scholarly journals HIV-1 Vif gained breadth in APOBEC3G specificity after cross-species transmission of its precursors

2021 ◽  
Author(s):  
Nicholas M Chesarino ◽  
Michael Emerman
Keyword(s):  
Amino Acids ◽  
Cytidine Deaminase ◽  
World Monkey ◽  
Evolutionary Potential ◽  
Old World ◽  
Mutagenesis Screen ◽  
Resistance Strategies ◽  
Subsequent Degradation ◽  
Combinatorial Mutagenesis ◽  
Hiv 1

APOBEC3G (A3G) is a host-encoded cytidine deaminase that potently restricts retroviruses, such as HIV-1, and depends on its ability to package into virions. As a consequence of this, HIV-1 protein Vif has evolved to antagonize human A3G by targeting it for ubiquitination and subsequent degradation. There is an ancient arms-race between Vif and A3G highlighted by amino acids 128 and 130 in A3G that have evolved under positive selection due to Vif-mediated selective pressure in Old World primates. Nonetheless, not all possible amino acid combinations at these sites have been sampled by nature and it is not clear the evolutionary potential of species to resist Vif antagonism. To explore the evolutionary space of positively selected sites in the Vif-binding region of A3G, we designed a combinatorial mutagenesis screen to introduce all 20 amino acids at sites 128 and 130. Our screen uncovered mutants of A3G with several interesting phenotypes, including loss of stability and resistance of Vif antagonism. However, HIV-1 Vif exhibited remarkable flexibility in antagonizing A3G 128 and 130 mutants, which significantly reduces viable Vif resistance strategies for hominid primates. Importantly, we find that broadened Vif specificity was conferred through Loop 5 adaptations that were required for cross-species adaptation from Old World monkey A3G to hominid A3G. Our evidence suggests that Vif adaptation to novel A3G interfaces during cross-species transmission may train Vif towards broadened specificity that can further facilitate cross-species transmissions and raise the barrier to host resistance.

scholarly journals HIV-1 Vif gained breadth in APOBEC3G specificity after cross-species transmission of its precursors

2021 ◽  
Author(s):  
Nicholas M. Chesarino ◽  
Michael Emerman
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Cytidine Deaminase ◽  
World Monkey ◽  
Arms Race ◽  
Single Amino Acid ◽  
Evolutionary Potential ◽  
Antiviral Protein ◽  
Old World ◽  
Hiv 1

APOBEC3G (A3G) is a host-encoded cytidine deaminase that potently restricts retroviruses, such as HIV-1, and depends on its ability to package into virions. As a consequence of this, HIV-1 protein Vif has evolved to antagonize human A3G by targeting it for ubiquitination and subsequent degradation. There is an ancient arms-race between Vif and A3G highlighted by amino acids 128 and 130 in A3G that have evolved under positive selection due to Vif-mediated selective pressure in Old World primates. Nonetheless, not all possible amino acid combinations at these sites have been sampled by nature and it is not clear the evolutionary potential of species to resist Vif antagonism. To explore the evolutionary space of positively selected sites in the Vif-binding region of A3G, we designed a combinatorial mutagenesis screen to introduce all 20 amino acids at sites 128 and 130. Our screen uncovered mutants of A3G with several interesting phenotypes, including loss of antiviral activity and resistance of Vif antagonism. However, HIV-1 Vif exhibited remarkable flexibility in antagonizing A3G 128 and 130 mutants, which significantly reduces viable Vif resistance strategies for hominid primates. Importantly, we find that broadened Vif specificity was conferred through Loop 5 adaptations that were required for cross-species adaptation from Old World monkey A3G to hominid A3G. Our evidence suggests that Vif adaptation to novel A3G interfaces during cross-species transmission may train Vif towards broadened specificity that can further facilitate cross-species transmissions and raise the barrier to host resistance. Importance APOBEC3G (A3G) is an antiviral protein that potently restricts retroviruses like HIV. In turn, the HIV-1 protein Vif has evolved to antagonize A3G through degradation. Two rapidly evolving sites in A3G confer resistance to unadapted Vif and act as a barrier to cross-species transmission of retroviruses. We recently identified a single amino acid mutation in an SIV Vif that contributed to the cross-species origins of SIV infecting chimpanzee, and ultimately the HIV-1 pandemic. This mutation broadened specificity of this Vif to both antagonize the A3G of its host while simultaneously overcoming the A3G barrier in the great apes. In this work, we explore the evolutionary space of human A3G at these rapidly evolving sites to understand if the broadened Vif specificity gained during cross-species transmission confers an advantage to HIV-1 Vif in its host-virus arms race with A3G.

scholarly journals Cyclophilin A is required for TRIM5 -mediated resistance to HIV-1 in Old World monkey cells

