What Does Virus Evolution Tell Us about Virus Origins?

Despite recent advances in our understanding of diverse aspects of virus evolution, particularly on the epidemiological scale, revealing the ultimate origins of viruses has proven to be a more intractable problem. Herein, I review some current ideas on the evolutionary origins of viruses and assess how well these theories accord with what we know about the evolution of contemporary viruses. I note the growing evidence for the theory that viruses arose before the last universal cellular ancestor (LUCA). This ancient origin theory is supported by the presence of capsid architectures that are conserved among diverse RNA and DNA viruses and by the strongly inverse relationship between genome size and mutation rate across all replication systems, such that pre-LUCA genomes were probably both small and highly error prone and hence RNA virus-like. I also highlight the advances that are needed to come to a better understanding of virus origins, most notably the ability to accurately infer deep evolutionary history from the phylogenetic analysis of conserved protein structures.     

14. Studies on Poliomyelitis Virus—Concentration and Purification of the Virus

ABSTRACT

For the purpose of determining the immunogenic potency of polio virus, relatively large amounts of concentrated virus material were prepared which had titres of the order of 10¹⁰ T.C.I.D.jo per ml. These were obtained by pervaporating large quantities of tissue culture fluid containing approximately 10⁶⁵ T.C.I.D.JQ per ml.     

Is the Gut the Major Source of Virus in Early Simian Immunodeficiency Virus Infection?

The acute phases of human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) infection are characterized by rapid and profound depletion of CD4⁺ T cells from the guts of infected individuals. The large number of CD4⁺ T cells in the gut (a large fraction of which are activated and express the HIV/SIV coreceptor CCR5), the high level of infection of these cells, and the temporal coincidence of this CD4⁺ T-cell depletion with the peak of virus in plasma in acute infection suggest that the intestinal mucosa may be the major source of virus driving the peak viral load. Here, we used data on CD4⁺ T-cell proportions in the lamina propria of the rectums of SIV-infected rhesus macaques (which progress to AIDS) and sooty mangabeys (which do not progress) to show that in both species, the depletion of CD4⁺ T cells from this mucosal site and its maximum loss rate are often observed several days before the peak in viral load, with few CD4⁺ T cells remaining in the rectum by the time of peak viral load. In contrast, the maximum loss rate of CD4⁺ T cells from bronchoalveolar lavage specimens and lymph nodes coincides with the peak in virus. Analysis of the kinetics of depletion suggests that, in both rhesus macaques and sooty mangabeys, CD4⁺ T cells in the intestinal mucosa are a highly susceptible population for infection but not a major source of plasma virus in acute SIV infection.The acute phase of human immunodeficiency virus (HIV) infection is characterized by moderate CD4⁺ T-cell depletion in blood, followed by a transient partial restoration of CD4⁺ T-cell numbers and eventually by a slow long-term CD4⁺ T-cell decline in the chronic phase that lasts for several years. Studies of CD4⁺ T-cell depletion in mucosal sites, often conducted with simian immunodeficiency virus (SIV)-infected macaques, have demonstrated that mucosal CD4⁺ T-cell depletion is more rapid and profound (3, 10, 13, 19, 21). The severe depletion of cells in the gut in early infection is thought to be driven in part by the phenotype of the cells present, which are predominantly CCR5⁺ and in general more activated than their circulating counterparts. As such, these mucosal CD4⁺ T cells are highly susceptible to productive infection with the dominant CCR5-tropic strains of HIV and SIV present in early infection (20). The rapid depletion of CD4⁺ T cells at mucosal sites is accompanied by relatively high numbers of infected cells (10, 13) and is temporally associated with the peak viral load in plasma, suggesting that the infection of mucosal CD4⁺ T cells may be responsible for the majority of virus replication occurring during acute infection (10, 15, 21, 22).The size of the CD4⁺ T-cell pool in the gut is a matter of some controversy, with estimates ranging from ∼5 to 50% of the total body pool of these cells (reviewed in reference 5). Regardless of the precise numbers, the gut (and particularly the mucosal lamina propria) contains a significant proportion of the body CD4⁺ CCR5⁺ memory T cells, which are depleted very early in infection. However, whether CD4⁺ T cells in the gut are merely a target of early infection or whether they are a major driver of early viral growth and peak viral loads in acute infection is unclear. Here we use a combination of experimental data and modeling to demonstrate that the gut is unlikely to be a major source of virus production in acute SIV infection.     

