Prophylactic and therapeutic benefits of short-term 9-[2-(R)- (phosphonomethoxy)propyl]adenine (PMPA) administration to newborn macaques following oral inoculation with simian immunodeficiency virus with reduced susceptibility to PMPA

Koen K.A. Van Rompay, Michael D. Miller, Marta Marthas, Nicolas A. Margot, Peter J. Dailey, Don R. Canfield, Ross P. Tarara, Julie M. Cherrington, Nancy L. Aguirre, Norbert Bischofberger, Niels C Pedersen

Research output: Contribution to journalArticle

69 Citations (Scopus)

Abstract

Simian immunodeficiency virus (SIV) infection of newborn macaques is a useful animal model of human pediatric AIDS to study pathogenesis and to develop intervention strategies aimed at preventing infection or delaying disease progression. In previous studies, we demonstrated that 9-[2-(R)- (phosphonomethoxy)propyl] adenine (PMPA; tenofovir) was highly effective in protecting newborn macaques against infection with virulent wild-type (i.e., drug-susceptible) SIVmac251. In the present study, we determined how reduced drug susceptibility of the virus inoculum affects the chemoprophylactic success. SIVmac055 is a virulent isolate that has a fivefold-reduced in vitro susceptibility to PMPA, associated with a K65R mutation and additional amino acid changes (N69T, R82K, A158S, S211N) in reverse transcriptase (RT). Eight newborn macaques were inoculated orally with SIVmac055. The three untreated control animals became SIVmac055 infected; these animals had persistently high viremia and developed fatal immunodeficiency within 3 months. Five animals were treated once daily with PMPA (at 30 mg/kg of body weight) for 4 weeks, starting 24 h prior to oral SIVmac055 inoculation. Two of the five PMPA-treated animals had no evidence of infection. The other three PMPA- treated infant macaques became infected but had a delayed viremia, enhanced antiviral antibody responses, and a slower disease course (AIDS in 5 to 15 months). No reversion to wild-type susceptibility or loss of the K65R mutation was detected in virus isolates from any of the PMPA-treated or untreated SIVmac055-infected animals. Several additional amino acid changes developed in RT, but they were not exclusively associated with PMPA therapy. The results of this study suggest that prophylactic administration of PMPA to human newborns and to adults following exposure to human immunodeficiency virus will still be beneficial even in the presence of vital variants with reduced susceptibility to PMPA.

Original languageEnglish (US)
Pages (from-to)1767-1774
Number of pages8
JournalJournal of Virology
Volume74
Issue number4
DOIs
StatePublished - 2000

Fingerprint

Simian immunodeficiency virus
Simian Immunodeficiency Virus
Macaca
Adenine
adenine
oral administration
neonates
therapeutics
Therapeutics
Tenofovir
RNA-directed DNA polymerase
Viremia
RNA-Directed DNA Polymerase
viremia
animals
disease course
infection
Acquired Immunodeficiency Syndrome
Infection
Viruses

ASJC Scopus subject areas

  • Immunology
  • Virology

Cite this

Prophylactic and therapeutic benefits of short-term 9-[2-(R)- (phosphonomethoxy)propyl]adenine (PMPA) administration to newborn macaques following oral inoculation with simian immunodeficiency virus with reduced susceptibility to PMPA. / Van Rompay, Koen K.A.; Miller, Michael D.; Marthas, Marta; Margot, Nicolas A.; Dailey, Peter J.; Canfield, Don R.; Tarara, Ross P.; Cherrington, Julie M.; Aguirre, Nancy L.; Bischofberger, Norbert; Pedersen, Niels C.

In: Journal of Virology, Vol. 74, No. 4, 2000, p. 1767-1774.

