scholarly journals The AKV Murine Leukemia Virus Is Restricted and Hypermutated by Mouse APOBEC3

2009 ◽  
Vol 83 (22) ◽  
pp. 11550-11559 ◽  
Author(s):  
Marc-André Langlois ◽  
Kristin Kemmerich ◽  
Cristina Rada ◽  
Michael S. Neuberger
Keyword(s):  
Cytidine Deaminase ◽  
Leukemia Virus ◽  
Endogenous Retrovirus ◽  
Mouse Strains ◽  
Restriction Factors ◽  
Retroviral Infection ◽  
Cytidine Deaminase Activity ◽  
Nucleotide Sequence Diversity ◽  
Apobec3 Proteins ◽  
Akr Mice

ABSTRACT APOBEC3 proteins are potent restriction factors against retroviral infection in primates. This restriction is accompanied by hypermutations in the retroviral genome that are attributable to the cytidine deaminase activity of the APOBEC3 proteins. Studies of nucleotide sequence diversity among endogenous gammaretroviruses suggest that the evolution of endogenous retroelements could have been shaped by the mutagenic cytidine deaminase activity of APOBEC3. In mice, however, APOBEC3 appears to restrict exogenous murine retroviruses in the absence of detectable levels of deamination. AKV is an endogenous retrovirus that is involved in causing a high incidence of thymic lymphoma in AKR mice. A comparative analysis of several mouse strains revealed a relatively low level of APOBEC3 expression in AKR mice. Here we show that endogenous mouse APOBEC3 restricts AKV infection and that this restriction likely reflects polymorphisms affecting APOBEC3 abundance rather than differences in the APOBEC3 isoforms expressed. We also observe that restriction of AKV by APOBEC3 is accompanied by G→A hypermutations in the viral genome. Our findings demonstrate that APOBEC3 acts as a restriction factor in rodents affecting the strain tropism of AKV, and they provide good support for the proposal that APOBEC3-mediated hypermutation contributed to the evolution of endogenous rodent retroviral genomes.

scholarly journals A novel HIV-1 inhibitor that blocks viral replication and rescues APOBEC3s by interrupting vif/CBFβ interaction

2020 ◽  
Vol 295 (43) ◽  
pp. 14592-14605
Author(s):  
Sizhu Duan ◽  
Shiqi Wang ◽  
Yanan Song ◽  
Nan Gao ◽  
Lina Meng ◽  
...  
Keyword(s):  
Drug Targets ◽  
Cytidine Deaminase ◽  
Family Members ◽  
Restriction Factors ◽  
Host Restriction ◽  
Development Of Resistance ◽  
Cytidine Deaminase Activity ◽  
Important Host ◽  
Apobec3 Proteins ◽  
Hiv 1

HIV remains a health challenge worldwide, partly because of the continued development of resistance to drugs. Therefore, it is urgent to find new HIV inhibitors and targets. Apolipoprotein B mRNA-editing catalytic polypeptide-like 3 family members (APOBEC3) are important host restriction factors that inhibit HIV-1 replication by their cytidine deaminase activity. HIV-1 viral infectivity factor (Vif) promotes proteasomal degradation of APOBEC3 proteins by recruiting the E3 ubiquitin ligase complex, in which core-binding factor β (CBFβ) is a necessary molecular chaperone. Interrupting the interaction between Vif and CBFβ can release APOBEC3 proteins to inhibit HIV-1 replication and may be useful for developing new drug targets for HIV-1. In this study, we identified a potent small molecule inhibitor CBFβ/Vif-3 (CV-3) of HIV-1 replication by employing structure-based virtual screening using the crystal structure of Vif and CBFβ (PDB: 4N9F) and validated CV-3's antiviral activity. We found that CV-3 specifically inhibited HIV-1 replication (IC50 = 8.16 µm; 50% cytotoxic concentration >100 µm) in nonpermissive lymphocytes. Furthermore, CV-3 treatment rescued APOBEC3 family members (human APOBEC3G (hA3G), hA3C, and hA3F) in the presence of Vif and enabled hA3G packaging into HIV-1 virions, which resulted in Gly-to-Ala hypermutations in viral genomes. Finally, we used FRET to demonstrate that CV-3 inhibited the interaction between Vif and CBFβ by simultaneously forming hydrogen bonds with residues Gln-67, Ile-102, and Arg-131 of CBFβ. These findings demonstrate that CV-3 can effectively inhibit HIV-1 by blocking the interaction between Vif and CBFβ and that this interaction can serve as a new target for developing HIV-1 inhibitors.

