AZT resistance of simian foamy virus reverse transcriptase is based on the excision of AZTMP in the presence of ATP

ABSTRACT Foamy virus (FV) replication is resistant to most nucleoside analog reverse transcriptase (RT) inhibitors. In an attempt to create a 2′,3′-dideoxy-3′-thiacytidine (3TC)-sensitive virus, the second residue in the highly conserved YXDD motif of simian foamy virus-chimpanzee (human isolate) [SFVcpz(hu)] RT was changed from Val (V) to Met (M). Unexpectedly, the resultant virus, SFVcpz(hu) RT-V313M, replicated poorly, and Met rapidly reverted to Val. Despite the presence of approximately 50% of wild-type RT activity in RT-V313M virions, full-length DNA products were not detected in transfected cells. Using purified recombinant enzymes, we found that the wild-type FV RT is significantly more processive than human immunodeficiency virus type 1 RT. However, the V313M mutant has about 40% of the wild-type level of FV RT activity and has a lower processivity than the wild-type FV enzyme. The V313M mutant RT is also relatively resistant to 3TC. These results suggest that the decrease in RT activity and processivity of FV RT-V313M prevents completion of reverse transcription and greatly diminishes viral replication.

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

Epidemiologia ◽

10.3390/epidemiologia2010005 ◽

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.

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Simian Foamy Virus Transmission from Apes to Humans, Rural Cameroon

Emerging Infectious Diseases ◽

10.3201/eid1309.061162 ◽

2007 ◽

Vol 13 (9) ◽

pp. 1314-1320 ◽

Cited By ~ 80

Author(s):

Sara Calattini ◽

Edouard B.A. Betsem ◽

Alain Froment ◽

Philippe Mauclère ◽

Patricia Tortevoye ◽

...

Keyword(s):

Foamy Virus ◽

Virus Transmission ◽

Simian Foamy Virus ◽

Rural Cameroon

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Novel Simian Foamy Virus infection of wild Indian rhesus macaque (Macaca mulatta)

Retrovirology ◽

10.1186/1742-4690-8-s1-a215 ◽

2011 ◽

Vol 8 (S1) ◽

Author(s):

Jayashree S Nandi ◽

Anil K Chhangani ◽

Surendra M Mohnot

Keyword(s):

Virus Infection ◽

Rhesus Macaque ◽

Macaca Mulatta ◽

Foamy Virus ◽

Simian Foamy Virus ◽

Indian Rhesus Macaque

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Foamy Virus in the Tree Shrew Tupaia Belangeri Is Highly Related to Simian Foamy Virus in Macaca Mulatta

AIDS Research and Human Retroviruses ◽

10.1089/aid.2013.0112 ◽

2013 ◽

Vol 29 (8) ◽

pp. 1177-1178 ◽

Cited By ~ 4

Author(s):

Fen Huang ◽

Wenhai Yu ◽

Zhanlong He

Keyword(s):

Macaca Mulatta ◽

Tree Shrew ◽

Foamy Virus ◽

Simian Foamy Virus ◽

Tupaia Belangeri

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Selective Excision of AZTMP by Drug-Resistant Human Immunodeficiency Virus Reverse Transcriptase

Journal of Virology ◽

10.1128/jvi.75.10.4832-4842.2001 ◽

2001 ◽

Vol 75 (10) ◽

pp. 4832-4842 ◽

Cited By ~ 185

Author(s):

Paul L. Boyer ◽

Stefan G. Sarafianos ◽

Edward Arnold ◽

Stephen H. Hughes

Keyword(s):

Human Immunodeficiency Virus ◽

Reverse Transcriptase ◽

Nucleoside Analogs ◽

Azido Group ◽

Resistance Mutations ◽

Immunodeficiency Virus ◽

Azt Resistance ◽

Hiv 1

ABSTRACT Two distinct mechanisms can be envisioned for resistance of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) to nucleoside analogs: one in which the mutations interfere with the ability of HIV-1 RT to incorporate the analog, and the other in which the mutations enhance the excision of the analog after it has been incorporated. It has been clear for some time that there are mutations that selectively interfere with the incorporation of nucleoside analogs; however, it has only recently been proposed that zidovudine (AZT) resistance can involve the excision of the nucleoside analog after it has been incorporated into viral DNA. Although this proposal resolves some important issues, it leaves some questions unanswered. In particular, how do the AZT resistance mutations enhance excision, and what mechanism(s) causes the excision reaction to be relatively specific for AZT? We have used both structural and biochemical data to develop a model. In this model, several of the mutations associated with AZT resistance act primarily to enhance the binding of ATP, which is the most likely pyrophosphate donor in the in vivo excision reaction. The AZT resistance mutations serve to increase the affinity of RT for ATP so that, at physiological ATP concentrations, excision is reasonably efficient. So far as we can determine, the specificity of the excision reaction for an AZT-terminated primer is not due to the mutations that confer resistance, but depends instead on the structure of the region around the HIV-1 RT polymerase active site and on its interactions with the azido group of AZT. Steric constraints involving the azido group cause the end of an AZT 5′-monophosphate-terminated primer to preferentially reside at the nucleotide binding site, which favors excision.

