Studying and Stopping Rectal Transmission of HIV

Jeffrey Laurence, M.D.

June 17, 2009—In recent years, several large clinical trials of microbicides designed to block penile-vaginal transmission of HIV have been completed. Limited, if not definitive success was obtained with only one product, PRO2000. Other products are in various stages of testing in women. But similar large trials have not been conducted with rectal products, despite the fact that anal intercourse is a key mode of transmission, not only for men who have sex with men but for many heterosexual women. Research by two amfAR-funded groups is yielding new information critical to the design and testing of rectal microbicides.

Writing in the May issue of the Journal of Experimental Medicine, amfAR fellow Dr. Brandon Keele of the University of Alabama, along with colleagues from six other research institutions, developed a model in rhesus macaque monkeys for rectal transmission of SIV, the monkey AIDS virus, and compared their results with HIV transmission in humans. Dr. Keele uncovered striking similarities between monkeys and people in terms of the amount of virus required for infection, the types of viruses later found in the blood, and immune response. These findings validated his system as a representative model with which to test strategies to inhibit rectal HIV transmission.

In order to infect the macaques, Dr. Keele used a mix of SIV viruses that closely mimicked the limited genetic diversity of viruses present in humans early after an infection. This is important, as people who are recently infected have very high levels of virus in their genital fluids and blood, and are more likely to transmit HIV during this stage of infection than in others. Regardless of whether a monkey was inoculated intravenously or rectally, within one to five weeks the viruses growing in the blood of all infected animals were similar, and represented progeny of just a single infecting virus. This is exactly what happens in people. Also reflecting the human situation, direct intravenous injection of SIV into monkeys was 2,000 times more efficient at originating an infection than rectal inoculation. And increasing the dose of virus increased the infection rate.

amfAR fellow Dr. Carolina Herrera, working at St. George’s University in London, took another approach to understanding rectal transmission. Using a test tube system involving human tissues, she sought to define the best cocktail of known anti-HIV drugs to include in a rectal microbicide.

In a report in the May issue of the journal Antimicrobial Agents and Chemotherapy, Dr. Herrera and colleagues studied both human cell lines as well as small pieces—about a tenth of an inch—of human intestine obtained from HIV-negative patients undergoing surgery. Like isolated cells, these “colorectal explants,” maintained in nutrient broths atop foam rafts, can be infected with HIV. Dr. Herrera asked what would happen if various combinations of anti-HIV drugs—a reverse transcriptase inhibitor and two non-nucleoside reverse transcriptase inhibitors—were added to the cells or tissues.

The results of her study indicated that various combinations of the three drugs proved much more effective in blocking HIV infection than any single drug. Combinations were also key to inhibiting infection by drug-resistant viruses. “These findings may have important implications for the rational design of effective rectal microbicides,” Dr. Herrera suggested. Considered in conjunction with the work of Dr. Keele and many other groups, her conclusion seems accurate.

These and other approaches, both clinical and behavioral, were the topic of an amfAR-sponsored think tank held in mid-March. To read more and view a video summary of that conference, click  here.

Dr. Jeffrey Laurence is amfAR’s senior scientific consultant.

RELATED LINKS

New amfAR Research Grants Aim to Advance Understanding and Prevention of Rectal HIV Transmission