Research output: Contribution to journalArticle

Van Rompay, Koen K.A. ; Miller, Michael D. ; Marthas, Marta ; Margot, Nicolas A. ; Dailey, Peter J. ; Canfield, Don R. ; Tarara, Ross P. ; Cherrington, Julie M. ; Aguirre, Nancy L. ; Bischofberger, Norbert ; Pedersen, Niels C. / Prophylactic and therapeutic benefits of short-term 9-[2-(R)- (phosphonomethoxy)propyl]adenine (PMPA) administration to newborn macaques following oral inoculation with simian immunodeficiency virus with reduced susceptibility to PMPA. In: Journal of Virology. 2000 ; Vol. 74, No. 4. pp. 1767-1774.
@article{f586c7747aef4550b63e6d9b5189c619,
title = "Prophylactic and therapeutic benefits of short-term 9-[2-(R)- (phosphonomethoxy)propyl]adenine (PMPA) administration to newborn macaques following oral inoculation with simian immunodeficiency virus with reduced susceptibility to PMPA",
abstract = "Simian immunodeficiency virus (SIV) infection of newborn macaques is a useful animal model of human pediatric AIDS to study pathogenesis and to develop intervention strategies aimed at preventing infection or delaying disease progression. In previous studies, we demonstrated that 9-[2-(R)- (phosphonomethoxy)propyl] adenine (PMPA; tenofovir) was highly effective in protecting newborn macaques against infection with virulent wild-type (i.e., drug-susceptible) SIVmac251. In the present study, we determined how reduced drug susceptibility of the virus inoculum affects the chemoprophylactic success. SIVmac055 is a virulent isolate that has a fivefold-reduced in vitro susceptibility to PMPA, associated with a K65R mutation and additional amino acid changes (N69T, R82K, A158S, S211N) in reverse transcriptase (RT). Eight newborn macaques were inoculated orally with SIVmac055. The three untreated control animals became SIVmac055 infected; these animals had persistently high viremia and developed fatal immunodeficiency within 3 months. Five animals were treated once daily with PMPA (at 30 mg/kg of body weight) for 4 weeks, starting 24 h prior to oral SIVmac055 inoculation. Two of the five PMPA-treated animals had no evidence of infection. The other three PMPA- treated infant macaques became infected but had a delayed viremia, enhanced antiviral antibody responses, and a slower disease course (AIDS in 5 to 15 months). No reversion to wild-type susceptibility or loss of the K65R mutation was detected in virus isolates from any of the PMPA-treated or untreated SIVmac055-infected animals. Several additional amino acid changes developed in RT, but they were not exclusively associated with PMPA therapy. The results of this study suggest that prophylactic administration of PMPA to human newborns and to adults following exposure to human immunodeficiency virus will still be beneficial even in the presence of vital variants with reduced susceptibility to PMPA.",
author = "{Van Rompay}, {Koen K.A.} and Miller, {Michael D.} and Marta Marthas and Margot, {Nicolas A.} and Dailey, {Peter J.} and Canfield, {Don R.} and Tarara, {Ross P.} and Cherrington, {Julie M.} and Aguirre, {Nancy L.} and Norbert Bischofberger and Pedersen, {Niels C}",
year = "2000",
doi = "10.1128/JVI.74.4.1767-1774.2000",
language = "English (US)",
volume = "74",
pages = "1767--1774",
journal = "Journal of Virology",
issn = "0022-538X",
publisher = "American Society for Microbiology",
number = "4",

}

TY - JOUR

T1 - Prophylactic and therapeutic benefits of short-term 9-[2-(R)- (phosphonomethoxy)propyl]adenine (PMPA) administration to newborn macaques following oral inoculation with simian immunodeficiency virus with reduced susceptibility to PMPA

AU - Van Rompay, Koen K.A.

AU - Miller, Michael D.

AU - Marthas, Marta

AU - Margot, Nicolas A.

AU - Dailey, Peter J.

AU - Canfield, Don R.

AU - Tarara, Ross P.

AU - Cherrington, Julie M.

AU - Aguirre, Nancy L.

