scholarly journals Gorilla APOBEC3 restricts SIVcpz and influences lentiviral evolution in great ape cross-species transmissions

2018 ◽  
Author(s):  
Yusuke Nakano ◽  
Keisuke Yamamoto ◽  
Andrew Soper ◽  
Ryuichi Kumata ◽  
Hirofumi Aso ◽  
...  
Keyword(s):  
List Type ◽  
Great Ape ◽  
Restriction Factors ◽  
Species Barrier ◽  
New Host ◽  
Antiviral Effects ◽  
Apobec3 Family ◽  
Vif Protein ◽  
Hiv 1 ◽  
New Host Species

SummaryRestriction factors including APOBEC3 family proteins have the potential prevent cross-species lentivirus transmissions. Such events as well as ensuing pathogenesis require the viral Vif protein to overcome/neutralize/degrade the APOBEC3 enzymes of the new host species. Previous investigations have focused on the molecular interaction between human APOBEC3s and HIV-1 Vif. However, the evolutionary interplay between lentiviruses and great ape (including human, chimpanzee and gorilla) APOBEC3s has not been fully investigated. Here we demonstrate that gorilla APOBEC3G plays a pivotal role in restricting lentiviral transmission from chimpanzee to gorilla. We also reveal that a sole amino acid substitution in Vif is sufficient to overcome the gorilla APOBEC3G-mediated species barrier. Moreover, the antiviral effects of gorilla APOBEC3D and APOBEC3F are considerably weaker than those of human and chimpanzee counterparts, which can result in the skewed evolution of great ape lentiviruses leading to HIV-1.HighlightsSIVcpz requires M16E mutation in Vif to counteract gorilla A3GAcidic residue at position 16 of Vif is crucial to counteract gorilla A3GGorilla A3D and A3F poorly suppress lentiviral infectivitySIVgor and related HIV-1s counteract human A3D and A3F independently of DRMR motif

scholarly journals Evolutionary rate shifts suggest species-specific adaptation events in HIV-1 and SIV

2017 ◽  
Author(s):  
Maoz Gelbart ◽  
Adi Stern
Keyword(s):  
Evolutionary Rate ◽  
Virus Transmission ◽  
Restriction Factors ◽  
Species Barrier ◽  
New Host ◽  
Major Barrier ◽  
Viral Adaptation ◽  
Rate Deceleration ◽  
Species Specific ◽  
Hiv 1

AbstractThe process of molecular adaptation following a cross-species virus transmission event is currently poorly understood. Here, we identified 137 protein sites that experienced deceleration in their rate of evolution along the HIV-1/SIV phylogeny, likely indicating gain-of-function and consequent adaptation. The majority of such events occurred in parallel to cross-species transmission events and varied between HIV-1 groups, indicating independent adaptation strategies. The evolutionary rate decelerations we found were particularly prominent in accessory proteins that counteract host antiviral restriction factors, suggesting that these factors are a major barrier to viral adaptation to a new host. Surprisingly, we observed that the non-pandemic HIV-1 group O, derived from gorillas, exhibited more rate deceleration events than the pandemic group M, derived from chimpanzees. We suggest that the species barrier is higher when the genetic distance of the hosts increases. Our approach paves the way for subsequent studies on cross-species transfers in other major pathogens.

scholarly journals Divergence in dimerization and activity of primate APOBEC3C

2021 ◽  
Author(s):  
Amit Gaba ◽  
Mark A Hix ◽  
Sana Suhail ◽  
Ben Flath ◽  
Brock Boysan ◽  
...  
Keyword(s):  
Amino Acid ◽  
Antiviral Activity ◽  
World Monkey ◽  
Restriction Factors ◽  
Cytidine Deaminases ◽  
Host Restriction ◽  
Dimerization Interface ◽  
Dynamics Simulations ◽  
Vif Protein ◽  
Hiv 1

The APOBEC3 (A3) family of single-stranded DNA cytidine deaminases are host restriction factors that inhibit lentiviruses, such as HIV-1, in the absence of the Vif protein that causes their degradation. Deamination of cytidine in HIV-1 (-)DNA forms uracil that causes inactivating mutations when uracil is used as a template for (+)DNA synthesis. For APOBEC3C (A3C), the chimpanzee and gorilla orthologues are more active than human A3C, and the Old World Monkey A3C from rhesus macaque (rh) is not active against HIV-1. Multiple integrated analyses determined why rhA3C was not active against HIV-1 and how to increase this activity. Biochemical, virological, and coevolutionary analyses combined with molecular dynamics simulations showed that the key amino acids needed to promote rhA3C antiviral activity also promoted dimerization. Although rhA3C shares a similar dimer interface with hominid A3C, the key amino acid contacts were different. Overall, our results determine the basis for why rhA3C is less active than human A3C, establish the amino acid network for dimerization and increased activity, and track the loss and gain of A3C antiviral activity in primates. The coevolutionary analysis of the A3C dimerization interface provides a basis from which to analyze dimerization interfaces of other A3 family members.