scholarly journals Retroviral Restriction Factors Fv1 and TRIM5α Act Independently and Can Compete for Incoming Virus before Reverse Transcription

2006 ◽  
Vol 80 (5) ◽  
pp. 2100-2105 ◽  
Author(s):  
Luca D. Passerini ◽  
Zuzana Keckesova ◽  
Greg J. Towers
Keyword(s):  
Life Cycle ◽  
Reverse Transcription ◽  
Murine Leukemia Virus ◽  
Leukemia Virus ◽  
Viral Life Cycle ◽  
Human Cells ◽  
Restriction Factors ◽  
Retroviral Infection ◽  
The Relationship ◽  
Murine Leukemia

ABSTRACT The restriction factors Fv1 and TRIM5α provide dominant blocks to retroviral infection, targeting incoming capsids at a postentry, preintegration step. They both restrict N-tropic murine leukemia virus with similar specificity yet act at different points in the viral life cycle. TRIM5α-restricted virus is usually unable to reverse transcribe, whereas Fv1-restricted virus reverse transcribes normally. Here we investigate the relationship between these two restriction factors by expressing Fv1 alleles in human cells. We demonstrate that Fv1 is able to compete with TRIM5α for virus before reverse transcription. In human cells expressing Fv1b, N-tropic restricted virus becomes less infectious but reverse transcribes more efficiently, indicating competition between the two antiviral molecules and protection of the virus from TRIM5α by Fv1. Our findings suggest that, like TRIM5α, Fv1 interacts with virus before reverse transcription, but the consequences of this interaction are not realized until a later stage of the life cycle. We also demonstrate that Fv1 is functionally independent of TRIM5α when expressed in human cells.

scholarly journals Amplified env and gag products on AKR cells. Origin from different murine leukemia virus genomes.

1980 ◽  
Vol 151 (4) ◽  
pp. 975-979 ◽  
Author(s):  
J S Tung ◽  
E Fleissner
Keyword(s):  
Murine Leukemia Virus ◽  
Leukemia Virus ◽  
Mouse Strains ◽  
Type Antigen ◽  
Mink Cell ◽  
Virus Expression ◽  
Virus Genomes ◽  
Akr Mice ◽  
Ecotropic Virus ◽  
Murine Leukemia

Thymocytes of AKR mice express two species of gp70, the envelope glycoprotein of murine leukemia virus (MuLV), encoded by the env gene. One is denoted Ec+ gp70 in reference to the type-antigen Ec and association with ecotropic virus. The other, Ec- gp70, resembles gp70 found also on thymocytes of mouse strains that are not overt producers of MuLV, and has no evident relation to ecotropic virus. Expression of Ec- gp70 type, but not of Ec+ gp70 type, is amplified with age on AKR thymocytes. In contrast, viral core polyproteins, encoded by the gag gene and simultaneously amplified with age, appear to be related to ecotropic virus. These observations imply selective amplification of products of env and gag genes from two sorts of provirus, a phenomenon which may be connected to the dual genetic origin of recombinant mink-cell-focus inducing viruses in AKR mice.

scholarly journals Hypermutation of an Ancient Human Retrovirus by APOBEC3G

2008 ◽  
Vol 82 (17) ◽  
pp. 8762-8770 ◽  
Author(s):  
Young Nam Lee ◽  
Michael H. Malim ◽  
Paul D. Bieniasz
Keyword(s):  
Human Genome ◽  
Cytidine Deaminase ◽  
Modern Human ◽  
Endogenous Retrovirus ◽  
Human Infection ◽  
Endogenous Retroviruses ◽  
Host Interactions ◽  
Apobec3 Proteins ◽  
Retroviral Infections

