Independent Transmissions Research Articles

NxtSPR: A deadlock-free shortest path routing dedicated to relaying for Triplet-Based many-core Architecture

Deadlock-free routing is a significant challenge in Network-on-Chip (NoC) design as it affects the network’s latency, power consumption, and load balance, impacting the performance of multi-processor systems-on-chip. However, achieving deadlock-free routing will routinely result in expensive overhead as previous solutions either sacrifice performance or power efficiency to proactively avoid deadlocks or impose high hardware complexity to resolve deadlocks when they occur reactively. Utilizing the various characteristics of NoC to implement deadlock-free routing can be significantly more cost-effective with less impact on performance. This paper proposes a relay routing algorithm (NxtSPR) with a shortest path property and a deadlock prevention mechanism based on a synchronized Hamiltonian ring. The proposal is based on an in-depth study of the characteristics of a Triplet-Based many-core Architecture (TriBA) NoC. We establish various important topology-related theories and perform a formal verification (proof-based) for them. By utilizing the critical subgraph and apex of TriBA, NxtSPR can pre-calculate downstream nodes forwarding ports for packets by using a concise judgment strategy. This significantly reduces the computational overhead required for data transmission while optimizing the pipeline design of routers to decrease packet transmission latency and power consumption compared to other TriBA routing algorithms. We group the data transmissions according to the levels of maximum Hamiltonian edges a packet will traverse during its transmission life cycle. Independent data transmissions between groups can avoid mutual interference and resource competition, eliminating potential deadlocks. Gem5 simulation results show that, under the synthetic traffic patterns, compared to the representative (Table) and up-to-date (SPR4T) routing algorithms, NxtSPR achieves a 20.19%, 14.76%, and 5.54%, 4.66% reduction in average packet latency and per-packet power consumption, respectively. Moreover, it has an average of 18.50% and 4.34% improvement in throughput, as compared to them. PARSEC benchmark results show that NxtSPR reduces application runtime by up to a maximum of 22.30% and 12.82% compared to Table and SPR4T, and running the same applications with TriBA results in a maximum runtime reduction of 10.77% compared to 2D-Mesh.

Underwater image enhancement via a channel‐wise transmission estimation network

AbstractUnderwater image enhancement for image processing and underwater robotic vision have recently attracted much academic attention. However, in most existing methods, underwater image enhancement is completed with a simple assumption: the attenuation coefficients are unified across the color channels. This assumption leads to unstable and visually unpleasing enhancement results. Moreover, these methods cannot be successfully applied to explore relatively independent transmissions from multiple color channels with complimentary feature information. To address these challenges, a novel channel‐wise transmission estimation network (CTEN) is proposed, which aims to pioneer the exploration of the transmission difference across the color channels in an underwater scene. Specifically, a color‐specific correction module is proposed to automatically quantify the transmission ability of multiple color channels in the underwater environment. Furthermore, a channel‐wise transmission estimation module is designed to simultaneously explore the relative independence of multi‐color channels and estimate the medium transmissions for each color channel, which represents the attenuation degree of different color radiances after reflecting in the water. Then, a novel residual strategy is introduced to integrate these two modules to complete the underwater enhancement. Using the model, the authors are able to provide an answer as to why channel‐wise transmission estimation are better than single transmission estimation and establish a generalization theory to show the effect of the independent transmission estimation model for each color channel. Experiments on several underwater image datasets verify the superiority of the proposed CTEN model.

Reconstructing early transmission networks of SARS-CoV-2 using a genomic mutation model.