AU - Bischofberger, Norbert

AU - Pedersen, Niels C

PY - 2000

Y1 - 2000

N2 - Simian immunodeficiency virus (SIV) infection of newborn macaques is a useful animal model of human pediatric AIDS to study pathogenesis and to develop intervention strategies aimed at preventing infection or delaying disease progression. In previous studies, we demonstrated that 9-[2-(R)- (phosphonomethoxy)propyl] adenine (PMPA; tenofovir) was highly effective in protecting newborn macaques against infection with virulent wild-type (i.e., drug-susceptible) SIVmac251. In the present study, we determined how reduced drug susceptibility of the virus inoculum affects the chemoprophylactic success. SIVmac055 is a virulent isolate that has a fivefold-reduced in vitro susceptibility to PMPA, associated with a K65R mutation and additional amino acid changes (N69T, R82K, A158S, S211N) in reverse transcriptase (RT). Eight newborn macaques were inoculated orally with SIVmac055. The three untreated control animals became SIVmac055 infected; these animals had persistently high viremia and developed fatal immunodeficiency within 3 months. Five animals were treated once daily with PMPA (at 30 mg/kg of body weight) for 4 weeks, starting 24 h prior to oral SIVmac055 inoculation. Two of the five PMPA-treated animals had no evidence of infection. The other three PMPA- treated infant macaques became infected but had a delayed viremia, enhanced antiviral antibody responses, and a slower disease course (AIDS in 5 to 15 months). No reversion to wild-type susceptibility or loss of the K65R mutation was detected in virus isolates from any of the PMPA-treated or untreated SIVmac055-infected animals. Several additional amino acid changes developed in RT, but they were not exclusively associated with PMPA therapy. The results of this study suggest that prophylactic administration of PMPA to human newborns and to adults following exposure to human immunodeficiency virus will still be beneficial even in the presence of vital variants with reduced susceptibility to PMPA.

AB - Simian immunodeficiency virus (SIV) infection of newborn macaques is a useful animal model of human pediatric AIDS to study pathogenesis and to develop intervention strategies aimed at preventing infection or delaying disease progression. In previous studies, we demonstrated that 9-[2-(R)- (phosphonomethoxy)propyl] adenine (PMPA; tenofovir) was highly effective in protecting newborn macaques against infection with virulent wild-type (i.e., drug-susceptible) SIVmac251. In the present study, we determined how reduced drug susceptibility of the virus inoculum affects the chemoprophylactic success. SIVmac055 is a virulent isolate that has a fivefold-reduced in vitro susceptibility to PMPA, associated with a K65R mutation and additional amino acid changes (N69T, R82K, A158S, S211N) in reverse transcriptase (RT). Eight newborn macaques were inoculated orally with SIVmac055. The three untreated control animals became SIVmac055 infected; these animals had persistently high viremia and developed fatal immunodeficiency within 3 months. Five animals were treated once daily with PMPA (at 30 mg/kg of body weight) for 4 weeks, starting 24 h prior to oral SIVmac055 inoculation. Two of the five PMPA-treated animals had no evidence of infection. The other three PMPA- treated infant macaques became infected but had a delayed viremia, enhanced antiviral antibody responses, and a slower disease course (AIDS in 5 to 15 months). No reversion to wild-type susceptibility or loss of the K65R mutation was detected in virus isolates from any of the PMPA-treated or untreated SIVmac055-infected animals. Several additional amino acid changes developed in RT, but they were not exclusively associated with PMPA therapy. The results of this study suggest that prophylactic administration of PMPA to human newborns and to adults following exposure to human immunodeficiency virus will still be beneficial even in the presence of vital variants with reduced susceptibility to PMPA.

UR - http://www.scopus.com/inward/record.url?scp=0033947591&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0033947591&partnerID=8YFLogxK

U2 - 10.1128/JVI.74.4.1767-1774.2000

DO - 10.1128/JVI.74.4.1767-1774.2000

M3 - Article

C2 - 10644348

AN - SCOPUS:0033947591

VL - 74

SP - 1767

EP - 1774

JO - Journal of Virology

JF - Journal of Virology

SN - 0022-538X

IS - 4

ER -