Transformation of Murine Cells by Two “Slow Viruses,” Visna Virus and Progressive Pneumonia Virus

Visna and progressive pneumonia virus (PPV), two antigenically related, non-oncogenic "slow viruses" which have ribonucleic acid (RNA)-dependent deoxyribonucleic acid (DNA) polymerase activity, were examined for their ability to transform cells. Murine cells which had been exposed to either visna or PPV developed foci of altered, spindle-shaped cells 3 to 4 weeks after infection. Visna and PPV transformed lines were established from these cultures. There was no evidence that other oncogenic DNA or RNA viruses were involved in the observed transformation. Visna or PPV could be "rescued" from all transformed lines by co-cultivation with normal sheep testis cells. "Rescued" virus was identified as visna or PPV, and they retained the capacity to transform mouse cells. These experiments may have important implications in the understanding of both viral carcinogenesis and "slow" viral infections.     

Effect of β-Propiolactone on Sendai Virus

The biological properties (infectivity, hemagglutination, hemolysis, cell fusion, neuraminidase) of Sendai virus were dissociated on the basis of sensitivity to beta-propiolactone, by freeze-thawing, by heating at different temperatures, and by adsorption-elution with formalinized chicken erythrocytes. Possible mechanisms whereby beta-propiolactone selectively destroys viral infectivity are discussed.     

Torque Teno Virus流行与多样性研究进展

Torque Teno Virus(TTV)是环状、无囊膜的人类DNA病毒,是首个感染人类的单链DNA病毒。TTV具有高流行率、全球分布、基因组异质性以及宿主泛嗜性等典型特点,但是其复制机制、基因组异质性的原因、感染机理和致病机制目前尚不清楚。现从TTV病毒流行情况,包括传播途径和流行率、病毒基因组的复制及异质性等方面展开综述。     

Dimerization of Hepatitis E Virus Capsid Protein E2s Domain Is Essential for Virus–Host Interaction

Hepatitis E virus (HEV), a non-enveloped, positive-stranded RNA virus, is transmitted in a faecal-oral manner, and causes acute liver diseases in humans. The HEV capsid is made up of capsomeres consisting of homodimers of a single structural capsid protein forming the virus shell. These dimers are believed to protrude from the viral surface and to interact with host cells to initiate infection. To date, no structural information is available for any of the HEV proteins. Here, we report for the first time the crystal structure of the HEV capsid protein domain E2s, a protruding domain, together with functional studies to illustrate that this domain forms a tight homodimer and that this dimerization is essential for HEV–host interactions. In addition, we also show that the neutralizing antibody recognition site of HEV is located on the E2s domain. Our study will aid in the development of vaccines and, subsequently, specific inhibitors for HEV.     

Autophagy during Early Virus–Host Cell Interactions

Autophagy refers to the conserved, multi-step mechanism that delivers cytosolic cargoes to vesicles of the endo-lysosomal system for degradation. It maintains cellular homeostasis by ensuring the continuous degradation of misformed/senescent intracellular components and the associated recycling of nutrients. Autophagy also represents an important cell-intrinsic defense mechanism against invasion by intracellular pathogens, including viruses. Autophagy might oppose viral invasion by targeting viral particles or viral components for degradation. It can also promote the interaction of viral constituents with receptors specialized in the activation of innate immunity pathways or facilitate the activation of anti-viral adaptive immunity. In response to such pressures, viruses have evolved various sophisticated strategies to avoid anti-viral autophagic responses or to manipulate the autophagic machinery to promote their own replication. This review focuses on our current knowledge of autophagy-related events that take place at early stages during interaction of viruses with host cells as well as on their associated consequences in terms of virus replication and cell fate.     

Immature Dengue Virus: A Veiled Pathogen?

Cells infected with dengue virus release a high proportion of immature prM-containing virions. In accordance, substantial levels of prM antibodies are found in sera of infected humans. Furthermore, it has been recently described that the rates of prM antibody responses are significantly higher in patients with secondary infection compared to those with primary infection. This suggests that immature dengue virus may play a role in disease pathogenesis. Interestingly, however, numerous functional studies have revealed that immature particles lack the ability to infect cells. In this report, we show that fully immature dengue particles become highly infectious upon interaction with prM antibodies. We demonstrate that prM antibodies facilitate efficient binding and cell entry of immature particles into Fc-receptor-expressing cells. In addition, enzymatic activity of furin is critical to render the internalized immature virus infectious. Together, these data suggest that during a secondary infection or primary infection of infants born to dengue-immune mothers, immature particles have the potential to be highly infectious and hence may contribute to the development of severe disease.     

Can Vaccination Save a Zika Virus Epidemic?