The coronavirus disease 2019 (COVID-19) pandemic has greatly damaged human society, but the origins and early transmission patterns of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pathogen remain unclear. Here, we reconstructed the transmission networks of SARS-CoV-2 during the first three and six months since its first report based on ancestor-offspring relationships using BANAL-52-referenced mutations. We explored the position (i.e., root, middle, or tip) of early detected samples in the evolutionary tree of SARS-CoV-2. In total, 6 799 transmission chains and 1 766 transmission networks were reconstructed, with chain lengths ranging from 1-9 nodes. The root node samples of the 1 766 transmission networks were from 58 countries or regions and showed no common ancestor, indicating the occurrence of many independent or parallel transmissions of SARS-CoV-2 when first detected (i.e., all samples were located at the tip position of the evolutionary tree). No root node sample was found in any sample ( n=31, all from the Chinese mainland) collected in the first 15 days from 24 December 2019. Results using six-month data or RaTG13-referenced mutation data were similar. The reconstruction method was verified using a simulation approach. Our results suggest that SARS-CoV-2 may have already been spreading independently worldwide before the outbreak of COVID-19 in Wuhan, China. Thus, a comprehensive global survey of human and animal samples is essential to explore the origins of SARS-CoV-2 and its natural reservoirs and hosts.

Link-Delay-Aware Reinforcement Scheduling for Data Aggregation in Massive IoT

Over the past few years, the use of wireless sensor networks in a range of Internet of Things (IoT) scenarios has grown in popularity. Since IoT sensor devices have restricted battery power, a proper IoT data aggregation approach is crucial to prolong the network lifetime. To this end, current approaches typically form a virtual aggregation backbone based on a connected dominating set or maximal independent set to utilize independent transmissions of dominators. However, they usually have a fairly long aggregation delay because the dominators become bottlenecks for receiving data from all dominatees. The problem of time-efficient data aggregation in multichannel duty-cycled IoT sensor networks is analyzed in this paper. We propose a novel aggregation approach, named LInk-delay-aware REinforcement (LIRE), leveraging active slots of sensors to explore a routing structure with pipeline links, then scheduling all transmissions in a bottom-up manner. The reinforcement schedule accelerates the aggregation by exploiting unused channels and time slots left off at every scheduling round. LIRE is evaluated in a variety of simulation scenarios through theoretical analysis and performance comparisons with a state-of-the-art scheme. The simulation results show that LIRE reduces more than 80% aggregation delay compared to the existing scheme.

The Tensor Multi-Linear Channel and Its Shannon Capacity

Tensors are multi-way arrays which can be used to model systems spanning many domains. This work proposes to use tensors for characterizing, analyzing, and designing multi-domain communication systems. Most modern day communication systems make use of coding and modulation across different domains such as space, frequency, time. Hence a unified mathematical framework characterizing such a multiple-domain system in an intuitive manner is well needed. In this paper, we present such a unified framework that characterizes a communication system with <inline-formula> <tex-math notation="LaTeX">$N$ </tex-math></inline-formula> input domains, <inline-formula> <tex-math notation="LaTeX">$M$ </tex-math></inline-formula> output domains and an <inline-formula> <tex-math notation="LaTeX">$M+N$ </tex-math></inline-formula> domains multi-linear tensor channel. The proposed framework is generic where the physical interpretation of the domains is system specific. We illustrate a few examples from multi-antenna multi-carrier and multi-user systems that fit the proposed framework. Assuming a fixed tensor channel, we provide an information theoretic analysis by deriving its Shannon capacity and input power allocation under a variety of power constraints. In this paper we show how the tensor framework&#x2019;s suitability to mathematically describe a family of power constraints can be used to design and analyze various multiple domain communication systems. The tensor based approach extends water-filling from a matrix setting to tensors, encapsulating the effects of multiple domains thereby allowing joint multi-domain precoding. We show that the capacity pre-log for a tensor channel increases exponentially in the number of domains, indicating the potential of tensor based multi-domain communication systems to provide the large information transmission rates envisaged for 5G and beyond systems. We also show the application of the tensor framework in characterizing the capacity and rate regions of multi-user MIMO channels. Both multiple access and interference channels are considered where the tensor based approach leads to a coordinated users transmission scheme. Such a scheme ensures higher achievable sum rates as compared to independent user transmissions.