2005 ◽  
Vol 102 (41) ◽  
pp. 14849-14853 ◽  
Author(s):  
L. Berthoux ◽  
S. Sebastian ◽  
E. Sokolskaja ◽  
J. Luban
Keyword(s):  
World Monkey ◽  
Cyclophilin A ◽  
Old World ◽  
Old World Monkey ◽  
Hiv 1

scholarly journals Fluorescent Image Analysis of HIV-1 and HIV-2 Uncoating Kinetics in the Presence of Old World Monkey TRIM5α

PLoS ONE ◽  
2015 ◽  
Vol 10 (3) ◽  
pp. e0121199 ◽  
Author(s):  
Eri Takeda ◽  
Ken Kono ◽  
Amy E. Hulme ◽  
Thomas J. Hope ◽  
Emi E. Nakayama ◽  
...  
Keyword(s):  
Image Analysis ◽  
World Monkey ◽  
Old World ◽  
Old World Monkey ◽  
Fluorescent Image ◽  
Hiv 1

scholarly journals Retrovirus Restriction by TRIM5α Variants from Old World and New World Primates

2005 ◽  
Vol 79 (7) ◽  
pp. 3930-3937 ◽  
Author(s):  
Byeongwoon Song ◽  
Hassan Javanbakht ◽  
Michel Perron ◽  
Do Hyun Park ◽  
Matthew Stremlau ◽  
...  
Keyword(s):  
New World ◽  
World Monkey ◽  
Old World Monkeys ◽  
Old World ◽  
New World Monkey ◽  
Monkey Species ◽  
Immunodeficiency Virus ◽  
Hiv 1 ◽  
B30.2 Domain ◽  
Antiretroviral Activity

ABSTRACT The TRIM5α proteins of humans and some Old World monkeys have been shown to block infection of particular retroviruses following virus entry into the host cell. Infection of most New World monkey cells by the simian immunodeficiency virus of macaques (SIVmac) is restricted at a similar point. Here we examine the antiretroviral activity of TRIM5α orthologs from humans, apes, Old World monkeys, and New World monkeys. Chimpanzee and orangutan TRIM5α proteins functionally resembled human TRIM5α, potently restricting infection by N-tropic murine leukemia virus (N-MLV) and moderately restricting human immunodeficiency virus type 1 (HIV-1) infection. Notably, TRIM5α proteins from several New World monkey species restricted infection by SIVmac and the SIV of African green monkeys, SIVagm. Spider monkey TRIM5α, which has an expanded B30.2 domain v3 region due to a tandem triplication, potently blocked infection by a range of retroviruses, including SIVmac, SIVagm, HIV-1, and N-MLV. Tandem duplications in the TRIM5α B30.2 domain v1 region of African green monkeys are also associated with broader antiretroviral activity. Thus, variation in TRIM5α proteins among primate species accounts for the observed patterns of postentry restrictions in cells from these animals. The TRIM5α proteins of some monkey species exhibit dramatic lengthening of particular B30.2 variable regions and an expanded range of susceptible retroviruses.

scholarly journals Cyclophilin A Renders Human Immunodeficiency Virus Type 1 Sensitive to Old World Monkey but Not Human TRIM5α Antiviral Activity

2006 ◽  
Vol 80 (10) ◽  
pp. 4683-4690 ◽  
Author(s):  
Zuzana Keckesova ◽  
Laura M. J. Ylinen ◽  
Greg J. Towers
Keyword(s):  
Human Immunodeficiency Virus ◽  
Antiviral Activity ◽  
Cyclosporine A ◽  
World Monkey ◽  
Cyclophilin A ◽  
Old World ◽  
Old World Monkey ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT TRIM5α is an important mediator of antiretroviral innate immunity influencing species-specific retroviral replication. Here we investigate the role of the peptidyl prolyl isomerase enzyme cyclophilin A in TRIM5α antiviral activity. Cyclophilin A is recruited into nascent human immunodeficiency virus type 1 (HIV-1) virions as well as incoming HIV-1 capsids, where it isomerizes an exposed proline residue. Here we show that cyclophilin A renders HIV-1 sensitive to restriction by TRIM5α in cells from Old World monkeys, African green monkey and rhesus macaque. Inhibition of cyclophilin A activity with cyclosporine A, or reducing cyclophilin A expression with small interfering RNA, rescues TRIM5α-restricted HIV-1 infectivity. The effect of cyclosporine A on HIV-1 infectivity is dependent on TRIM5α expression, and expression of simian TRIM5α in permissive feline cells renders them able to restrict HIV-1 in a cyclosporine A-sensitive way. We use an HIV-1 cyclophilin A binding mutant (CA G89V) to show that cyclophilin A has different roles in restriction by Old World monkey TRIM5α and owl monkey TRIM-Cyp. TRIM-Cyp, but not TRIM5α, recruits its tripartite motif to HIV-1 capsid via cyclophilin A and, therefore, HIV-1 G89V is insensitive to TRIM-Cyp but sensitive to TRIM5α. We propose that cyclophilin A isomerization of a proline residue in the TRIM5α sensitivity determinant of the HIV-1 capsid sensitizes it to restriction by Old World monkey TRIM5α. In humans, where HIV-1 has adapted to bypass TRIM5α activity, the effects of cyclosporine A are independent of TRIM5α. We speculate that cyclophilin A alters HIV-1 sensitivity to a TRIM5α-independent innate immune pathway in human cells.

scholarly journals Dating the primigenial C4-CYP21 duplication in primates.