scholarly journals Modern-Day SIV Viral Diversity Generated by Extensive Recombination and Cross-Species Transmission

2017 ◽  
Author(s):  
Sidney M. Bell ◽  
Trevor Bedford
Keyword(s):  
Host Species ◽  
Character Trait ◽  
New Host ◽  
Colobus Monkeys ◽  
Immunodeficiency Virus ◽  
Discrete Character ◽  
History Of ◽  
Specific Species ◽  
Hiv 1 ◽  
New Host Species

AbstractCross-species transmission (CST) has led to many devastating epidemics, but is still a poorly understood phenomenon. HIV-1 and HIV-2 (human immunodeficiency virus 1 and 2), which have collectively caused over 35 million deaths, are the result of multiple CSTs from chimpanzees, gorillas, and sooty mangabeys. While the immediate history of HIV is known, there are over 45 lentiviruses that infect specific species of primates, and patterns of host switching are not well characterized. We thus took a phylogenetic approach to better understand the natural history of SIV recombination and CST. We modeled host species as a discrete character trait on the viral phylogeny and inferred historical host switches and the pairwise transmission rates between each pair of 24 primate hosts. We identify 14 novel, well-supported, ancient cross-species transmission events. We also find that lentiviral lineages vary widely in their ability to infect new host species: SIVcol (from colobus monkeys) is evolutionarily isolated, while SIVagms (from African green monkeys) frequently move between host subspecies. We also examine the origins of SIVcpz (the predecessor of HIV-1) in greater detail than previous studies, and find that there are still large portions of the genome with unknown origins. Observed patterns of CST are likely driven by a combination of ecological circumstance and innate immune factors.

scholarly journals Vif of Feline Immunodeficiency Virus from Domestic Cats Protects against APOBEC3 Restriction Factors from Many Felids

2010 ◽  
Vol 84 (14) ◽  
pp. 7312-7324 ◽  
Author(s):  
Jörg Zielonka ◽  
Daniela Marino ◽  
Henning Hofmann ◽  
Naoya Yuhki ◽  
Martin Löchelt ◽  
...  
Keyword(s):  
Feline Immunodeficiency Virus ◽  
Domestic Cat ◽  
Moderate Degree ◽  
Restriction Factors ◽  
Cytidine Deaminases ◽  
Immunodeficiency Virus ◽  
Specific Restriction ◽  
Species Specific ◽  
Vif Protein ◽  
Hiv 1

ABSTRACT To get more insight into the role of APOBEC3 (A3) cytidine deaminases in the species-specific restriction of feline immunodeficiency virus (FIV) of the domestic cat, we tested the A3 proteins present in big cats (puma, lion, tiger, and lynx). These A3 proteins were analyzed for expression and sensitivity to the Vif protein of FIV. While A3Z3s and A3Z2-Z3s inhibited Δvif FIV, felid A3Z2s did not show any antiviral activity against Δvif FIV or wild-type (wt) FIV. All felid A3Z3s and A3Z2-Z3s were sensitive to Vif of the domestic cat FIV. Vif also induced depletion of felid A3Z2s. Tiger A3s showed a moderate degree of resistance against the Vif-mediated counter defense. These findings may imply that the A3 restriction system does not play a major role to prevent domestic cat FIV transmission to other Felidae. In contrast to the sensitive felid A3s, many nonfelid A3s actively restricted wt FIV replication. To test whether VifFIV can protect also the distantly related human immunodeficiency virus type 1 (HIV-1), a chimeric HIV-1.VifFIV was constructed. This HIV-1.VifFIV was replication competent in nonpermissive feline cells expressing human CD4/CCR5 that did not support the replication of wt HIV-1. We conclude that the replication of HIV-1 in some feline cells is inhibited only by feline A3 restriction factors and the absence of the appropriate receptor or coreceptor.

scholarly journals HIV-1 Vif protein is stabilized by AKT-mediated phosphorylation to enhance APOBEC3G degradation