Abū Yūsuf’s Ikhtilāf Abī Ḥanīfa wa-Ibn Abī Laylā and the Transmission of Knowledge in the Formative Period of the Ḥanafī School

Abstract In this essay, I address the longstanding debate on attributing legal texts to formative-period authors by focusing on the transmission of one early text: Ikhtilāf Abī Ḥanīfa wa-Ibn Abī Laylā, attributed to Abū Yūsuf (d. 182/798), and its reception by one early jurist: Abū Jaʿfar al-Ṭaḥāwī (d. 321/933). I argue that al-Ṭaḥāwī’s written work attests to the existence of multiple independent transmissions of Abū Yūsuf’s text and that these transmissions confirm the attribution of the text to Abū Yūsuf. I then reflect on the formative-period written materials consulted by al-Ṭaḥāwī and his contemporaries, arguing that their access to material from a period in which oral transmission was predominant gave them a unique standing in the eyes of classical-era jurists. Finally, I reflect on the role of digests (mukhtaṣars), particularly those of al-Ṭaḥāwī and al-Qudūrī (d. 428/1037), in sealing the movement from orality in the formative period to fixed written texts in the classical period.

Using host genetics to infer the global spread and evolutionary history of HCV subtype 3a.

Studies have shown that hepatitis C virus subtype 3a (HCV-3a) is likely to have been circulating in South Asia before its global spread. However, the time and route of this dissemination remain unclear. For the first time, we generated host and virus genome-wide data for more than 500 patients infected with HCV-3a from the UK, North America, Australia, and New Zealand. We used the host genomic data to infer the ancestry of the patients and used this information to investigate the epidemic history of HCV-3a. We observed that viruses from hosts of South Asian ancestry clustered together near the root of the tree, irrespective of the sampling country, and that they were more diverse than viruses from other host ancestries. We hypothesized that South Asian hosts are more likely to have been infected in South Asia and used the inferred host ancestries to distinguish between the location where the infection was acquired and where the sample was taken. Next, we inferred that three independent transmission events resulted in the spread of the virus from South Asia to the UK, North America, and Oceania. This initial spread happened during or soon after the end of World War II. This was subsequently followed by many independent transmissions between the UK, North America, and Oceania. Using both host and virus genomic information can be highly informative in studying the virus epidemic history, especially in the context of chronic infections where migration histories need to be accounted for.

TOTAL FOCUSING METHOD BASED ULTRASONIC PHASED ARRAY IMAGING IN THICK STRUCTURES

Abstract Ultrasonic non-destructive testing traditionally uses a conventional monolithic transducer. An approach similar to this comprising of independent single transmissions but with reception performed by all the elements in phased array ultrasonics is known as Full Matrix Capture (FMC). The acquired data is processed by Total Focusing Method (TFM). Conventional FMC-TFM has limitations in the inspection at large depth in attenuating materials due to single element transmission. To improve the beam forming process, coherent recombination of the plane wave with specific angles is utilized in transmission and the same aperture is used for the reception in Plane Wave Imaging (PWI). A new methodology called Angle Beam Virtual Source FMC-TFM (ABVSFMC-TFM) is proposed to inspect thick attenuating materials such as nickel base alloys. The ABVSFMC method leads to improved Signal to Noise Ratio (SNR) as compared to the conventional FMC due to increased energy with directivity during transmission using a group of elements and improved divergence as compared to the PWI due to a small virtual source near the sample surface. In the present paper, FMC-TFM, PWI-TFM and ABVSFMC-TFM methods are compared for inspection of thick nickel base superalloy (Alloy 617) with slots at various depths in the range of 25-200 mm. Optimization of the incidence angle has been performed by beam computation in CIVA software. Results obtained by CIVA simulations are discussed and also compared for the three methods.

