The new PLoS Medicine features a study conducted by Martin Cranage and colleagues evaluating tenofovir gel as a potential rectal microbicide in the SIV challenge model. The researchers report that application of the gel two hours prior to exposure to the SIVmac251/32H challenge virus protected six out of nine macaques. Of the remaining three, two showed lowered viral loads post-infection compared to controls. Interestingly, most of the protected animals also displayed detectable SIV-specific T cell responses even though sensitive assays could find no trace of virus.
The PLoS editor’s summary raises the concern that these SIV-specific T cells may be associated with enhanced susceptibility to infection upon re-exposure; however, Cranage et al note in their discussion that transient tenofovir treatment immediately post SIV infection has been shown to lead to induction of SIV-specific T cell responses, and macaques in this study subsequently resisted both homologous and heterologous SIV challenges. The question of whether the SIV-specific T cell responses observed in Cranage’s study have the potential to be protective can only be definitively addressed by another experiment in which the macaques are re-challenged with SIV.
An additional implication of these data is that human trials of microbicides and pre-exposure prophylaxis (PrEP) should include monitoring for HIV-specific T cell responses.
PLoS Medicine Vol. 5, No. 8, e157 doi:10.1371/journal.pmed.0050157
Prevention of SIV Rectal Transmission and Priming of T Cell Responses in Macaques after Local Pre-exposure Application of Tenofovir Gel
Martin Cranage1*, Sally Sharpe2, Carolina Herrera1, Alethea Cope1, Mike Dennis2, Neil Berry3, Claire Ham3, Jonathan Heeney4,5, Naser Rezk6, Angela Kashuba6, Peter Anton7, Ian McGowan7¤, Robin Shattock1
1 Centre for Infection, Division of Cellular & Molecular Medicine, St George's University of London, London, United Kingdom, 2 Centre for Emergency Preparedness and Response, Health Protection Agency, Porton Down, Salisbury, United Kingdom, 3 Division of Retrovirology, National Institute for Biological Standards & Control, South Mimms, United Kingdom, 4 Department of Virology, Biomedical Primate Research Centre, Rijswijk, The Netherlands, 5 Department of Veterinary Medicine, University of Cambridge, Cambridge, United Kingdom, 6 University of North Carolina Centers for Aids Research (CFAR) Clinical Pharmacology and Analytical Chemistry Core, Chapel Hill, North Carolina, United States of America, 7 Center for Prevention Research, David Geffen School of Medicine at the University of California Los Angeles (UCLA), Los Angeles, California, United States of America
Background
The rectum is particularly vulnerable to HIV transmission having only a single protective layer of columnar epithelium overlying tissue rich in activated lymphoid cells; thus, unprotected anal intercourse in both women and men carries a higher risk of infection than other sexual routes. In the absence of effective prophylactic vaccines, increasing attention is being given to the use of microbicides and preventative antiretroviral (ARV) drugs. To prevent mucosal transmission of HIV, a microbicide/ARV should ideally act locally at and near the virus portal of entry. As part of an integrated rectal microbicide development programme, we have evaluated rectal application of the nucleotide reverse transcriptase (RT) inhibitor tenofovir (PMPA, 9-[(R)-2-(phosphonomethoxy) propyl] adenine monohydrate), a drug licensed for therapeutic use, for protective efficacy against rectal challenge with simian immunodeficiency virus (SIV) in a well-established and standardised macaque model.
Methods and Findings
A total of 20 purpose-bred Indian rhesus macaques were used to evaluate the protective efficacy of topical tenofovir. Nine animals received 1% tenofovir gel per rectum up to 2 h prior to virus challenge, four macaques received placebo gel, and four macaques remained untreated. In addition, three macaques were given tenofovir gel 2 h after virus challenge. Following intrarectal instillation of 20 median rectal infectious doses (MID50) of a noncloned, virulent stock of SIVmac251/32H, all animals were analysed for virus infection, by virus isolation from peripheral blood mononuclear cells (PBMC), quantitative proviral DNA load in PBMC, plasma viral RNA (vRNA) load by sensitive quantitative competitive (qc) RT-PCR, and presence of SIV-specific serum antibodies by ELISA. We report here a significant protective effect (p = 0.003; Fisher exact probability test) wherein eight of nine macaques given tenofovir per rectum up to 2 h prior to virus challenge were protected from infection (n = 6) or had modified virus outcomes (n = 2), while all untreated macaques and three of four macaques given placebo gel were infected, as were two of three animals receiving tenofovir gel after challenge. Moreover, analysis of lymphoid tissues post mortem failed to reveal sequestration of SIV in the protected animals. We found a strong positive association between the concentration of tenofovir in the plasma 15 min after rectal application of gel and the degree of protection in the six animals challenged with virus at this time point. Moreover, colorectal explants from non-SIV challenged tenofovir-treated macaques were resistant to infection ex vivo, whereas no inhibition was seen in explants from the small intestine. Tissue-specific inhibition of infection was associated with the intracellular detection of tenofovir. Intriguingly, in the absence of seroconversion, Gag-specific gamma interferon (IFN-γ)-secreting T cells were detected in the blood of four of seven protected animals tested, with frequencies ranging from 144 spot forming cells (SFC)/106 PBMC to 261 spot forming cells (SFC)/106 PBMC.
Conclusions
These results indicate that colorectal pretreatment with ARV drugs, such as tenofovir, has potential as a clinically relevant strategy for the prevention of HIV transmission. We conclude that plasma tenofovir concentration measured 15 min after rectal administration may serve as a surrogate indicator of protective efficacy. This may prove to be useful in the design of clinical studies. Furthermore, in vitro intestinal explants served as a model for drug distribution in vivo and susceptibility to virus infection. The finding of T cell priming following exposure to virus in the absence of overt infection is provocative. Further studies would reveal if a combined modality microbicide and vaccination strategy is feasible by determining the full extent of local immune responses induced and their protective potential.
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