The recruitment of TRiC chaperonin in rotavirus viroplasms correlates with virus replication.

Rotavirus (RV) replication takes place in the viroplasms, cytosolic inclusions that allow the synthesis of virus genome segments and their encapsidation in the core shell, followed by the addition of the second layer of the virion. The viroplasms are composed of several viral proteins, including NSP5, which serves as the main building block. Microtubules, lipid droplets, and miRNA-7 are among the host components recruited in viroplasms. We investigated the interaction between RV proteins and host components of the viroplasms by performing a pull-down assay of lysates from RV-infected cells expressing NSP5-BiolD2. Subsequent tandem mass spectrometry identified all eight subunits of the tailless complex polypeptide I ring complex (TRiC), a cellular chaperonin responsible for folding at least 10% of the cytosolic proteins. Our confirmed findings reveal that TRiC is brought into viroplasms and wraps around newly formed double-layered particles. Chemical inhibition of TRiC and silencing of its subunits drastically reduced virus progeny production. Through direct RNA sequencing, we show that TRiC is critical for RV replication by controlling dsRNA genome segment synthesis, particularly negative-sense single-stranded RNA. Importantly, cryo-electron microscopy analysis shows that TRiC inhibition results in defective virus particles lacking genome segments and polymerase complex (VP1/VP3). Moreover, TRiC associates with VP2 and NSP5 but not with VP1. Also, VP2 is shown to be essential for recruiting TRiC in viroplasms and preserving their globular morphology. This study highlights the essential role of TRiC in viroplasm formation and in facilitating virion assembly during the RV life cycle. IMPORTANCE: The replication of rotavirus takes place in cytosolic inclusions termed viroplasms. In these inclusions, the distinct 11 double-stranded RNA genome segments are co-packaged to complete a genome in newly generated virus particles. In this study, we show for the first time that the tailless complex polypeptide I ring complex (TRiC), a cellular chaperonin responsible for the folding of at least 10% of the cytosolic proteins, is a component of viroplasms and is required for the synthesis of the viral negative-sense single-stranded RNA. Specifically, TRiC associates with NSP5 and VP2, the cofactor involved in RNA replication. Our study adds a new component to the current model of rotavirus replication, where TRiC is recruited to viroplasms to assist replication.

Political Ideology Direction of Policy Agendas and Maternal Mortality Outcomes in the U.S., 1915-2007.

OBJECTIVES: The causes for persistently high and increasing maternal mortality rates in the United States have been elusive. METHODS: We use the shift in the ideological direction of the Republican and the Democratic parties in the 1960s, to test the hypothesis that fluctuations in overall and race-specific maternal mortality rates (MMR) follow the power shifts between the parties before and after the Political Realignment (PR) of the 1960s. RESULTS: Using time-series data analysis methods, we find that, net of trend, overall and race-specific MMRs were higher under Democratic administrations than Republican ones before the PR (1915-1965)-i.e., when the Democratic Party was a protector of the Jim Crow system. This pattern, however, changed after the PR (1966-2007), with Republican administrations underperforming Democratic ones-i.e., during the period when the Republican Party shifted toward a more economically and socially conservative agenda. The pre-post PR partisan shifts in MMRs were larger for Black (9.5%, p < . 01 ) relative to White mothers (7.4%, p < . 05 ) during the study period. CONCLUSIONS FOR PRACTICE: These findings imply that parties and the ideological direction of their agendas substantively affect the social determinants of maternal health and produce politized health outcomes.

Mechanical disassembly of human picobirnavirus like particles indicates that cargo retention is tuned by the RNA-coat protein interaction.