Zika virus (ZIKV) is a vector-borne disease that has rapidly spread during the year 2016 in more than 50 countries around the world. If a woman is infected during pregnancy, the virus can cause severe birth defects and brain damage in their babies. The virus can be transmitted through the bites of infected mosquitoes as well as through direct contact from human to human (e.g., sexual contact and blood transfusions). As an intervention for controlling the spread of the disease, we study a vaccination model for preventing Zika infections. Although there is no formal vaccine for ZIKV, The National Institute of Allergy and Infectious Diseases (part of the National Institutes of Health) has launched a vaccine trial at the beginning of August 2016 to control ZIKV transmission, patients who received the vaccine are expected to return within 44 weeks to determine if the vaccine is safe. Since it is important to understand ZIKV dynamics under vaccination, we formulate a vaccination model for ZIKV spread that includes mosquito as well as sexual transmission. We calculate the basic reproduction number of the model to analyze the impact of relatively, perfect and imperfect vaccination rates. We illustrate several numerical examples of the vaccination model proposed as well as the impact of the basic reproduction numbers of vector and sexual transmission and the effect of vaccination effort on ZIKV spread. Results show that high levels of sexual transmission create larger cases of infection associated with the peak of infected humans arising in a shorter period of time, even when a vaccine is available in the population. However, a high level of transmission of Zika from vectors to humans compared with sexual transmission represents that ZIKV will take longer to invade the population providing a window of opportunities to control its spread, for instance, through vaccination.     

Virus infections and apoptosis: Lessons from HIV

Many viruses establish life-long infections in their natural host with few if any clinical manifestations. The relationship between virus and host is a dynamic process in which the virus has evolved the means to coexist by reducing its visibility, while the host immune system attempts to suppress and eliminate infection without damage to itself. We are now beginning to understand that viruses can employ a variety of strategies to evade host immune responses. These include escape from T cell recognition, resistance to     

Dissecting Virus Entry: Replication-Independent Analysis of Virus Binding,Internalization, and Penetration Using Minimal Complementation of β-Galactosidase

Studies of viral entry into host cells often rely on the detection of post-entry parameters, such as viral replication or the expression of a reporter gene, rather than on measuring entry per se. The lack of assays to easily detect the different steps of entry severely hampers the analysis of this key process in virus infection. Here we describe novel, highly adaptable viral entry assays making use of minimal complementation of the E. coli β-galactosidase in mammalian cells. Enzyme activity is reconstituted when a small intravirion peptide (α-peptide) is complementing the inactive mutant form ΔM15 of β-galactosidase. The method allows to dissect and to independently detect binding, internalization, and fusion of viruses during host cell entry. Here we use it to confirm and extend current knowledge on the entry process of two enveloped viruses: vesicular stomatitis virus (VSV) and murine hepatitis coronavirus (MHV).     

High Prevalence of Hepatitis E Virus in Swedish Moose – A Phylogenetic Characterization and Comparison of the Virus from Different Regions

Background

Hepatitis E virus (HEV) infects a range of species, including humans, pigs, wild boars and deer. Zoonotic transmission may contribute to the high HEV seroprevalence in the human population of many countries. A novel divergent HEV from moose (Alces alces) in Sweden was recently identified by partial genome sequencing. Since only one strain was found, its classification within the HEV family, prevalence in moose and zoonotic potential was unclear. We therefore investigated samples from 231 moose in seven Swedish counties for HEV, and sequenced a near complete moose HEV genome. Phylogenetic analysis to classify this virus within the family Hepeviridae and to explore potential host specific determinants was performed.

Methods and Findings

The HEV prevalence of moose was determined by PCR (marker for active infection) and serological assays (marker of past infection) of sera and 51 fecal samples from 231 Swedish moose. Markers of active and past infection were found in 67 (29%) animals, while 34 (15%) were positive for HEV RNA, 43 (19%) were seropositive for anti-HEV antibodies, and 10 (4%) had both markers. The number of young individuals positive for HEV RNA was larger than for older individuals, and the number of anti-HEV antibody positive individuals increased with age. The high throughput sequenced moose HEV genome was 35-60% identical to existing HEVs. Partial ORF1 sequences from 13 moose strains showed high similarity among them, forming a distinct monophyletic clade with a common ancestor to HEV genotype 1-6 group, which includes members known for zoonotic transmission.

Conclusions

This study demonstrates a high frequency of HEV in moose in Sweden, with markers of current and past infection demonstrated in 30% of the animals. Moose is thus an important animal reservoir of HEV. The phylogenetic relationship demonstrated that the moose HEV belonged to the genotype 1-6 group, which includes strains that also infect humans, and therefore may signify a potential for zoonotic transmission of this HEV.