2021 ◽  
Author(s):  
Rameez Raja ◽  
Chenyao Wang ◽  
Akhil C Banerjea
Keyword(s):  
Cytosine Deaminase ◽  
Dominant Negative ◽  
Kinase Assay ◽  
Restriction Factors ◽  
Akt Phosphorylation ◽  
Protein Levels ◽  
Dominant Negative Form ◽  
Successful Replication ◽  
Vif Protein ◽  
Hiv 1

HIV-1 virus has to counter anti-viral restriction factors for its successful replication after its entry in the cell. The host-pathogen dynamics operate as soon as HIV-1 interacts with the cell. HIV-1 Vif has been known for its role in degradation of APOBEC3G; a cytosine deaminase which leads to hyper mutations in the viral DNA leading to aberrant viral replication. The cellular proteins regulating the intracellular HIV-1 Vif protein levels can have profound impact on HIV-1 pathogenesis. MDM2 is known to induce degradation of Vif with subsequent effects on APOBEC3G. Here, we have identified AKT/PKB as one of the crucial regulators of HIV-1 Vif protein. The rationale for selecting Vif as a target substrate for AKT was the presence of RMRINT motif in it, which is similar to the AKT phosphorylation motif RxRxxS/T. Immunoprecipitation assay and Kinase assay revealed that AKT and Vif interact strongly with each other and Vif is phosphorylated at T20 position by AKT. This phosphorylation stabilizes HIV-1 Vif while Vif mutant T20A degrades faster. Moreover, use of dominant negative form of AKT (KD-AKT) and AKT inhibitors were found to destabilise Vif and increase its K48-ubiquitination profile. The consequences of this AKT-Vif interplay were also validated on APOBEC3G degradation, a target of Vif. AKT inhibition was found to restore APOBEC3G levels. This process can be interpreted as a strategy used by virus to prevent MDM2 mediated Vif degradation; AKT stabilises Mdm2, which then targets Vif for degradation but at the same time AKT stabilises Vif by phosphorylating it. Thus, AKT mediated stabilization of Vif might compensate for its degradation by MDM2. This study can have significant implications as HIV-1 Tat protein and growth factors like insulin activate PI3-K/AKT Kinase pathway and can potentially affect Vif and APOBEC3G protein levels and hence HIV-1 pathogenesis.

scholarly journals APOBEC3 versus Retroviruses, Immunity versus Invasion: Clash of the Titans

2012 ◽  
Vol 2012 ◽  
pp. 1-11 ◽  
Author(s):  
Ann M. Sheehy ◽  
Julie Erthal
Keyword(s):  
Clinical Intervention ◽  
Immune Defense ◽  
Restriction Factors ◽  
Defense Proteins ◽  
Tremendous Amount ◽  
Unexpected Findings ◽  
And Function ◽  
Vif Protein ◽  
Hiv 1

Since the identification of APOBEC3G (A3G) as a potent restriction factor of HIV-1, a tremendous amount of effort has led to a broadened understanding of both A3G and the APOBEC3 (A3) family to which it belongs. In spite of the fine-tuned viral counterattack to A3 activity, in the form of the HIV-1 Vif protein, enthusiasm for leveraging the Vif : A3G axis as a point of clinical intervention remains high. In an impressive explosion of information over the last decade, additional A3 family members have been identified as antiviral proteins, mechanistic details of the restrictive capacity of these proteins have been elucidated, structure-function studies have revealed important molecular details of the Vif : A3G interaction, and clinical cohorts have been scrutinized for correlations between A3 expression and function and viral pathogenesis. In the last year, novel and unexpected findings regarding the role of A3G in immunity have refocused efforts on exploring the potential of harnessing the natural power of this immune defense. These most recent reports allude to functions of the A3 proteins that extend beyond their well-characterized designation as restriction factors. The emerging story implicates the A3 family as not only defense proteins, but also as participants in the broader innate immune response.

scholarly journals The Battle between Retroviruses and APOBEC3 Genes: Its Past and Present

Viruses ◽  
2021 ◽  
Vol 13 (1) ◽  
pp. 124
Author(s):  
Keiya Uriu ◽  
Yusuke Kosugi ◽  
Jumpei Ito ◽  
Kei Sato
Keyword(s):  
Causative Agent ◽  
Viral Protein ◽  
Viral Infections ◽  
Current Knowledge ◽  
Restriction Factors ◽  
Antiviral Effects ◽  
Apobec3 Family ◽  
Apobec3 Proteins

