A study published this summer in the journal Science found, for the first time, significant success in preventing HIV infection using a vaginal microbicidal gel [1]. This finding is an important step in our understanding of HIV prevention and in curbing the global HIV pandemic. The goal of this article is to provide some background on HIV/AIDS, the current state of treatment/prevention, as well as what this new study might mean for the future of HIV prevention.
What is HIV and how does it cause AIDS?
Human immunodeficiency virus (HIV) is the virus that can manifest as acquired immune deficiency syndrome, commonly known as AIDS. AIDS was first recognized as a new disease by researchers at the Centers for Disease Control (CDC) in 1981, and HIV was identified as the culprit underlying AIDS just two years later. The symptoms of AIDS are caused by destruction of immune cells. AIDS does not fully manifest until the HIV infection has compromised the immune system to a degree that it can no longer defend the body from other infections. Therefore, it is possible for a person to live with HIV but never reach the point of AIDS.
HIV is a type of virus known as a retrovirus. The genetic material of HIV is made of RNA, a type of molecule with many similarities to DNA. In most organisms, including humans, genetic information is stored as DNA, which is “transcribed” into RNA and then “translated” into proteins to carry out cellular functions. When HIV infects a human cell (the “host”), it uses a molecular machine or enzyme known as reverse transcriptase to convert its RNA into DNA. This process of “reverse transcription” is where retroviruses get their name, and allows another viral enzyme, integrase, to insert the newly made HIV DNA into the host’s genome, where it can stay indefinitely. Once the HIV DNA is part of the host’s genetic blueprint, it is transcribed by host’s cellular machinery to produce more RNA copies of itself, effectively turning the cell into a virus factory. Reverse transcriptase is a critical enzyme that retroviruses depend on, and, importantly, does not exist in humans, making it a major target for anti-HIV therapy.
HIV is thought to destroy the immune system in a number of different ways, including the direct killing of some immune cells. However, the majority of immune cell death is thought to be caused by “hyperactivation” [2]. Normally, our immune cells die and get replaced at a certain rate. When the immune system is activated (for example, by an infection), the rate of cell death increases. It makes sense that some immune cells should be short lived, as this turnover helps to limit the damage caused by inflammation once the infection is cleared — we have all heard how chronic inflammation is bad for our health. The problem with HIV is that the infection is never cleared, so the high rate of cell death is maintained, essentially exhausting the immune system. This leaves the body vulnerable to secondary infections such as tuberculosis, which is the leading cause of death associated with HIV [3]. Other secondary infections include pneumonia, septicaemia (blood poisoning), and malaria.
Who has HIV?
The World Health Organization (WHO) reported in 2004 that HIV/AIDS was the 6th biggest killer worldwide with 2 million deaths; the number decreased to 1.8 million in 2009 [4]. By the end of 2009, more than 33 million people worldwide were living with HIV/AIDS. That is equivalent to a tenth of the entire US population, and more than triple the number of people infected in 1990. Two-thirds of those infected live in Sub-Saharan Africa, while the rest are dispersed throughout the globe, with 1.1 million living in the US. Women made up roughly 50% of all HIV/AIDS cases, while children less than 15 years old made up about 7%. Moreover, AIDS has orphaned over 14 million children in Africa alone. For perspective, that’s as if all the children under the age of 18 living in Maine, Vermont, New Hampshire, Massachusetts, Connecticut, Rhode Island, New York, Pennsylvania, and Maryland were all orphans.
In the US the number of reported AIDS cases rapidly increased during the 1980s, and peaked in 1993 when the CDC modified their definition of AIDS to the current one based on the count of a particular type of immune cell in the patient’s blood. The most dramatic drop in cases and deaths began in 1996, with widespread use of antiretroviral therapy. However, developing countries have not been so fortunate. Only 36% of people in immediate need of AIDS treatment were receiving it by December 2009, highlighting the great deal of good that can still come from simply expanding the use of existing treatments [4].
How do we treat HIV/AIDS?
The treatment of HIV/AIDS has come a long way since the discovery of the disease almost 30 years ago. However, current treatments can only suppress rather than eliminate the infection. The first anti-HIV drug developed, azidothymidine or AZT, is an inhibitor of the HIV reverse transcriptase. Despite showing good results in the laboratory, AZT failed to extend the lifespan of AIDS patients. This failure was not due to a defect in the drug, but instead due to the inherently high variability of HIV.