Here we investigate the cargo retention of individual human picobirnavirus (hPBV) virus-like particles (VLPs) which differ in the N-terminal of their capsid protein (CP): (i) hPBV CP contains the full-length CP sequence; (ii) hPBV Δ45-CP lacks the first 45 N-terminal residues; and (iii) hPBV Ht-CP is the full-length CP with a N-terminal 36-residue tag that includes a 6-His segment. Consequently, each VLP variant holds a different interaction with the ssRNA cargo. We used atomic force microscopy (AFM) to induce and monitor the mechanical disassembly of individual hPBV particles. First, while Δ45-CP particles that lack ssRNA allowed a fast tip indentation after breakage, CP and Ht-CP particles that pack heterologous ssRNA showed a slower tip penetration after being fractured. Second, mechanical fatigue experiments revealed that the increased length in 8% of the N-terminal (Ht-CP) makes the virus particles to crumble ∼10 times slower than the wild type N-terminal CP, indicating enhanced RNA cargo retention. Our results show that the three differentiated N-terminal topologies of the capsid result in distinct cargo release dynamics during mechanical disassembly experiments because of the different interaction with RNA.

Rotavirus Particle Disassembly and Assembly In Vivo and In Vitro.

Rotaviruses (RVs) are non-enveloped multilayered dsRNA viruses that are major etiologic agents of diarrheal disease in humans and in the young in a large number of animal species. The viral particle is composed of three different protein layers that enclose the segmented dsRNA genome and the transcriptional complexes. Each layer defines a unique subparticle that is associated with a different phase of the replication cycle. Thus, while single- and double-layered particles are associated with the intracellular processes of selective packaging, genome replication, and transcription, the viral machinery necessary for entry is located in the third layer. This modular nature of its particle allows rotaviruses to control its replication cycle by the disassembly and assembly of its structural proteins. In this review, we examine the significant advances in structural, molecular, and cellular RV biology that have contributed during the last few years to illuminating the intricate details of the RV particle disassembly and assembly processes.

Spontaneous Interconversion between Different Narrowly Defined Shapes of Rotavirus Double-Layered Particles Studied in Real Time by High-Resolution Mobility Analysis.

Rotavirus double-layered particles (DLPs) are studied in the gas phase with a high-resolution differential mobility analyzer (DMA). DLPs were transferred to 10 mM aqueous ammonium acetate, electrosprayed into the gas phase, converted into primarily singly charged particles, and DMA-analyzed. Up to seven slightly different conformations were resolved, whose apparently random, fast (minutes), and reversible interconversions were followed in real time. They sometimes evolved into just two distinct structures, with periods of one dominating over the other and vice versa. Differences between the DLP structures in solution and in the gas phase are clearly revealed by the smaller DLP diameter found here (60 versus 70 nm). Nevertheless, we argue that the multiple gas-phase conformers observed originate in as many conformations pre-existing in solution. We further hypothesize that these conformers correspond to incomplete DLPs having lost some of the VP6 trimer quintets surrounding each of the 12 5-fold axes. Instances of this peculiar loss have been previously documented by cryoelectron microscopy for the rotavirus Wa strain, as well as via charge detection mass spectrometry for five other rotavirus strains included in the RotaTec vaccine. Evidence of this loss systematically found for all 7 rotavirus types so far studied in aqueous ammonium acetate may be a special feature of this electrolyte.

Black-White differences in perceived lifetime discrimination by education and income in the MIDUS Study in the U.S.

There is growing evidence on the negative effects of perceived discrimination on health outcomes and their interactions with indicators of socioeconomic status. However, less has been studied on whether income and education lead individuals of a different race to encounter different discriminatory experiences in their lifetime. Using data from the national survey of the Midlife Development in the United States-MIDUS 1 (1995-1996) and MIDUS Refresher (2011-2014)-on eight measures of perceived lifetime discrimination, this study compares discriminatory experiences of Black and White persons in two time periods. We applied generalized structural equation models and generalized linear models to test multiplicative effects of income and education by race on lifetime discrimination. In both periods, we find substantive disparities between White and Black people in all types of lifetime discrimination, with Black people reporting much higher levels of discrimination. Such disparities exacerbated in the top cohorts of society, yet these associations have changed in time, with White individuals reporting increasing levels of discrimination. Results show that, for Black people in the mid-1990s, perceived discrimination increased as education and income increased. This finding persisted for education by the early 2010s; income effects changed as now both, low- and high-income Black people, reported the highest levels of discrimination. These findings highlight a policy conundrum, given that increasing income and education represent a desirable course of action to improve overall discrimination and health outcomes. Yet, we show that they may unintendingly exacerbate racial disparities in discrimination. We also show that the U.S. is moving toward a stagnation period in health outcomes improvement, with racial disparities in discrimination shrinking at the expense of a deterioration of whites' lifetime discriminatory experiences. Our results highlight the need for a multi-systems policy approach to prevent all forms of discrimination including those due to historical, institutional, legal, and sociopolitical structures.