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Identification of a Conserved Residue of Foamy Virus Gag Required for Intracellular Capsid Assembly

Journal of Virology ◽

10.1128/jvi.75.15.6857-6864.2001 ◽

2001 ◽

Vol 75 (15) ◽

pp. 6857-6864 ◽

Cited By ~ 47

Author(s):

Scott W. Eastman ◽

Maxine L. Linial

Keyword(s):

Foamy Virus ◽

Specific Interaction ◽

Capsid Assembly ◽

Particle Assembly ◽

Simian Foamy Virus ◽

Viral Budding ◽

Extracellular Release ◽

Infected Cells ◽

Targeting Signal ◽

Strict Requirement

ABSTRACT In contrast to all retroviruses but similar to the hepatitis B virus, foamy viruses (FV) require expression of the envelope protein for budding of intracellular capsids from the cell, suggesting a specific interaction between the Gag and Env proteins. Capsid assembly occurs in the cytoplasm of infected cells in a manner similar to that for the B- and D-type viruses; however, in contrast to these retroviruses, FV Gag lacks an N-terminal myristylation signal and capsids are not targeted to the plasma membrane (PM). We have found that mutation of an absolutely conserved arginine (Arg) residue at position 50 to alanine (R50A) of the simian foamy virus SFV cpz(hu) inhibits proper capsid assembly and abolishes viral budding even in the presence of the envelope (Env) glycoproteins. Particle assembly and extracellular release of virus can be restored to this mutant with the addition of an N-terminal Src myristylation signal (Myr-R50A), presumably by providing an alternate site for assembly to occur at the PM. In addition, the strict requirement of Env expression for capsid budding can be bypassed by addition of a PM-targeting signal to Gag. These results suggest that intracellular capsid assembly may be mediated by a signal akin to the cytoplasmic targeting and retention signal CTRS found in Mason-Pfizer monkey virus and that FV Gag has the inherent ability to assemble capsids at multiple sites like conventional retroviruses. The necessity of Env expression for particle egress is most probably due to the lack of a membrane-targeting signal within FV Gag to direct capsids to the PM for release and indicates that Gag-Env interactions are essential to drive particle budding.

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The M184V Mutation Reduces the Selective Excision of Zidovudine 5′-Monophosphate (AZTMP) by the Reverse Transcriptase of Human Immunodeficiency Virus Type 1

Journal of Virology ◽

10.1128/jvi.76.7.3248-3256.2002 ◽

2002 ◽

Vol 76 (7) ◽

pp. 3248-3256 ◽

Cited By ~ 66

Author(s):

Paul L. Boyer ◽

Stefan G. Sarafianos ◽

Edward Arnold ◽

Stephen H. Hughes

Keyword(s):

Human Immunodeficiency Virus ◽

Reverse Transcriptase ◽

Human Immunodeficiency Virus Type ◽

Virus Type ◽

Published Data ◽

Immunodeficiency Virus ◽

Azt Resistance ◽

Hiv 1 ◽

M184v Mutation

ABSTRACT The M184V mutation in human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) causes resistance to lamivudine, but it also increases the sensitivity of the virus to zidovudine (3′-azido-3′-deoxythymidine; AZT). This sensitization to AZT is seen both in the presence and the absence of the mutations that confer resistance to AZT. AZT resistance is due to enhanced excision of AZT 5′-monophosphate (AZTMP) from the end of the primer by the RT of the resistant virus. Published data suggest that the excision reaction involves pyrophosphorolysis but that the likely in vivo pyrophosphate donor is not pyrophosphate but ATP. The mutations that lead to AZT resistance enhance ATP binding and, in so doing, enhance pyrophosphorolysis. The excision reaction is specific for AZT because HIV-1 RT, which can form a closed complex with a dideoxy-terminated primer and an incoming deoxynucleoside triphosphate (dNTP), does not form the closed complex with an AZTMP-terminated primer and an incoming dNTP. This means that an AZTMP-terminated primer has better access to the site where it can be excised. The M184V mutation alters the polymerase active site in a fashion that specifically interferes with ATP-mediated excision of AZTMP from the end of the primer strand. The M184V mutation does not affect the incorporation of AZT 5′-triphosphate (AZTTP), either in the presence or the absence of mutations that enhance AZTMP excision. However, in the presence of ATP, the M184V mutation does decrease the ability of HIV-1 RT to carry out AZTMP excision. Based on these results, and on the results of other excision experiments, we present a model to explain how the M184V mutation affects AZTMP excision.

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