Genetics ◽  
1993 ◽  
Vol 134 (1) ◽  
pp. 331-339 ◽  
Author(s):  
Y Horiuchi ◽  
H Kawaguchi ◽  
F Figueroa ◽  
C O'hUigin ◽  
J Klein
Keyword(s):  
World Monkey ◽  
Orthologous Genes ◽  
Pigtail Macaque ◽  
Single Chromosome ◽  
Old World ◽  
Histocompatibility Complex ◽  
Cyp21 Gene ◽  
Multiple Copies ◽  
Fourth Component ◽  
Flanking Regions

Abstract C4 and CYP21 are two adjacent, but functionally unrelated genes residing in the middle of the mammalian major histocompatibility complex (Mhc). The C4 gene codes for the fourth component of the complement cascade, whereas the CYP21 gene specifies an enzyme (cytochrome P450c21) of the glucocorticoid and mineralocorticoid pathways. The genes occur frequently in multiple copies on a single chromosome arranged in the order C4 ... CYP21 ... C4 ... CYP21. The unit of duplication (a module) is the C4-CYP21 gene pair. We sequenced the flanking regions of the C4-CYP21 modules and the intermodular regions of the chimpanzee, gorilla, and orangutan, as well as the intermodular region of an Old World monkey, the pigtail macaque. By aligning the sequences, we could identify the duplication breakpoints in these species. The breakpoint turned out to be at exactly the same position as that found previously in humans. The sequences flanking paralogous genes in the same species were found to be more similar to one another than sequences flanking orthologous genes in different species. We interpret these results as indicating that the original (primigenial) duplication occurred before the separation of apes from Old World monkeys more than 23 million years ago. The nature of the sequence at the breakpoint suggests that the duplication occurred by nonhomologous recombination. Since then, the C4-CYP21 haplotypes have been expanding and contracting by homologous crossing over which has homogenized the sequences in each species.(ABSTRACT TRUNCATED AT 250 WORDS)

scholarly journals SINE Insertions in Cladistic Analyses and the Phylogenetic Affiliations of Tarsius bancanus to Other Primates

Genetics ◽  
2001 ◽  
Vol 157 (2) ◽  
pp. 777-784
Author(s):  
Jürgen Schmitz ◽  
Martina Ohme ◽  
Hans Zischler
Keyword(s):  
New World ◽  
World Monkey ◽  
Old World ◽  
Alu Elements ◽  
Alu Sequences ◽  
Short Interspersed Elements ◽  
Divergence Point ◽  
Tarsius Bancanus ◽  
Cladistic Analyses ◽  
The Common

Abstract Transpositions of Alu sequences, representing the most abundant primate short interspersed elements (SINE), were evaluated as molecular cladistic markers to analyze the phylogenetic affiliations among the primate infraorders. Altogether 118 human loci, containing intronic Alu elements, were PCR analyzed for the presence of Alu sequences at orthologous sites in each of two strepsirhine, New World and Old World monkey species, Tarsius bancanus, and a nonprimate outgroup. Fourteen size-polymorphic amplification patterns exhibited longer fragments for the anthropoids (New World and Old World monkeys) and T. bancanus whereas shorter fragments were detected for the strepsirhines and the outgroup. From these, subsequent sequence analyses revealed three Alu transpositions, which can be regarded as shared derived molecular characters linking tarsiers and anthropoid primates. Concerning the other loci, scenarios are represented in which different SINE transpositions occurred independently in the same intron on the lineages leading both to the common ancestor of anthropoids and to T. bancanus, albeit at different nucleotide positions. Our results demonstrate the efficiency and possible pitfalls of SINE transpositions used as molecular cladistic markers in tracing back a divergence point in primate evolution over 40 million years old. The three Alu insertions characterized underpin the monophyly of haplorhine primates (Anthropoidea and Tarsioidea) from a novel perspective.

scholarly journals Contemporary Distribution, Estimated Age, and Prehistoric Migrations of Old World Monkey Retroviruses