The Political Realignment of Health: How Partisan Power Shaped Infant Health in the United States, 1915-2017.

The US two-party system was transformed in the 1960s when the Democratic Party abandoned its Jim Crow protectionism to incorporate the policy agenda fostered by the civil rights movement, and the Republican Party redirected its platform toward socioeconomic and racial conservatism. The authors argue that the policy agendas promoted by the two parties through presidents and state legislatures codify a racially patterned access to resources and power detrimental to the health of all. To test the hypothesis that fluctuations in overall and race-specific infant mortality rates (IMRs) shift between the parties in power before and after the political realignment (PR), the authors apply panel data analysis methods to state-level data from the National Center for Health Statistics for the period 1915 through 2017. Net of trend, overall, and race-specific IMRs were not statistically different between presidential parties before the PR. This pattern, however, changed after the PR, with Republican administrations consistently underperforming Democratic ones. Net of trend, non-Southern state legislatures controlled by Republicans underperform Democratic ones in overall and racial IMRs in both periods.

Partisan Control of U.S. State Governments: Politics as a Social Determinant of Infant Health.

INTRODUCTION: State policies and programs affect population health; yet, little is known about the connections between health and the political institutions and actors that prescribe and execute those policies and programs. METHODS: The 2-way fixed-effects regression models were fitted to data from the National Center for Health Statistics, 1969-2014, to estimate logged infant mortality rate differentials between Republican- and non-Republican‒controlled state legislatures. These data were used in 2020 to hypothesize that net of trend, fluctuations in infant mortality rates-overall and by race-correlate with the party that controls state legislatures (the Lower House, the Upper House, and Congress). RESULTS: Findings show that state infant and postneonatal mortality rates are substantively higher under Republican-controlled state legislatures than under non-Republican‒controlled ones. The effect size is larger for postneonatal than for neonatal mortality. Findings suggest that effects may be greater for Black than for White infants, although the race-specific results are estimated imprecisely. The governor's party shows no substantive impacts on infant mortality rates net of party control of the Lower House. CONCLUSIONS: Findings support the proposition that the social determinants of health are constructed, at least in part, by the power vested in governments.

Nanotechnological Applications Based on Bacterial Encapsulins.

Encapsulins are proteinaceous nanocontainers, constructed by a single species of shell protein that self-assemble into 20-40 nm icosahedral particles. Encapsulins are structurally similar to the capsids of viruses of the HK97-like lineage, to which they are evolutionarily related. Nearly all these nanocontainers encase a single oligomeric protein that defines the physiological role of the complex, although a few encapsulate several activities within a single particle. Encapsulins are abundant in bacteria and archaea, in which they participate in regulation of oxidative stress, detoxification, and homeostasis of key chemical elements. These nanocontainers are physically robust, contain numerous pores that permit metabolite flux through the shell, and are very tolerant of genetic manipulation. There are natural mechanisms for efficient functionalization of the outer and inner shell surfaces, and for the in vivo and in vitro internalization of heterologous proteins. These characteristics render encapsulin an excellent platform for the development of biotechnological applications. Here we provide an overview of current knowledge of encapsulin systems, summarize the remarkable toolbox developed by researchers in this field, and discuss recent advances in the biomedical and bioengineering applications of encapsulins.

Highly vulnerable communities and the Affordable Care Act: Health insurance coverage effects, 2010-2018.