The APOBEC3 family of proteins in mammals consists of cellular cytosine deaminases and well-known restriction factors against retroviruses, including lentiviruses. APOBEC3 genes are highly amplified and diversified in mammals, suggesting that their evolution and diversification have been driven by conflicts with ancient viruses. At present, lentiviruses, including HIV, the causative agent of AIDS, are known to encode a viral protein called Vif to overcome the antiviral effects of the APOBEC3 proteins of their hosts. Recent studies have revealed that the acquisition of an anti-APOBEC3 ability by lentiviruses is a key step in achieving successful cross-species transmission. Here, we summarize the current knowledge of the interplay between mammalian APOBEC3 proteins and viral infections and introduce a scenario of the coevolution of mammalian APOBEC3 genes and viruses.

scholarly journals Vif Proteins from Diverse Human Immunodeficiency Virus/Simian Immunodeficiency Virus Lineages Have Distinct Binding Sites in A3C

2016 ◽  
Vol 90 (22) ◽  
pp. 10193-10208 ◽  
Author(s):  
Zeli Zhang ◽  
Qinyong Gu ◽  
Ananda Ayyappan Jaguva Vasudevan ◽  
Manimehalai Jeyaraj ◽  
Stanislaw Schmidt ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Simian Immunodeficiency Virus ◽  
Salt Bridge ◽  
Proteasomal Degradation ◽  
Sooty Mangabey ◽  
Restriction Factors ◽  
Interaction Sites ◽  
Immunodeficiency Virus ◽  
Vif Protein ◽  
Hiv 1

ABSTRACTLentiviruses have evolved the Vif protein to counteract APOBEC3 (A3) restriction factors by targeting them for proteasomal degradation. Previous studies have identified important residues in the interface of human immunodeficiency virus type 1 (HIV-1) Vif and human APOBEC3C (hA3C) or human APOBEC3F (hA3F). However, the interaction between primate A3C proteins and HIV-1 Vif or natural HIV-1 Vif variants is still poorly understood. Here, we report that HIV-1 Vif is inactive against A3Cs of rhesus macaques (rhA3C), sooty mangabey monkeys (smmA3C), and African green monkeys (agmA3C), while HIV-2, African green monkey simian immunodeficiency virus (SIVagm), and SIVmac Vif proteins efficiently mediate the depletion of all tested A3Cs. We identified that residues N/H130 and Q133 in rhA3C and smmA3C are determinants for this HIV-1 Vif-triggered counteraction. We also found that the HIV-1 Vif interaction sites in helix 4 of hA3C and hA3F differ. Vif alleles from diverse HIV-1 subtypes were tested for degradation activities related to hA3C. The subtype F-1 Vif was identified to be inactive for degradation of hA3C and hA3F. The residues that determined F-1 Vif inactivity in the degradation of A3C/A3F were located in the C-terminal region (K167 and D182). Structural analysis of F-1 Vif revealed that impairing the internal salt bridge of E171-K167 restored reduction capacities to A3C/A3F. Furthermore, we found that D101 could also form an internal interaction with K167. Replacing D101 with glycine and R167 with lysine in NL4-3 Vif impaired its counteractivity to A3F and A3C. This finding indicates that internal interactions outside the A3 binding region in HIV-1 Vif influence the capacity to induce degradation of A3C/A3F.IMPORTANCEThe APOBEC3 restriction factors can serve as potential barriers to lentiviral cross-species transmissions. Vif proteins from lentiviruses counteract APOBEC3 by proteasomal degradation. In this study, we found that monkey-derived A3C, rhA3C and smmA3C, were resistant to HIV-1 Vif. This was determined by A3C residues N/H130 and Q133. However, HIV-2, SIVagm, and SIVmac Vif proteins were found to be able to mediate the depletion of all tested primate A3C proteins. In addition, we identified a natural HIV-1 Vif (F-1 Vif) that was inactive in the degradation of hA3C/hA3F. Here, we provide for the first time a model that explains how an internal salt bridge of E171-K167-D101 influences Vif-mediated degradation of hA3C/hA3F. This finding provides a novel way to develop HIV-1 inhibitors by targeting the internal interactions of the Vif protein.

scholarly journals Remarkable Lethal G-to-A Mutations in vif-Proficient HIV-1 Provirus by Individual APOBEC3 Proteins in Humanized Mice