Movement energy consumption and thermal mode of GTS operation of a small loader with non-controlled wheels

Transmission of small wheeled loaders with onboard rotary system has two independent adjustable hydraulic volume transmissions. The efficiency of this type of transmission is determined by the thermal state of its components. The thermal mode of the hydro-volumetric gears of the drive depends not only on the energy consumption for the vehicle movement, but also on the design of the cooling system. The article deals with the movement of the loader with the onboard system of rotation in the most loaded modes of operation: acceleration, deceleration and at turning. The regularities that determine the load of the hydro-volumetric gears of the traction drive and their heat emission are established. The maximum moment of resistance of rotation of the right and left sides of the car, including that for the cylindrical tires, the tangential force on the wheels of the most loaded running board and the coefficient of resistance to the rotation of each of the sides with allowance for hydrodynamic losses and pressure whose fluid is in the drive of traction motors have been determined. The dependence of the pressure in the running and trailing sides depending on the radius of rotation of the machine was obtained, the magnitude of the power was found, which is converted into thermal energy and the oil temperature in the traction drive. As a result of the conducted researches the dependence of thermal power losses in the transmission of the loader on the distance of cargo transportation is proposed and rational modes of operation of the vehicle are determined.

Zoonotic spillover infections with Borna disease virus 1 leading to fatal human encephalitis, 1999–2019: an epidemiological investigation

In 2018-19, Borna disease virus 1 (BoDV-1), the causative agent of Borna disease in horses, sheep, and other domestic mammals, was reported in five human patients with severe to fatal encephalitis in Germany. However, information on case frequencies, clinical courses, and detailed epidemiological analyses are still lacking. We report the occurrence of BoDV-1-associated encephalitis in cases submitted to the Institute of Clinical Microbiology and Hygiene, Regensburg University Hospital, Regensburg, Germany, and provide a detailed description of newly identified cases of BoDV-1-induced encephalitis. All brain tissues from 56 encephalitis cases from Bavaria, Germany, of putative viral origin (1999-2019), which had been submitted for virological testing upon request of the attending clinician and stored for stepwise diagnostic procedure, were systematically screened for BoDV-1 RNA. Two additional BoDV-1-positive cases were contributed by other diagnostic centres. Positive results were confirmed by deep sequencing, antigen detection, and determination of BoDV-1-reactive antibodies in serum and cerebrospinal fluid. Clinical and epidemiological data from infected patients were collected and analysed. BoDV-1 RNA and bornavirus-reactive antibodies were detected in eight newly analysed encephalitis cases and the first human BoDV-1 isolate was obtained from an unequivocally confirmed human BoDV-1 infection from the endemic area. Six of the eight BoDV-1-positive patients had no record of immunosuppression before the onset of fatal disease, whereas two were immunocompromised after solid organ transplantation. Typical initial symptoms were headache, fever, and confusion, followed by various neurological signs, deep coma, and severe brainstem involvement. Seven of nine patients with fatal encephalitis of unclear cause were BoDV-1 positive within one diagnostic centre. BoDV-1 sequence information and epidemiological analyses indicated independent spillover transmissions most likely from the local wild animal reservoir. BoDV-1 infection has to be considered as a potentially lethal zoonosis in endemic regions with reported spillover infections in horses and sheep. BoDV-1 infection can result in fatal encephalitis in immunocompromised and apparently healthy people. Consequently, all severe encephalitis cases of unclear cause should be tested for bornaviruses especially in endemic regions. German Federal Ministry of Education and Research.

WFRFT-Aided Power-Efficient Multi-Beam Directional Modulation Schemes Based on Frequency Diverse Array

The artificial noise (AN) aided multi-beam directional modulation (DM) technology is capable of wireless physical layer secure (PLS) transmissions for multiple desired receivers in free space. The application of AN, however, makes it less power-efficient for such a DM system. To address this problem, the weighted fractional Fourier transform (WFRFT) technology is employed in this paper to achieve power-efficient multi-beam DM transmissions. Specifically, a power-efficient multi-beam WFRFT-DM scheme with cooperative receivers and a power-efficient multi-beam WFRFT-DM scheme with independent receivers are proposed based on frequency diverse array (FDA), respectively. The bit error rate (BER), secrecy rate, and robustness of the proposed multi-beam WFRFT-DM schemes are analyzed. Simulations demonstrate that 1) the proposed multi-beam WFRFT-DM schemes are more power-efficient than the conventional multi-beam AN-DM scheme; 2) the transmission security can also be guaranteed even if the eavesdroppers are located close to or the same as the desired receivers; and 3) the proposed multi-beam WFRFT-DM schemes are capable of independent transmissions for different desired receivers with different modulations.