Initially implemented in 2014 in some U.S. states, the Medicaid expansions under the Affordable Care Act (ACA) aimed to make health insurance coverage more accessible to the low-income population. This paper aims to quantify the impact of the ACA Medicaid expansions on insurance coverage among racial/ethnic minorities, immigrants, single mothers, veterans, and low-education whites-i.e., the sectors of the population identified with some of the highest healthcare needs. We focus on individuals 18-64 years of age earning 138% or less of the federal poverty level from the American Community Survey, 2010-2018 (n = 2,927,402). We use difference-in-differences (DD) and difference-in-difference-in-differences (DDD) approaches with propensity scores matched comparison groups to estimate pre-post ACA insurance coverage differences between individuals living in states that participated in the ACA Medicaid expansions and those living in non-participating states, and to estimate if such differences vary across subgroups. We find that insurance coverage rates increased for all subgroups; yet, the ACA benefits have not been evenly distributed across them. Low-education whites, non-Hispanic whites, females, and non-Hispanic Native Americans exhibited the highest improvements in insurance coverage. Our results contribute to the understanding of recent trends in racial and socioeconomic disparities in healthcare and the appropriate policy prescriptions to ameliorate them.

Cryo-electron Microscopy Structure, Assembly, and Mechanics Show Morphogenesis and Evolution of Human Picobirnavirus.

Despite their diversity, most double-stranded-RNA (dsRNA) viruses share a specialized T=1 capsid built from dimers of a single protein that provides a platform for genome transcription and replication. This ubiquitous capsid remains structurally undisturbed throughout the viral cycle, isolating the genome to avoid triggering host defense mechanisms. Human picobirnavirus (hPBV) is a dsRNA virus frequently associated with gastroenteritis, although its pathogenicity is yet undefined. Here, we report the cryo-electron microscopy (cryo-EM) structure of hPBV at 2.6-Å resolution. The capsid protein (CP) is arranged in a single-shelled, ∼380-Å-diameter T=1 capsid with a rough outer surface similar to that of dsRNA mycoviruses. The hPBV capsid is built of 60 quasisymmetric CP dimers (A and B) stabilized by domain swapping, and only the CP-A N-terminal basic region interacts with the packaged nucleic acids. hPBV CP has an α-helical domain with a fold similar to that of fungal partitivirus CP, with many domain insertions in its C-terminal half. In contrast to dsRNA mycoviruses, hPBV has an extracellular life cycle phase like complex reoviruses, which indicates that its own CP probably participates in cell entry. Using an in vitro reversible assembly/disassembly system of hPBV, we isolated tetramers as possible assembly intermediates. We used atomic force microscopy to characterize the biophysical properties of hPBV capsids with different cargos (host nucleic acids or proteins) and found that the CP N-terminal segment not only is involved in nucleic acid interaction/packaging but also modulates the mechanical behavior of the capsid in conjunction with the cargo.IMPORTANCE Despite intensive study, human virus sampling is still sparse, especially for viruses that cause mild or asymptomatic disease. Human picobirnavirus (hPBV) is a double-stranded-RNA virus, broadly dispersed in the human population, but its pathogenicity is uncertain. Here, we report the hPBV structure derived from cryo-electron microscopy (cryo-EM) and reconstruction methods using three capsid protein variants (of different lengths and N-terminal amino acid compositions) that assemble as virus-like particles with distinct properties. The hPBV near-atomic structure reveals a quasisymmetric dimer as the structural subunit and tetramers as possible assembly intermediates that coassemble with nucleic acids. Our structural studies and atomic force microscopy analyses indicate that hPBV capsids are potentially excellent nanocages for gene therapy and targeted drug delivery in humans.

Structure and assembly of double-stranded RNA mycoviruses.

