14th Conference on Retroviruses and Opportunistic Infections Los Angeles, California - February 25-28, 2007

Conf Retrovir Opportunistic Infect 2007 Feb 25-28;14: (abstract no. 29)

Martin Cranage¹, S Sharpe², A Cope¹, C Herrera¹, M Dennis², N Berry³, C Ham³, P Anton⁴, I McGowan⁴, and R Shattock^1
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 SIV_mac.

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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2007-02-25
29

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