SHIV provides a monkey model for HIV; it contains the inner parts of the simian immunodeficiency virus (SIV) and the outer parts of HIV. This study is published in the 15 October issue of the journal Science published by AAAS the nonprofit science society.
The experimental drug is a chemically synthesized protein called PSC-RANTES, designed by Science coauthors Robin Offord and Oliver Hartley from the University of Geneva in Geneva, Switzerland. It acts by preventing SHIV (and, when human cells are concerned, HIV) from latching on to cell-surface receptors called CCR5. Although in some settings, HIV may use other receptors to get into cells, the success of PSC-RANTES against SHIV in these experiments suggests that CCR5-inhibition -- alone or coupled with other approaches -- might prevent sexual HIV transmission between humans, according to the authors.
The majority of HIV infections are acquired via transmission across mucosal surfaces, especially the vagina and rectum, and substances that prevent mucosal transmission (commonly called microbicides) are urgently needed, the authors write.
"We have identified a key target for strategies to prevent vaginal HIV transmission and have a candidate molecule that blocks this target," said Science author Michael Lederman from Case Western Reserve University in Cleveland, Ohio.
"There is a real need for a topical HIV prevention strategy that women can control. This is particularly important in settings where men won't necessarily use condoms," Lederman said.
Moving from a candidate molecule to a topical agent that effectively prevents sexual transmission of HIV will require resolving many difficult issues. The required drug dosage, for example, must be better understood and reduced. Also, the authors did not test if the drug protects against transmission of SHIV contained within infected donor cells, a mechanism of uncertain importance in HIV acquisition.
Despite the challenges ahead, the authors say their findings represent an important proof-of-concept: topical application of a substance that blocks CCR5 can protect against vaginal transmission of SHIV in monkeys. Science coauthor Ronald Veazey and colleagues from Tulane National Primate Research Center in Covington, Louisiana examined the capability of PSC-RANTES to prevent vaginal acquisition of SHIV in 30 adult female rhesus macaques, Macacca mulatto, ranging from 5 to 12 years of age.
Each monkey was treated with progesterone, a hormone that thins the mucosal wall and facilitates SHIV infection. Next, the researchers split the monkeys into six groups of five, anesthetized them and intravaginally treated them with one of five concentrations of PSC-RANTES or saline placebo. Fifteen minutes later, the researchers exposed each monkey to SHIV strain SF162.
The highest dose of PSC-RANTES protected all five recipients from SHIV infection. This dose consisted of 4 milliliters of a one-millimolar concentration of the protein. The second-highest concentration (330 micromolar) protected four out of five monkeys treated. The third-strongest concentration (100 micromolar) protected three of five animals.
PSC-RANTES is a modified version of RANTES, a natural human protein. RANTES is an immune system messenger protein or "chemokine" that induces the movement of human cells and is well known for its antiviral properties.
The new molecule shows more potent antiviral activity than earlier versions produced by the same group and much greater potency than the natural protein.
PSC-RANTES seems to have blocked enough CCR5 receptors on cells in the monkeys' vaginas to prevent SHIV from continuing its multi-step infection process.
It is not clear what PSC-RANTES concentration would be needed to block HIV infections in humans -- if research were to progress that far. The concentration that prevented infection in all five monkeys is far greater than the concentrations sufficient to block infection in cells grown in the laboratory. Many factors could be responsible for this in dose disparity between live animals and cultured cells, including difficulties getting the drug to all targets within mucosal membranes of the animals.
In addition, the progesterone treatments and large doses of SHIV used to ensure near-universal infection of control monkeys could put the monkeys at an especially high risk of infection. The high drug doses used in this experiment, therefore, may not necessarily be needed to protect humans during sexual exposure.
The Science authors emphasize that PSC-RANTES is not currently authorized for use in humans, and that it is not known when or if it will be available for humans.
Michael M. Lederman, Janelle R. Salkowitz and Benigno Rodriguez are at Case Western Reserve U. in Cleveland, OH; Ronald S. Veazey, Jason Dufour and Megan Mefford are at Tulane National Primate Research Center in Covington, LA; Robin Offord and Olivier Hartley are at U. of Geneva, in Geneva, Switzerland; Donald E. Mosier is at Scripps Research Institute in La Jolla, CA; Michael Piatak Jr. and Jeffrey D. Lifson are at National Cancer Institute, NIH in Frederick, MD; Andrew Blauvelt was at National Cancer Institute, NIH in Bethesda, MD and presently at Oregon Health and Science U. in Portland, OR.
Robin Offord is a co-founder of Gryphon Pharmaceuticals, which focuses on therapeutic applications of synthetic proteins. Offord both holds equity in the company and is a paid consultant.
This work was supported by grants from the NIH, the Swiss National Science Foundation and the National Cancer Institute, NIH
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