VerCoLib: Fast and Versatile Communication for FPGAs via PCI Express

PCI Express plays a vital role in including FPGA accelerators into high-performance computing systems. This also includes direct communication between multiple FPGAs, without any involvement of the main memory of the host. We present a highly configurable hardware interface that supports DMA-based connections to a host system as well as direct communication between multiple FPGAs. Our implementation offers unidirectional channels to connect FPGAs, allowing for precise adaptation to all kinds of use cases. Multiple channels to the same endpoint can be used to realise independent data transmissions. While the main focus of this work is flexibility, we are able to show maximum throughput for connections between two FPGAs and up to 92% of the available bandwidth for connections between the FPGA and the host system.

On the Implementation of a Dynamic Direction Modulation System with Vector Modulators

Dynamic directional modulation (DDM) has already proven to be an efficient technique to achieve physical layer security in wireless communications. System architectures based on vector modulators provide a flexible framework to implement synthesis methods that allow us to obtain increased security and/or independent multichannel transmissions. However, the implementation of DDM with vector modulators requires an accurate calibration (amplitude and phase) of every component in the RF path. In this contribution, we study the sensitivity of the response of a DDM system based on commercial vector modulators showing how to correct the nonideal behavior of all the components thanks to the flexibility provided by the vector modulator.

Real-Time Molecular Survey of &lt;i&gt;Mycobacterium tuberculosis&lt;/i&gt; Isolates from 2008 to 2018 Reveals Tuberculosis Transmission in a Tertiary-Care University Hospital

Background: Molecular survey including whole-genome sequencing (WGS) of Mycobacterium tuberculosis isolates is a reliable tool to reveal clonal outbreaks. Here, both genomic and epidemiological investigations were coupled in a prospective approach to assess nosocomial tuberculosis (TB) transmission in a tertiary-care hospital. Methods: Since 2008, the Mycobacteria laboratory of the Lyon university hospital, has implemented a prospective population-based survey by systematic genotyping (first using spoligo- and MIRU typing, and WGS since 2017) of M. tuberculosis isolates in the Rhone-Alpes region. Conventional contact-tracing of TB cases was conducted in accordance with French guidelines. Findings: Since 2008, among 3230 cases of microbiologically-proven TB, 96 molecular clusters with confirmed transmissions were identified. Four clusters were health care-related, representing eight patients, including three independent transmissions of susceptible M. tuberculosis in lung transplant recipients, and one transmission of a multi-resistant strain. Epidemiological investigation validated nosocomial transmissions in these four health care-related clusters. One nosocomial transmission was imbedded in a much larger community transmission chain involving ten patients. Corrective measures implemented were to discard any admission of TB patients in the transplant surgery hospital, and to construct a building equipped with negative-pressure ventilation rooms dedicated to TB management. Interpretation: TB molecular survey is a valuable strategy to detect unsuspected transmission chains, particularly among health-care facilities. Prospective monitoring and tight partnership with public health agencies render survey-guided prevention control measures possible. Funding Statement: LABEX ECOFECT (ANR-11-LABX-0048) of the Lyon University as part of the research program Investissements d'Avenir (ANR-11-IDEX-0007) operated by the French National Research Agency (ANR). Declaration of Interests: The authors declare no competing interests. Ethics Approval Statement: The study was approved by the Lyon University Hospital Ethical Committee.

All Cognitive MIMO: New Multiuser Detection Approach With Different Priorities

A new detection scheme for multiuser multiple-input multiple-output (MIMO) systems is analytically presented. In particular, the transmitting users are being categorized in two distinct priority service groups, while they communicate directly with a multi-antenna receiver. The linear zero-forcing scheme is applied in two consecutive detection stages upon the signal reception. In the first stage, the signals of one service group are detected, followed by the second stage, including the corresponding detection of the remaining signals. An appropriate switching scheme based on specific transmission quality requirements is utilized prior to the detection so as to allocate the signals of a given service group to the suitable detection stage. The objective is the provision of the reception quality for both service groups. The proposed approach can be implemented directly in cognitive radio communication assigning the secondary users to the appropriate service group. The exact outage probability of the considered system is derived in closed form. The special case of massive MIMO is further studied yielding some useful engineering outcomes; the effective channel coherence time and a certain optimality condition defining both the transmission quality and effective number of independent transmissions.