Mycoviruses are a diverse group that includes ssRNA, dsRNA, and ssDNA viruses, with or without a protein capsid, as well as with a complex envelope. Most mycoviruses are transmitted by cytoplasmic interchange and are thought to lack an extracellular phase in their infection cycle. Structural analysis has focused on dsRNA mycoviruses, which usually package their genome in a 120-subunit T=1 icosahedral capsid, with a capsid protein (CP) dimer as the asymmetric unit. The atomic structure is available for four dsRNA mycovirus from different families: Saccharomyces cerevisiae virus L-A (ScV-L-A), Penicillium chrysogenum virus (PcV), Penicillium stoloniferum virus F (PsV-F), and Rosellinia necatrix quadrivirus 1 (RnQV1). Their capsids show structural variations of the same framework, with asymmetric or symmetric CP dimers respectively for ScV-L-A and PsV-F, dimers of similar domains of a single CP for PcV, or of two different proteins for RnQV1. The CP dimer is the building block, and assembly proceeds through dimers of dimers or pentamers of dimers, in which the genome is packed as ssRNA by interaction with CP and/or viral polymerase. These capsids remain structurally undisturbed throughout the viral cycle. The T=1 capsid participates in RNA synthesis, organizing the viral polymerase (1-2 copies) and a single loosely packaged genome segment. It also acts as a molecular sieve, to allow the passage of viral transcripts and nucleotides, but to prevent triggering of host defense mechanisms. Due to the close mycovirus-host relationship, CP evolved to allocate peptide insertions with enzyme activity, as reflected in a rough outer capsid surface.

Structural Insights into Rotavirus Entry.

To initiate infection, non-enveloped viruses must recognize a target cell and penetrate the cell membrane by pore formation or membrane lysis. Rotaviruses are non-enveloped dsRNA viruses that infect the mature intestinal epithelium. They are major etiologic agents of diarrheal disease in human infants, as well as in young individuals of various avian and mammalian species. Rotavirus entry into the cell is a complex multistep process initiated by the interaction of the tip of the viral spike with glycan ligands at the cell surface, and driven by conformational changes of the proteins present in the outer protein capsid, the viral machinery for entry. This review feeds on the abundant structural information produced for rotavirus during the past 30 years and focuses on the structure and the dynamics of the rotavirus entry machinery. We survey the current models for rotavirus entry into cells.

The politics hypothesis and racial disparities in infants' health in the United States.

We propose the politics hypothesis-i.e., the hypothesis that political forces comprise either a powerful predecessor of the social determinants of health or are essential social determinants of health themselves. We examine the hypothesis that political actors like presidents, their ideology, and institutions like the political parties they represent shape overall and race-specific health outcomes. Using census and Vital Statistics data among many other sources, we apply both theory- and data-driven statistical methods to assess the role of the president's party and the president's political ideology as predictors of overall and race-specific infant mortality in the United States, 1965-2010. We find that, net of trend, Republican presidencies and socially-conservative ideology of U.S. presidents are strongly associated with slower declines of infant mortality rates, overall and for white and black infants, compared to Democratic and socially-liberal presidents in the U.S. Approximately half (46%) of the white-black infant mortality gap, about 20,000 additional infant deaths, and most if not all the infant mortality rate gap between the U.S. and the rest of the developed world, can be attributed to the 28 years of Republican administrations during the study period. These findings are consistent with the politicization of public health and the conceptualization of politics as a powerful predecessor, in the causal chain, of the social determinants of health. Understanding the political ideological and institutional contexts in which health policies and healthcare and welfare programs are implemented, as well as how governments construct culture and social psychology, provide a more comprehensive framework for understanding and improving population patterns of disease, mortality, and entrenched racial disparities in health in the U.S.

Weathering, Drugs, and Whack-a-Mole: Fundamental and Proximate Causes of Widening Educational Inequity in U.S. Life Expectancy by Sex and Race, 1990-2015.

Discussion of growing inequity in U.S. life expectancy increasingly focuses on the popularized narrative that it is driven by a surge of "deaths of despair." Does this narrative fit the empirical evidence? Using census and Vital Statistics data, we apply life-table methods to calculate cause-specific years of life lost between ages 25 and 84 by sex and educational rank for non-Hispanic blacks and whites in 1990 and 2015. Drug overdoses do contribute importantly to widening inequity for whites, especially men, but trivially for blacks. The contribution of suicide to growing inequity is unremarkable. Cardiovascular disease, non-lung cancers, and other internal causes are key to explaining growing life expectancy inequity. Results underline the speculative nature of attempts to attribute trends in life-expectancy inequity to an epidemic of despair. They call for continued investigation of the possible weathering effects of tenacious high-effort coping with chronic stressors on the health of marginalized populations.

