Stability of 5P12-RANTES, A Candidate Rectal Microbicide, in Human Rectal Lavage.
In the absence of an effective vaccine, strategies to prevent HIV transmission are urgently needed. Condomless receptive anal intercourse represents a major route of transmission, and efforts are being made to develop strategies, in which potent anti-HIV drugs are formulated for topical application to the rectum before sex. 5P12-RANTES is a promising candidate for such a purpose. It is an analog of the human chemokine RANTES/CCL5, which potently blocks CCR5, the principal coreceptor used by HIV to enter and infect target cells. As a protein, 5P12-RANTES is potentially vulnerable to attack by proteases in the rectal environment. In this study, we tested the stability of 5P12-RANTES on exposure to rectal lavage samples obtained from healthy volunteers, using a sensitive HIV entry inhibition assay as an indicator of stability. Varying levels of inactivating activity toward 5P12-RANTES were detected across the different lavage samples. Analysis of even the most aggressive samples indicated that protease activity in the rectal environment is unlikely to impact on the anti-HIV activity of 5P12-RANTES when applied pericoitally at the envisaged clinical dose (1 mM). This study indicates that 5P12-RANTES has adequate stability for further development as an HIV prevention drug for rectal use.
1 Department of Pathology and Immunology, Faculty of Medicine, University of Geneva , Geneva, Switzerland .
Fabrice
F
Cerini
2 The Mintaka Foundation for Medical Research , Geneva, Switzerland .
Robin
R
Offord
3 Department of Medicine, University of Pittsburgh School of Medicine , Pittsburgh, Pennsylvania.
Ian
I
McGowan
1 Department of Pathology and Immunology, Faculty of Medicine, University of Geneva , Geneva, Switzerland .|2 The Mintaka Foundation for Medical Research , Geneva, Switzerland .
Oliver
O
Hartley
D000890:Anti-Infective Agents / Q000378:metabolism*; D019742:Chemokines, CC / Q000378:metabolism*; D004355:Drug Stability; D064368:Healthy Volunteers; D006801:Humans; D006868:Hydrolysis; D012007:Rectum / Q000201:enzymology*
C539265:5P12-RANTES; D000890:Anti-Infective Agents; D019742:Chemokines, CC
HIV entry inhibitors; HIV prevention; PrEP; coreceptor; microbicides