Endogenous retroviruses of non-avian/mammalian vertebrates illuminate diversity and deep history of retroviruses.

The deep history and early diversification of retroviruses remains elusive, largely because few retroviruses have been characterized in vertebrates other than mammals and birds. Endogenous retroviruses (ERVs) documented past retroviral infections and thus provide ‘molecular fossils’ for studying the deep history of retroviruses. Here we perform a comprehensive phylogenomic analysis of ERVs within the genomes of 92 non-avian/mammalian vertebrates, including 72 fishes, 4 amphibians, and 16 reptiles. We find that ERVs are present in all the genomes of jawed vertebrates, revealing the ubiquitous presence of ERVs in jawed vertebrates. We identify a total of >8,000 ERVs and reconstruct ~450 complete or partial ERV genomes, which dramatically expands the phylogenetic diversity of retroviruses and suggests that the diversity of exogenous retroviruses might be much underestimated in non-avian/mammalian vertebrates. Phylogenetic analyses show that retroviruses cluster into five major groups with different host distributions, providing important insights into the classification and diversification of retroviruses. Moreover, we find retroviruses mainly underwent frequent host switches in non-avian/mammalian vertebrates, with exception of spumavirus-related viruses that codiverged with their ray-finned fish hosts. Interestingly, ray-finned fishes and turtles appear to serve as unappreciated hubs for the transmission of retroviruses. Finally, we find retroviruses underwent many independent water-land transmissions, indicating the water-land interface is not a strict barrier for retrovirus transmission. Our analyses provide unprecedented insights into and valuable resources for studying the diversification, key evolutionary transitions, and macroevolution of retroviruses.

A system to evaluate gas network capacities: Concepts and implementation

In 2005 the European Union liberalized the gas market with a disruptive change and decoupled trading of natural gas from its transport. The gas is now transported by independent so-called transmissions system operators or TSOs. The market model established by the European Union views the gas transmission network as a black box, providing shippers (gas traders and consumers) the opportunity to transport gas from any entry to any exit. TSOs are required to offer the maximum possible capacities at each entry and exit such that any resulting gas flow can be realized by the network. The revenue from selling these capacities is more than one billion Euro in Germany alone, but overestimating the capacity might compromise the security of supply. Therefore, evaluating the available transport capacities is extremely important to the TSOs.This is a report on a large project in mathematical optimization, set out to develop a new toolset for evaluating gas network capacities. The goals and the challenges as they occurred in the project are described, as well as the developments and design decisions taken to meet the requirements.

High Rates of Transmission of Drug-resistant HIV in Aruba Resulting in Reduced Susceptibility to the WHO Recommended First-line Regimen in Nearly Half of Newly Diagnosed HIV-infected Patients

In Western countries emergence of human immunodeficiency virus (HIV) drug resistance has tremendously decreased, and transmission of drug resistance has merely stabilized in recent years. However, in many endemic settings with limited resources rates of emerging and transmitted drug resistance are not regularly assessed. We performed a survey including all HIV-infected individuals who received resistance testing in 2010-2015 in Aruba, a highly endemic HIV area in the Caribbean. Transmitted HIV drug resistance was determined using World Health Organization (WHO) criteria. Transmission dynamics were investigated using phylogenetic analyses. In a subset, baseline samples were re-analyzed using next generation sequencing (NGS). Baseline resistance testing was performed in 104 newly diagnosed untreated individuals (54% of all newly diagnosed individuals in 2010-2015): 86% were men, 39% were foreign-born, and 22% had AIDS at diagnosis. And 33% (95% CI: 24-42%) was infected with a drug-resistant HIV variant. The prevalence of resistance to non-nucleoside reverse transcriptase inhibitors (NNRTIs) reached 45% (95% CI: 27-64%) in 2015, all based on the prevalence of mutation K103N. NGS did not demonstrate additional minority K103N-variants compared to routine resistance testing. K103N-harboring strains were introduced into the therapy-unexposed population via at least 6 independent transmissions epidemiologically linked to the surrounding countries. Virological failure of the WHO-recommended first-line NNRTI-based regimen was higher in the presence of K103N. The prevalence of resistant HIV in Aruba has increased to alarming levels, compromising the WHO-recommended first-line regimen. As adequate surveillance as advocated by the WHO is limited, the Caribbean region could face an unidentified rise of NNRTI-resistant HIV.