ABSTRACT Human endogenous retroviruses (HERVs) comprise approximately 8% of the human genome, but all are remnants of ancient retroviral infections and harbor inactivating mutations that render them replication defective. Nevertheless, as viral “fossils,” HERVs may provide insights into ancient retrovirus-host interactions and their evolution. Indeed, one endogenous retrovirus [HERV-K(HML-2)], which has replicated in humans for the past few million years but is now thought to be extinct, was recently reconstituted in a functional form, and infection assays based on it have been established. Here, we show that several human APOBEC3 proteins are intrinsically capable of mutating and inhibiting infection by HERV-K(HML-2) in cell culture. We also present striking evidence that two HERV-K(HML-2) proviruses that are fixed in the modern human genome (HERV-K60 and HERV-KI) were subjected to hypermutation by a cytidine deaminase. Inspection of the spectrum of mutations that are found in HERV-K proviruses in the human genome and HERV-K DNA generated during in vitro replication in the presence of each of the human APOBEC3 proteins unequivocally identifies APOBEC3G as the cytidine deaminase responsible for hypermutation of HERV-K60 and HERV-KI. This is a rare example of the antiretroviral effects of APOBEC3G in the setting of natural human infection, whose consequences have been fossilized in human DNA, and a striking example of inactivation of ancient retroviruses in humans through enzymatic cytidine deamination.

scholarly journals Deaminase-Dead Mouse APOBEC3 Is anIn VivoRetroviral Restriction Factor

2018 ◽  
Vol 92 (11) ◽  
Author(s):  
Spyridon Stavrou ◽  
Wenming Zhao ◽  
Kristin Blouch ◽  
Susan R. Ross
Keyword(s):  
Transgenic Mice ◽  
Cytidine Deaminase ◽  
Restriction Factor ◽  
Wild Type ◽  
Restriction Factors ◽  
Dead Mouse ◽  
Apobec3 Proteins ◽  
Cytidine Deamination ◽  
Retrovirus Infection

ABSTRACTThe apolipoprotein B editing complex 3 (APOBEC3) proteins are potent retroviral restriction factors that are under strong positive selection, both in terms of gene copy number and sequence diversity. A common feature of all the members of the APOBEC3 family is the presence of one or two cytidine deamination domains, essential for cytidine deamination of retroviral reverse transcripts as well as packaging into virions. Several studies have indicated that human and mouse APOBEC3 proteins restrict retrovirus infection via cytidine deaminase (CD)-dependent and -independent means. To understand the relative contribution of CD-independent restrictionin vivo, we created strains of transgenic mice on an APOBEC3 knockout background that express a deaminase-dead mouse APOBEC3 due to point mutations in both CD domains (E73Q/E253Q). Here, we show that the CD-dead APOBEC3 can restrict murine retrovirusesin vivo. Moreover, unlike the wild-type protein, the mutant APOBEC3 is not packaged into virions but acts only as a cell-intrinsic restriction factor that blocks reverse transcription by incoming viruses. Finally, we show that wild-type and CD-dead mouse APOBEC3 can bind to murine leukemia virus (MLV) reverse transcriptase. Our findings suggest that the mouse APOBEC3 cytidine deaminase activity is not required for retrovirus restriction.IMPORTANCEAPOBEC3 proteins are important host cellular restriction factors essential for restricting retrovirus infection by causing mutations in the virus genome and by blocking reverse transcription. While both methods of restriction functionin vitro, little is known about their role duringin vivoinfection. By developing transgenic mice with mutations in the cytidine deamination domains needed for enzymatic activity and interaction with viral RNA, we show that APOBEC3 proteins can still restrictin vivoinfection by interacting with reverse transcriptase and blocking its activity. These studies demonstrate that APOBEC3 proteins have evolved multiple means for blocking retrovirus infection and that all of these means functionin vivo.

scholarly journals Suppression of endogenous murine leukemia virus by maternal resistance factor.