Epidemiologia ◽  
2021 ◽  
Vol 2 (1) ◽  
pp. 46-67
Author(s):  
Antoinette C. van der Kuyl
Keyword(s):  
Close Contact ◽  
World Monkey ◽  
Foamy Virus ◽  
Endogenous Retrovirus ◽  
Papio Cynocephalus ◽  
Endogenous Virus ◽  
Simian Foamy Virus ◽  
Old World ◽  
T Lymphotropic Virus ◽  
Type D

Old World monkeys (OWM), simians inhabiting Africa and Asia, are currently affected by at least four infectious retroviruses, namely, simian foamy virus (SFV), simian immunodeficiency virus (SIV), simian T-lymphotropic virus (STLV), and simian type D retrovirus (SRV). OWM also show chromosomal evidence of having been infected in the past with four more retroviral species, baboon endogenous virus (BaEV), Papio cynocephalus endogenous virus (PcEV), simian endogenous retrovirus (SERV), and Rhesus endogenous retrovirus-K (RhERV-K/SERV-K1). For some of the viruses, transmission to other primates still occurs, resulting, for instance, in the HIV pandemic. Retroviruses are intimately connected with their host as they are normally spread by close contact. In this review, an attempt to reconstruct the distribution and history of OWM retroviruses will be made. A literature overview of the species infected by any of the eight retroviruses as well as an age estimation of the pathogens will be given. In addition, primate genomes from databases have been re-analyzed for the presence of endogenous retrovirus integrations. Results suggest that some of the oldest retroviruses, SERV and PcEV, have travelled with their hosts to Asia during the Miocene, when a higher global temperature allowed simian expansions. In contrast, younger viruses, such as SIV and SRV, probably due to the lack of a primate continuum between the continents in later times, have been restricted to Africa and Asia, respectively.

scholarly journals A Protein Antagonist of Activation-Induced Cytidine Deaminase Encoded by a Complex Mouse Retrovirus

mBio ◽  
2019 ◽  
Vol 10 (4) ◽  
Author(s):  
Gurvani B. Singh ◽  
Hyewon Byun ◽  
Almas F. Ali ◽  
Frank Medina ◽  
Dennis Wylie ◽  
...  
Keyword(s):  
Mouse Mammary Tumor Virus ◽  
Cytidine Deaminase ◽  
Wild Type ◽  
Mammary Tumor Virus ◽  
Mouse Mammary Tumor ◽  
Activation Induced Cytidine Deaminase ◽  
Immunodeficiency Virus ◽  
Tumor Virus ◽  
Hiv 1

ABSTRACT Complex human-pathogenic retroviruses cause high morbidity and mortality worldwide, but resist antiviral drugs and vaccine development due to evasion of the immune response. A complex retrovirus, mouse mammary tumor virus (MMTV), requires replication in B and T lymphocytes for mammary gland transmission and is antagonized by the innate immune restriction factor murine Apobec3 (mA3). To determine whether the regulatory/accessory protein Rem affects innate responses to MMTV, a splice-donor mutant (MMTV-SD) lacking Rem expression was injected into BALB/c mice. Mammary tumors induced by MMTV-SD had a lower proviral load, lower incidence, and longer latency than mammary tumors induced by wild-type MMTV (MMTV-WT). MMTV-SD proviruses had many G-to-A mutations on the proviral plus strand, but also C-to-T transitions within WRC motifs. Similarly, a lymphomagenic MMTV variant lacking Rem expression showed decreased proviral loads and increased WRC motif mutations relative to those in wild-type-virus-induced tumors, consistent with activation-induced cytidine deaminase (AID) mutagenesis in lymphoid cells. These mutations are typical of the Apobec family member AID, a B-cell-specific mutagenic protein involved in antibody variable region hypermutation. In contrast, mutations in WRC motifs and proviral loads were similar in MMTV-WT and MMTV-SD proviruses from tumors in AID-insufficient mice. AID was not packaged in MMTV virions. Rem coexpression in transfection experiments led to AID proteasomal degradation. Our data suggest that rem specifies a human-pathogenic immunodeficiency virus type 1 (HIV-1) Vif-like protein that inhibits AID and antagonizes innate immunity during MMTV replication in lymphocytes. IMPORTANCE Complex retroviruses, such as human-pathogenic immunodeficiency virus type 1 (HIV-1), cause many human deaths. These retroviruses produce lifelong infections through viral proteins that interfere with host immunity. The complex retrovirus mouse mammary tumor virus (MMTV) allows for studies of host-pathogen interactions not possible in humans. A mutation preventing expression of the MMTV Rem protein in two different MMTV strains decreased proviral loads in tumors and increased viral genome mutations typical of an evolutionarily ancient enzyme, AID. Although the presence of AID generally improves antibody-based immunity, it may contribute to human cancer progression. We observed that coexpression of MMTV Rem and AID led to AID destruction. Our results suggest that Rem is the first known protein inhibitor of AID and that further experiments could lead to new disease treatments.

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