Tracking HCV protease population diversity during transmission and susceptibility of founder populations to antiviral therapy

Due to the highly restricted species-tropism of Hepatitis C virus (HCV) a limited number of animal models exist for pre-clinical evaluation of vaccines and antiviral compounds. The human-liver chimeric mouse model allows heterologous challenge with clinically relevant strains derived from patients. However, to date, the transmission and longitudinal evolution of founder viral populations in this model have not been characterized in-depth using state-of-the-art sequencing technologies. Focusing on NS3 protease encoding region of the viral genome, mutant spectra in a donor inoculum and individual recipient mice were determined via Illumina sequencing and compared, to determine the effects of transmission on founder viral population complexity. In all transmissions, a genetic bottleneck was observed, although diverse viral populations were transmitted in each case. A low frequency cloud of mutations (<1%) was detectable in the donor inoculum and recipient mice, with single nucleotide variants (SNVs) > 1% restricted to a subset of nucleotides. The population of SNVs >1% was reduced upon transmission while the low frequency SNV cloud remained stable. Fixation of multiple identical synonymous substitutions was apparent in independent transmissions, and no evidence for reversion of T-cell epitopes was observed. In addition, susceptibility of founder populations to antiviral therapy was assessed. Animals were treated with protease inhibitor (PI) monotherapy to track resistance associated substitution (RAS) emergence. Longitudinal analyses revealed a decline in population diversity under therapy, with no detectable RAS >1% prior to therapy commencement. Despite inoculation from a common source and identical therapeutic regimens, unique RAS emergence profiles were identified in different hosts prior to and during therapeutic failure, with complex mutational signatures at protease residues 155, 156 and 168 detected. Together these analyses track viral population complexity at high-resolution in the human-liver chimeric mouse model post-transmission and under therapeutic intervention, revealing novel insights into the evolutionary processes which shape viral protease population composition at various critical stages of the viral life-cycle.

Vpu-Mediated Counteraction of Tetherin Is a Major Determinant of HIV-1 Interferon Resistance

ABSTRACTHuman immunodeficiency virus type 1 (HIV-1) groups M, N, O, and P are the result of independent zoonotic transmissions of simian immunodeficiency viruses (SIVs) infecting great apes in Africa. Among these, only Vpu proteins of pandemic HIV-1 group M strains evolved potent activity against the restriction factor tetherin, which inhibits virus release from infected cells. Thus, effective Vpu-mediated tetherin antagonism may have been a prerequisite for the global spread of HIV-1. To determine whether this particular function enhances primary HIV-1 replication and interferon resistance, we introduced mutations into the vpu genes of HIV-1 group M and N strains to specifically disrupt their ability to antagonize tetherin, but not other Vpu functions, such as degradation of CD4, down-modulation of CD1d and NTB-A, and suppression of NF-κB activity. Lack of particular human-specific adaptations reduced the ability of HIV-1 group M Vpu proteins to enhance virus production and release from primary CD4+ T cells at high levels of type I interferon (IFN) from about 5-fold to 2-fold. Interestingly, transmitted founder HIV-1 strains exhibited higher virion release capacity than chronic control HIV-1 strains irrespective of Vpu function, and group M viruses produced higher levels of cell-free virions than an N group HIV-1 strain. Thus, efficient virus release from infected cells seems to play an important role in the spread of HIV-1 in the human population and requires a fully functional Vpu protein that counteracts human tetherin.