Social stratification and allostatic load: shapes of health differences in the MIDUS study in the United States.

Social stratification is an important mechanism of human organization that helps to explain health differences between demographic groups commonly associated with socioeconomic gradients. Individuals, or group of individuals, with similar health profiles may have had different stratification experiences. This is particularly true as social stratification is a significant non-measurable source of systematic unobservable differences in both SES indicators and health statuses of disadvantage. The goal of the present study was to expand the bulk of research that has traditionally treated socioeconomic and demographic characteristics as independent, additive influences on health by examining data from the United States. It is hypothesized that variation in an index of multi-system physiological dysregulation - allostatic load - is associated with social differentiation factors, sorting individuals with similar demographic and socioeconomic characteristics into mutually exclusive econo-demographic classes. The data were from the Longitudinal and Biomarker samples of the national Study of Midlife Development in the US (MIDUS) conducted in 1995 and 2004/2006. Latent class analyses and regression analyses revealed that physiological dysregulation linked to socioeconomic variation among black people, females and older adults are associated with forces of stratification that confound socioeconomic and demographic indicators. In the United States, racial stratification of health is intrinsically related to the degree to which black people in general, and black females in particular, as a group, share an isolated status in society. Findings present evidence that disparities in health emerge from group-differentiation processes to the degree that individuals are distinctly exposed to the ecological, political, social, economic and historical contexts in which social stratification is ingrained. Given that health policies and programmes emanate from said legal and political environments, interventions should target the structural conditions that expose different subgroups to different stress risks in the first place.

Biophysical properties of single rotavirus particles account for the functions of protein shells in a multilayered virus.

The functions performed by the concentric shells of multilayered dsRNA viruses require specific protein interactions that can be directly explored through their mechanical properties. We studied the stiffness, breaking force, critical strain and mechanical fatigue of individual Triple, Double and Single layered rotavirus (RV) particles. Our results, in combination with Finite Element simulations, demonstrate that the mechanics of the external layer provides the resistance needed to counteract the stringent conditions of extracellular media. Our experiments, in combination with electrostatic analyses, reveal a strong interaction between the two outer layers and how it is suppressed by the removal of calcium ions, a key step for transcription initiation. The intermediate layer presents weak hydrophobic interactions with the inner layer that allow the assembly and favor the conformational dynamics needed for transcription. Our work shows how the biophysical properties of the three shells are finely tuned to produce an infective RV virion.

Health disparities, politics, and the maintenance of the status quo: A new theory of inequality.

Individuals participate in politics to influence the politicians that prescribe the policies and programs that distribute the public goods and services that shape the social determinants of health. But the opportunity to participate in politics is conditional on survival, and in the U.S., the haves enjoy a significant survival advantage over the have-nots. This process can be detected looking at the relationship between age and participation: It is inflated by the fact that, as time progresses, a higher proportion of low-SES, low-level participation individuals die and are therefore excluded from the available pool of participants faster than high-SES, high-level participation individuals. We analyze this mechanism applying propensity scores matching and multivariate regressions on data from MIDUS I (Midlife in the United States: A National Study of Health and Well-being) and its 10-year mortality follow-up. Results show that health differences between 10-year survivors and non-survivors explain 56% of their differences in socio-political participation. Survivors participate at higher levels than non-survivors across all age groups and SES levels; without detrimental differences in health, individuals would participate 28% more as they age. The same disadvantaged individuals whose increased participation would pressure for redistributive policies are those who die off from the available pool of participants at much higher rates than socioeconomically advantaged individuals. The proposed conceptual model helps to explain how, through the early disappearance of the poor, continuing socio-political participation of high-SES survivors helps to perpetuate inequality in the status quo.

