Microbicide gel can prevent HIV and herpes infection of human cells

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A gel containing the microbicide PRO 2000 can prevent infection of human cells by HIV and the herpes simplex virus after being inserted into the vagina, according to a study presented in the 1st January edition of The Journal of Infectious Diseases. This is the first study to show the activity of a microbicide after application in humans.

At present, male or female condoms are the best form of protection against HIV infection during sex. However, their effectiveness is limited by the need for both partners to initiate and agree to their use, which is impossible in some situations.

Microbicides are drugs that are intended for use to prevent infection with sexually transmitted infections, such as HIV. They are being investigated as they may allow women to gain more control over their risk of contracting HIV or other infections. Microbicides may also reduce HIV transmission during sex between men.

Glossary

microbicide

A product (such as a gel or cream) that is being tested in HIV prevention research. It could be applied topically to genital surfaces to prevent or reduce the transmission of HIV during sexual intercourse. Microbicides might also take other forms, including films, suppositories, and slow-releasing sponges or vaginal rings.

placebo

A pill or liquid which looks and tastes exactly like a real drug, but contains no active substance.

cytokines

Chemical "messengers" exchanged between immune cells that affect the function of the immune system. Interleukins such as IL-2 are a particular type of cytokine.

strain

A variant characterised by a specific genotype.

 

receptor

In cell biology, a structure on the surface of a cell (or inside a cell) that selectively receives and binds to a specific substance. There are many receptors. CD4 T cells are called that way because they have a protein called CD4 on their surface. Before entering (infecting) a CD4 T cell (that will become a “host” cell), HIV binds to the CD4 receptor and its coreceptor. 

PRO 2000 is a microbicide developed by Indevus Pharmaceuticals that binds to the surface of HIV and prevents it entering cells. Although its activity has been demonstrated in test tube and animal studies, its effectiveness has not been demonstrated in human trials. To assess whether the drug could prevent infection of human cells with HIV or the herpes simplex virus, investigators assessed the effectiveness of a gel containing 0.5% PRO 2000.

Ten women were randomised to receive PRO 2000, while ten received an identical placebo gel that did not contain the active ingredient. None of the women or investigators knew which treatment each woman was receiving. In this study, all of the women were HIV-positive.

The investigators took 10-ml saline washes of the vagina from each woman 48 hours before they applied 2ml of the gel into the vagina. One hour later, another 10-ml wash was taken from each woman. The investigators claim that this is similar to what happens when the vaginal contents are diluted with semen after sex: the typical volume of semen ejaculated is between 2 and 6ml.

The investigators ‘spiked’ the washes with a strain of HIV that was engineered to be unable to make copies of itself. The strain also contained the gene for luciferase, an enzyme from the firefly that glows in the presence of specific chemicals.

After applying the HIV-spiked washes to human cells, the investigators were able to see how many cells had been infected with the defective HIV by measuring the light intensity emitted. They used cells that had the CD4 and CCR5 receptors on their surface: HIV binds to these receptors before entering the cells.

By comparing the amounty of light emitted from each sample, the investiagtors could discover the degree to which HIV's infectiousness was reduced by the application of the microbicide and the placebo gel.

The researchers found that the PRO 2000 gel inhibited HIV infection by at least 1000-fold, with a mean 4.03 log10 reduction in infectivity after the gel was applied. In contrast, washes from the women receiving the placebo gel had similar anti-HIV activity before and after the gel was applied (mean 1.25 log10 reduction). This difference was highly statistically significant (p

Similar results were seen when the investigators used a strain of HIV that uses the CCR5 co-receptor to enter its target cells, and tested whether it infected human macrophage cells. These ‘R5-topic’ viruses are more common in early HIV infection following sexual transmission and may be more readily transmitted during sex.

Three women in each group experienced side-effects, but these were not judged to be due to PRO 2000.

This study demonstrates that PRO 2000 may work in preventing infection by demonstrating that the drug is effective after application to the vagina. “PRO 2000 gel (0.5%) is sufficiently bioavailable and retains substantial antiviral activity after intravaginal application,” the investigators write.

Previous studies of a microbicide called nonoxynol-9 showed no protection against HIV infection, since it caused inflammation in the vagina that counteracted the drug’s antiviral effects. To examine whether the PRO-2000 gel had any similar effects, the investigators measured the levels of three immune system ‘cytokines’ that are released during inflammation: interleukin-8, interleukin-1 beta and secretory leukocyte protease inhibitor (SLPI).

The levels of the cytokines were reduced following PRO 2000 and placebo gel applications. The investigators found no differences in levels between the drug and placebo groups. “These results suggest that there is no influx or activation of inflammatory cells, which may induce cytokine release,” they conclude.

The PRO 2000 gel also protected against herpes simplex virus infection of human cells (mean reduction: 3.10 vs. 0.64 log10; p

Despite its promising findings, the study is limited by its assessment of HIV infection in the test tube. “How these findings translate in vivo and whether this degree of in vitro anti-HIV activity will be effective even in the presence of acute HIV or other sexually transmitted infections is difficult to predict,” the investigators write.

In an accompanying review article, Darpun Dhawan from Brown University and Kenneth Mayer from Fenway Community Health, Boston, outline some of the reasons for the delay in production of an effective microbicide despite promising findings from test tube and animal studies.

Although more than 15 candidate drugs are being tested with various methods of action, the production has been delayed by limitations in understanding of how HIV infection occurs, difficulties in applying the results of animal studies to humans and the lack of clear endpoints for studies that would indicate that a microbicide is effective.

The lack of a clear endpoint for microbicide studies has led to the design of large, multicentre studies comparing the rates of HIV infection between different microbicides or placebos in cohorts of people at risk of HIV infection. In addition to ethical difficulties surrounding the potential exposure of participants to HIV infection, these studies are large, long-lasting and expensive.

PRO 2000 is currently being tested in two large, multicentre trials, to examine whether it can reduce the number of HIV transmissions. This study adds weight to previous evidence from test tube and animal studies suggesting that it will be active in reducing HIV infections following application into the vagina.

It is possible that the luciferase technique used in the PRO 2000 study could provide additional information on the effectiveness of microbicides after application into the vagina. These could form a better predictor of a microbicide’s effectiveness in humans before larger trials are initiated.

Further problems in the design of microbicide trials include the risks of study participants developing HIV resistance if infected, the need for promotion of condom use by trial participants, limited sources of funding, and potential effects of microbicides on sperm and pregnancy.

References

Dhawan D et al. Microbicides to prevent HIV transmission: overcoming obstacles to chemical barrier protection. J Infect Dis 193: 36-44, 2006.

Keller MJ et al. PRO 2000 gel inhibits HIV and herpes simplex virus infection following vaginal application: a double-blind placebo-controlled trial. J Infect Dis 193: 27-35, 2006.