2010 ◽  
Vol 84 (18) ◽  
pp. 9546-9556 ◽  
Author(s):  
Kei Sato ◽  
Taisuke Izumi ◽  
Naoko Misawa ◽  
Tomoko Kobayashi ◽  
Yoshiki Yamashita ◽  
...  
Keyword(s):  
Humanized Mouse ◽  
Hematopoietic Stem ◽  
Immunodeficiency Virus ◽  
Apobec3 Family ◽  
Apobec3 Proteins ◽  
Vif Protein ◽  
Hiv 1 ◽  
Human Apobec3g

ABSTRACT Genomic hypermutation of RNA viruses, including human immunodeficiency virus type 1 (HIV-1), can be provoked by intrinsic and extrinsic pressures, which lead to the inhibition of viral replication and/or the progression of viral diversity. Human APOBEC3G was identified as an HIV-1 restriction factor, which edits nascent HIV-1 DNA by inducing G-to-A hypermutations and debilitates the infectivity of vif-deficient HIV-1. On the other hand, HIV-1 Vif protein has the robust potential to degrade APOBEC3G protein. Although subsequent investigations have revealed that lines of APOBEC3 family proteins have the capacity to mutate HIV-1 DNA, it remains unclear whether these endogenous APOBEC3s, including APOBEC3G, contribute to mutations of vif-proficient HIV-1 provirus in vivo and, if so, what is the significance of these mutations. In this study, we use a human hematopoietic stem cell-transplanted humanized mouse (NOG-hCD34 mouse) model and demonstrate the predominant accumulation of G-to-A mutations in vif-proficient HIV-1 provirus displaying characteristics of APOBEC3-mediated mutagenesis. Notably, the APOBEC3-associated G-to-A mutation of HIV-1 DNA that leads to the termination of translation was significantly observed. We further provide a novel insight suggesting that HIV-1 G-to-A hypermutation is independently induced by individual APOBEC3 proteins. In contrast to the prominent mutation in intracellular proviral DNA, viral RNA in plasma possessed fewer G-to-A mutations. Taken together, these results provide the evidence indicating that endogenous APOBEC3s are associated with G-to-A mutation of HIV-1 provirus in vivo, which can result in the abrogation of HIV-1 infection.

scholarly journals Influenza in birds, pigs and humans: how strong is the species barrier?

2017 ◽  
Vol 58 (3) ◽  
pp. 208 ◽  
Author(s):  
K. Van REETH ◽  
A. De VLEESCHAUWER ◽  
C. S. KYRIAKIS
Keyword(s):  
Avian Influenza ◽  
Host Species ◽  
Experimental Studies ◽  
Influenza Viruses ◽  
Interspecies Transmission ◽  
Species Barrier ◽  
New Host ◽  
Highly Pathogenic ◽  
Avian Viruses ◽  
New Host Species

The recent epizootics of the highly pathogenic H5N1 avian influenza in poultry and the occasional infections of humans and other mammals, including pigs and felines, have alerted the international scientific community. New questions over the interspecies transmission of influenza viruses have been raised and the role of the pig as a "mixing vessel" of avian and human viruses has been criticized. The major aim of this review is to evaluate the zoonotic potential of avian and swine influenza. Interspecies transmissions of influenza viruses are rare virus-evolution events and very few viruses have succeeded to become established in new host species. Until the appearance of the H5N1 virus in 1996 only 3 cases of humans infected with avian viruses were recorded. The lack of human-to-human transmission of H5N1 demonstrates that extensive changes in the virus genome are required in order to overcome the species barrier. Although avian influenza viruses have been isolated from pigs, only in one occasion an avian H I N I virus transmitted from wild ducks to pigs was able to further spread in the swine population. The susceptibility of swine to highly and low pathogenic avian viruses has been confirmed in experimental studies, but pig-to-pig transmission has not been demonstrated. Experimental and natural transmission of highly pathogenic avian viruses to felines, mice, ferrets and maqacues are also discussed, showing the major differences in the virus pathogenesis among different mammalian species. The study of this pathogenesis may offer insights to the reasons of limited virus spread within a new host. We may conclude that, contrary to common believes, the species barrier remains a serious obstacle for the spread of novel influenza viruses in new host species, including humans. Our experience with H5N1 and H7N7 has tested old established theories, proving them insufficient. Further study of the factors which influence and limit the transmission of influenza viruses from one species to another is needed to better understand and evaluate the risk of the emergence of new pandemic influenza viruses.

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