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Pre-exposure Prophylaxis in Macaques against Rectal SIV Challenge by Mucosally Applied PMPA: Potential for Complementation of Microbicide and Vaccination Strategies
Martin Cranage*1, S Sharpe2, A Cope1, C Herrera1, M Dennis2, N Berry3, C Ham3, P Anton4, I McGowan4, and R Shattock1
1St George's, Univ of London, UK; 2Hlth Protection Agency, Porton Down, UK; 3Natl Inst for Biological Standards and Control, South Mimms, UK; and 4David Geffen Sch of Med, Univ of California, Los Angeles, US
Background: Rectal transmission is a significant route for
the acquisition of HIV. The pre-exposure prophylactic use of anti-retroviral
nucleotide analogues has given mixed results in preclinical tests. We
hypothesized that a rectally applied nucleoside reverse transcriptase inhibitor
(NRTI) may have enhanced protective efficacy against mucosal virus challenge.
Methods: The nucleotide analogue, 9-[(R)-2-(phosphonmethoxy)
propyl] adenine monohydrate (PMPA) formulated as tenofovir (TDF) gel was given rectally in a single dose 15
minutes or 2 hours before, or 2 hours after, intrarectal
challenge of rhesus macaques with SIVmac.
Results: In 4 of 4 untreated macaques and 3 of 4
macaques given placebo gel, virus was recovered at every time-point tested. In
contrast, 6 of 9 animals given TDF prior to challenge were protected from overt
infection, and virus detection was intermittent or delayed in 2 other animals.
Including historical controls, this indicates a very significant degree of
protection (p <0.001; Fisher’s exact
test). Virus was isolated on every occasion of testing from 2 of 3 animals
where gel was administered 2 hours after virus challenge. Polymerase chain
reaction (PCR) for proviral DNA in uncultured peripheral
blood mononuclear cells (PBMC) confirmed the results of virus isolation and no
evidence of viral sequestration was detected in lymphoid tissues tested 20
weeks after virus challenge. Furthermore, plasma vRNA
profiles were modified in animals given gel prior to challenge and were not
protected from infection. Protection was associated with the concentration of TDF
detected in plasma at the time of virus challenge. Interestingly, Gag-specific
interferon-γ-secreting T cells were detected by ELISpot
in 4 of 7 protected animals, despite absence of seroconversion,
with frequencies ranging from 144 spot forming cells (SFC)/106 PBMC
to 261 SFC/106 PBMC.
Conclusions: These data indicate that rectal pre-dosing
with TDF gel has potential as part of a microbicide
strategy and may enable priming of the immune system through mucosal exposure
to virus challenge.
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