HIV mutates at an extremely high rate for many reasons, such as mistakes made by the reverse transcriptase and the instability of an RNA genome. As a result, even within a single person there is a variety of slightly different viruses being produced. This means it is very likely that one of those viruses will be resistant to a specific drug. When that drug is administered, the resistant virus continues to grow, taking over the population to create a new generation of viruses — again with slight differences, but all resistant to the original drug. This is exactly what was seen in the first clinical trials of AZT, where viral resistance developed so quickly that it negated any positive effects of slowing susceptible viruses.
It wasn’t until 1995, with the development of a second class of anti-HIV drugs, that we began to make real progress in controlling the pandemic. These drugs target the HIV protease, an enzyme involved in processing HIV proteins into their functional forms. Today, 20 out of the 21 USDA-approved antiretroviral drugs target either the reverse transcriptase or the viral protease [5]. With the introduction of multiple antiretroviral therapies, clinicians began a treatment regime known as HAART (Highly Active Antiretroviral Therapy) that involves combinations of 3-4 drugs at once. Despite the fact that there might be viruses resistant to one drug, they can still be suppressed by one of the other drugs being used. Just as the probability of getting struck by lightning twice in a row is much lower than getting struck once, the probability of finding a virus resistant to multiple drugs is much lower than being resistant to one. By reducing the probability of resistance, HAART was finally able to increase patient lifespan by suppressing viral replication and curbing immune cell loss. Although HAART has been very successful in preventing those infected with HIV from progressing to AIDS, it is not a cure, thus making prevention of new HIV cases a critical component of the strategy against HIV/AIDS.
Microbicides and the future of HIV prevention
We know that non-biological prevention strategies, such as condom use, are highly effective in preventing the spread of HIV. However, the study in Science introduced at the beginning of this article was the first example of a biological intervention significantly reducing HIV spread. Nearly 900 South African women were enrolled in this study of a vaginal gel containing the anti-HIV drug Tenofovir. Researchers found that, on average, women using the Tenofovir gel had a 39% lower risk of contracting HIV compared to those using a placebo gel. The rate of risk reduction went up to 54% in women who used the gel more than 80% of the time [1].
Microbicides are topical products used inside the vagina or rectum to prevent sexually transmitted infections in a variety of ways. The first to be developed was a class of molecules called surfactants, which disrupt the integrity of a virus’s outer protective layer. Other types of microbicides work by blocking viral binding to host cells or by inhibiting viral replication [6]. Tenofovir was adapted from an oral treatment that targets the reverse transcriptase of retroviruses, thus inhibiting replication. An added benefit of some microbicides is that, because their mechanisms of action are fairly general, many offer protection against other sexually transmitted infections such as herpes.
This study demonstrates not only that microbicidal gels are a plausible avenue for preventing HIV infection, but that they are also an important form of protection for women in particular. Because they can be used without the knowledge of a male partner, microbicides offer an alternative for women living in areas, such as Sub-Saharan Africa, where condom use is stigmatized and therefore very low [7]. With clinical trials for other promising microbicides already under way, we may be witnessing a new milestone in the fight against HIV.
Erin Clark is at Harvard Medical School
References
1. Abdool Karim, Q., et al., Effectiveness and safety of tenofovir gel, an antiretroviral microbicide, for the prevention of HIV infection in women. Science. 329(5996): p. 1168-74.
2. Hunt, P.W., Role of immune activation in HIV pathogenesis. Curr HIV/AIDS Rep, 2007. 4(1): p. 42-7.
3. World Health Organization website on Tuberculosis and HIV: http://www.who.int/hiv/topics/tb/en/index.html
4. World Health Organization website on HIV/AIDS: http://www.who.int/topics/hiv_aids/en/
5. Simon, V., D.D. Ho, and Q. Abdool Karim, HIV/AIDS epidemiology, pathogenesis, prevention, and treatment. Lancet, 2006. 368(9534): p. 489-504.
6. Weber, J., K. Desai, and J. Darbyshire, The development of vaginal microbicides for the prevention of HIV transmission. PLoS Med, 2005. 2(5): p. e142.
7. Jones, D.L., et al., Acceptability of microbicidal surrogates among Zambian women. Sex Transm Dis, 2008. 35(2): p. 147-53.
Links of Interest
New York Times article on the Tenofovir gel clinical trial http://www.nytimes.com/2010/11/09/health/09microbicide.html?_r=1
WHO factsheet on top 10 causes of disease: http://www.who.int/mediacentre/factsheets/fs310/en/index.html