengue cases were infectious for 4-5 d after illness onset (range, 2-12 d). The human viremia level required to infect Ae. aegypti mosquitoes is unknown, and therefore it is uncertain what percentage of symptomatic (or asymptomatic...

Background. Dengue is the most common arboviral infection of humans. There are currently no specific treatments for dengue. Balapiravir is a prodrug of a nucleoside analogue (called R1479) and an inhibitor of hepatitis C virus replication in vivo.Methods. We conducted in vitro experiments to determine the potency of balapiravir against dengue viruses and then an exploratory, dose-escalating, randomized placebo-controlled trial in adult male patients with dengue with <48 hours of fever.Results. The clinical and laboratory adverse event profile in patients receiving balapiravir at doses of 1500 mg (n = 10) or 3000 mg (n = 22) orally for 5 days was similar to that of patients receiving placebo (n = 32), indicating balapiravir was well tolerated. However, twice daily assessment of viremia and daily assessment of NS1 antigenemia indicated balapiravir did not measurably alter the kinetics of these virological markers, nor did it reduce the fever clearance time. The kinetics of plasma cytokine concentrations and the whole blood transcriptional profile were also not attenuated by balapiravir treatment.Conclusions. Although this trial, the first of its kind in dengue, does not support balapiravir as a candidate drug, it does establish a framework for antiviral treatment trials in dengue and provides the field with a clinically evaluated benchmark molecule.Clinical Trials Registration. NCT01096576.

Electrochemical and spectroscopic measurements were used to characterize the electrochromic behavior of sputtered V 20 5 films. In response to lithium intercalation, the fundamental optical absorption edge of V 20 5 shifts to high energies by 0.20-0.31 eV as the lithium concentration increases from Li o . o V 20 5 to Lio.86 V 20S' There is a corresponding increase in the near-infrared absorption that exhibits Beer's law behavior at low lithium concentrations. The shift in absorption edge results in a large decrease in absorbance in the 350-4:50 nm wavelength range. This effect is most prevalent in thin films which exhibit a yel10w to colorless optical modulation on lithium intercalation. The cathodic coloration in the near infrared is relatively weak with a maximum coloration efficiency of 35 cm 2 /C [This article is copyrighted as indicated in the article. Reuse of AIP content is subject to the terms at: http://scitation.aip.org/termsconditions. Downloaded to ] IP: 137.

SignificanceIn laboratory experiments, Wolbachia (wMel strain)-infected Aedes aegypti are refractory to disseminated arboviral infections. Yet previous characterizations of wMel-mediated blocking have not considered several biologically and ecologically important factors likely to influence the virus–mosquito interaction. After direct feeding on 141 viremic dengue patients, we demonstrate wMel lowers dengue virus (DENV) transmission potential and lengthens the extrinsic incubation period. Subsequently, using established field populations of wild-type and wMel-infected Ae. aegypti, we compared field- versus laboratory-rearing conditions on mosquito susceptibility to disseminated DENV infection. The magnitude of wMel-mediated virus blocking was even greater when mosquitoes developed under field conditions. These clinically and ecologically relevant findings support Wolbachia introgression into Ae. aegypti populations as a biocontrol method to reduce the transmission of DENV and other arboviruses.

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