Acquisition of functions on the outer capsid surface during evolution of double-stranded RNA fungal viruses.

Unlike their counterparts in bacterial and higher eukaryotic hosts, most fungal viruses are transmitted intracellularly and lack an extracellular phase. Here we determined the cryo-EM structure at 3.7 Å resolution of Rosellinia necatrix quadrivirus 1 (RnQV1), a fungal double-stranded (ds)RNA virus. RnQV1, the type species of the family Quadriviridae, has a multipartite genome consisting of four monocistronic segments. Whereas most dsRNA virus capsids are based on dimers of a single protein, the ~450-Å-diameter, T = 1 RnQV1 capsid is built of P2 and P4 protein heterodimers, each with more than 1000 residues. Despite a lack of sequence similarity between the two proteins, they have a similar α-helical domain, the structural signature shared with the lineage of the dsRNA bluetongue virus-like viruses. Domain insertions in P2 and P4 preferential sites provide additional functions at the capsid outer surface, probably related to enzyme activity. The P2 insertion has a fold similar to that of gelsolin and profilin, two actin-binding proteins with a function in cytoskeleton metabolism, whereas the P4 insertion suggests protease activity involved in cleavage of the P2 383-residue C-terminal region, absent in the mature viral particle. Our results indicate that the intimate virus-fungus partnership has altered the capsid genome-protective and/or receptor-binding functions. Fungal virus evolution has tended to allocate enzyme activities to the virus capsid outer surface.

BA71ΔCD2: a New Recombinant Live Attenuated African Swine Fever Virus with Cross-Protective Capabilities.

African swine fever is a highly contagious viral disease of mandatory declaration to the World Organization for Animal Health (OIE). The lack of available vaccines makes its control difficult; thus, African swine fever virus (ASFV) represents a major threat to the swine industry. Inactivated vaccines do not confer solid protection against ASFV. Conversely, live attenuated viruses (LAV), either naturally isolated or obtained by genetic manipulation, have demonstrated reliable protection against homologous ASFV strains, although little or no protection has been demonstrated against heterologous viruses. Safety concerns are a major issue for the use of ASFV attenuated vaccine candidates and have hampered their implementation in the field so far. While trying to develop safer and efficient ASFV vaccines, we found that the deletion of the viral CD2v (EP402R) gene highly attenuated the virulent BA71 strain in vivo Inoculation of pigs with the deletion mutant virus BA71ΔCD2 conferred protection not only against lethal challenge with the parental BA71 but also against the heterologous E75 (both genotype I strains). The protection induced was dose dependent, and the cross-protection observed in vivo correlated with the ability of BA71ΔCD2 to induce specific CD8+ T cells capable of recognizing both BA71 and E75 viruses in vitro Interestingly, 100% of the pigs immunized with BA71ΔCD2 also survived lethal challenge with Georgia 2007/1, the genotype II strain of ASFV currently circulating in continental Europe. These results open new avenues to design ASFV cross-protective vaccines, essential to fight ASFV in areas where the virus is endemic and where multiple viruses are circulating.IMPORTANCE African swine fever virus (ASFV) remains enzootic in most countries of Sub-Saharan Africa, today representing a major threat for the development of their swine industry. The uncontrolled presence of ASFV has favored its periodic exportation to other countries, the last event being in Georgia in 2007. Since then, ASFV has spread toward neighboring countries, reaching the European Union's east border in 2014. The lack of available vaccines against ASFV makes its control difficult; so far, only live attenuated viruses have demonstrated solid protection against homologous experimental challenges, but they have failed at inducing solid cross-protective immunity against heterologous viruses. Here we describe a new LAV candidate with unique cross-protective abilities: BA71ΔCD2. Inoculation of BA71ΔCD2 protected pigs not only against experimental challenge with BA71, the virulent parental strain, but also against heterologous viruses, including Georgia 2007/1, the genotype II strain of ASFV currently circulating in Eastern Europe.