1983 ◽  
Vol 158 (2) ◽  
pp. 506-514 ◽  
Author(s):  
M Melamedoff ◽  
F Lilly ◽  
M L Duran-Reynals
Keyword(s):  
Murine Leukemia Virus ◽  
Infectious Virus ◽  
Leukemia Virus ◽  
Inbred Mouse ◽  
Resistance Factor ◽  
Mouse Strains ◽  
B Mice ◽  
Akr Mice ◽  
Old Females ◽  
Murine Leukemia

Females of the RF and SJL inbred mouse strains transmit to their progeny of both sexes a nonmendelian maternal resistance factor (MRF) able to suppress the expression of endogenous ecotropic murine leukemia virus (E-MuLV). This MRF is demonstrable in crosses with AKR mice by comparing E-MuLV expression in the spleens and thymuses of reciprocal F1 generations. DBA/2 and ST/b mice are MRF negative by these criteria. Neonatal inoculation of E-MuLV-containing spleen extracts gives rise to persistent expression of infectious virus in mice of the MRF- but not the MRF+ strains. However, inoculation of the virus in 30-d-old females of the MRF- strains no longer leads to a state of persistent infection; instead, these females become MRF+ and transmit protection against E-MuLV expression to their progeny by AKR and RF males. The MRF appears to be transmitted to the progeny mainly through the milk, since foster-nursing AKR neonates on RF (but not DBA/2) mothers greatly reduces E-MuLV expression in the progeny. These RF-fostered AKR mice also show a reduced and delayed lymphoma incidence, a finding consistent with the idea that maternally transmitted resistance to E-MuLV expression is the basis for the classic maternal resistance to lymphomagenesis seen in the progeny of RF mothers.

scholarly journals Natural Infection of Dairy Cows with Bovine Leukemia Virus Affects Immunoglobulin Levels in Saliva and Serum but Not Milk

Pathogens ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 907
Author(s):  
Monika Dziuba ◽  
Vickie J. Ruggiero ◽  
Catherine Wilson ◽  
Paul C. Bartlett ◽  
Paul M. Coussens
Keyword(s):  
Pilot Study ◽  
Dairy Cows ◽  
Bovine Leukemia Virus ◽  
Leukemia Virus ◽  
Natural Infection ◽  
Total Serum ◽  
Serum Samples ◽  
Retroviral Infection ◽  
Serum Iga ◽  
The Impact

Bovine leukemia virus (BLV) is a retroviral infection that disrupts the immune function of infected animals. It is widespread among U.S. dairy cattle. In this pilot study, the average total IgA and IgM concentrations in milk, saliva, and serum samples from BLV ELISA-positive (ELISA+) dairy cows were compared against samples from BLV ELISA-negative (ELISA−) cows using the Kruskal–Wallis test (with ties). The results from ELISA+ cows were also stratified by lymphocyte count (LC) and proviral load (PVL). In milk and saliva from ELISA+ cows, the average total IgA and IgM concentrations were decreased compared to ELISA− cows, although this was only statistically significant for saliva IgM in cows with low PVL (p = 0.0424). Numerically, the average total IgA concentrations were 33.6% lower in milk and 23.7% lower in saliva, and the average total IgM concentrations were 42.4% lower in milk and 15.5% lower in saliva. No significant differences were observed in the total serum IgA concentrations, regardless of PVL and LC. The total serum IgM from ELISA+ cows was significantly decreased (p = 0.0223), with the largest decreases occurring in the highest PVL and LC subgroups. This pilot study is a first step in investigating the impact of BLV on mucosal immunity and will require further exploration in each of the various stages of disease progression.

scholarly journals Deaminase-Independent Mode of Antiretroviral Action in Human and Mouse APOBEC3 Proteins

2020 ◽  
Vol 8 (12) ◽  
pp. 1976
Author(s):  
Yoshiyuki Hakata ◽  
Masaaki Miyazawa
Keyword(s):  
Molecular Mechanisms ◽  
Restriction Factors ◽  
Mrna Editing ◽  
Antiviral Function ◽  
Apobec3 Proteins ◽  
And Function ◽  
Editing Enzyme ◽  
Dependent Pathway ◽  
Independent Mode ◽  
Human Apobec3g

Apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like 3 (APOBEC3) proteins (APOBEC3s) are deaminases that convert cytosines to uracils predominantly on a single-stranded DNA, and function as intrinsic restriction factors in the innate immune system to suppress replication of viruses (including retroviruses) and movement of retrotransposons. Enzymatic activity is supposed to be essential for the APOBEC3 antiviral function. However, it is not the only way that APOBEC3s exert their biological function. Since the discovery of human APOBEC3G as a restriction factor for HIV-1, the deaminase-independent mode of action has been observed. At present, it is apparent that both the deaminase-dependent and -independent pathways are tightly involved not only in combating viruses but also in human tumorigenesis. Although the deaminase-dependent pathway has been extensively characterized so far, understanding of the deaminase-independent pathway remains immature. Here, we review existing knowledge regarding the deaminase-independent antiretroviral functions of APOBEC3s and their molecular mechanisms. We also discuss the possible unidentified molecular mechanism for the deaminase-independent antiretroviral function mediated by mouse APOBEC3.

scholarly journals APOBEC3F constitutes a barrier to successful cross-species transmission of SIVsmm to humans

2021 ◽  
Author(s):  
Rayhane Nchioua ◽  
Dorota Kmiec ◽  
Amit Gaba ◽  
Christina M. Stürzel ◽  
Tyson Follack ◽  
...  
Keyword(s):  
T Cells ◽  
Sub Saharan Africa ◽  
Intrinsic Activity ◽  
Significant Activity ◽  
Restriction Factors ◽  
Innate Defense ◽  
Human T Cells ◽  
Sooty Mangabeys ◽  
Apobec3 Proteins ◽  
Species Specific

SIVsmm infecting sooty mangabeys has been transmitted to humans on at least nine occasions, giving rise to HIV-2 groups A to I. SIVsmm isolates replicate in human T cells and seem capable of overcoming major human restriction factors without adaptation. However, only groups A and B are responsible for the HIV-2 epidemic in Sub-Saharan Africa and it is largely unclear whether adaptive changes were associated with spread in humans. To address this, we examined the sensitivity of infectious molecular clones (IMCs) of five HIV-2 strains and representatives of five different SIVsmm lineages to various APOBEC3 proteins. We confirmed that SIVsmm strains replicate in human T cells, albeit with more variable and frequently lower efficiency than HIV-2 IMCs. Efficient viral propagation was generally dependent on intact vif genes, highlighting the need for counteraction of APOBEC3 proteins. On average, SIVsmm was more susceptible to inhibition by human APOBEC3D, F, G and H than HIV-2. For example, human APOBEC3F reduced infectious virus yield of SIVsmm by ∼80% but achieved only ∼40% in the case of HIV-2. Functional and mutational analyses of human and monkey derived alleles revealed that an R128T polymorphism in APOBEC3F contributes to species-specific counteraction by HIV-2 and SIVsmm Vif proteins. In addition, a T84S substitution in SIVsmm Vif increased its ability to counteract human APOBEC3F. Altogether, our results confirm that SIVsmm Vifs show intrinsic activity against human ABOBEC3 proteins but also demonstrate that epidemic HIV-2 strains evolved an increased ability to counteract this class of restriction factors during human adaptation. IMPORTANCE Viral zoonoses pose a significant threat to human health and it is important to understand determining factors. SIVs infecting great apes gave rise to HIV-1. In contrast, SIVs infecting African monkey species have not been detected in humans, with one notable exception. SIVsmm from sooty mangabeys crossed the species barrier to humans on at least nine independent occasions and seems capable of overcoming many innate defense mechanisms without adaptation. Here, we confirmed that SIVsmm Vif proteins show significant activity against human APOBEC3 proteins. Our analyses also revealed, however, that different lineages of SIVsmm are significantly more susceptible to inhibition by various human APOBEC3 proteins than HIV-2 strains. Mutational analyses suggest that a R128T substitution in APOBEC3F and a T84S change in Vif contribute to species-specific counteraction by HIV-2 and SIVsmm. Altogether, our results support that epidemic HIV-2 strains acquired increased activity against human APOBEC3 proteins to clear this restrictive barrier.

Sign in / Sign up

Export Citation Format

Share Document