Women, HIV-AIDS, and the Need for Research on Microbiocides
The following is a paper written by Linda Barlow in 2005 for a graduate class in physiology about the need for more research and development on microbiocides to protect women against HIV-AIDS. Research is ongoing, although progress has been slow.
Viral Entry Inhibitors for HIV – A Potential Preventative Strategy for AIDS
Linda R. Barlow
Overview
Microbiocides that operate at the mucous linings represent a possible breakthrough in the treatment of HIV/AIDS. With the total number of cases of AIDS in the world today approaching 40 million, new approaches are needed to combat the pandemic. Viral entry inhibitors that can block the virus from entering target cells by inhibiting the binding of the HIV envelope proteins to the CD4 receptor and its co-factor CCR5 could prevent new infections. Although the current multiple-drug combination therapy for AIDS has delayed the progress of the syndrome in many people infected with HIV, it is not a cure. HIV’s ability to mutate and thus evade every drug that has yet been devised makes it a formidable opponent.
AIDS is continuing to spread – there were nearly 5 million new infections in 2004. Given the vast economic and social costs of AIDS, preventing the disease would be preferable to treating it. A microbiocide that could be applied vaginally prior to intercourse, even if only 60 % effective, could prevent an estimated 2.5 million new infections over a three year period. This would greatly benefit women at risk for AIDS, an important goal since women now represent close to 50 percent of the global total of AIDS-infected individuals. It would also benefit children, since 97 percent of infants with AIDS acquire the virus from their mothers.
The Disease: HIV/AIDS, The Primary Target: The Immune System
Since the emergence of AIDS as a global health threat in the early 1980s, there have been multiple advances in our understanding of retroviruses, but only a few successes in effectively treating this deadly illness. However, an exciting new area of research focuses on viral entry inhibitors that operate at the mucous membranes and prevent HIV from entering the cell (7).
Acquired Immune Deficiency Syndrome (AIDS), which causes a broad constellation of disorders and diseases, attacks and weakens the human immune system, depleting T-4 lymphocytes and eventually causing death from opportunistic infections and/or malignancies. Although the period during which an infected individual can live with AIDS has been extended, there is no cure. Most, if not all, of the people infected with the AIDS virus (HIV-1) who have actually progressed to AIDS will eventually die of AIDS-related disease (8).
The infectious agent that causes AIDS, the retrovirus HIV-1, was isolated in 1983 by Luc Montagnier’s lab in Paris (2). HIV turned out to be a simian virus, SIV cpz, that had crossed from chimpanzees to humans and started to spread in Sub-Saharan Africa circa 1930 (8). It primarily infects the immune system, targeting T-lymphocytes (CD-4 cells) and macrophages. After gaining entry to these cells, HIV-1 replicates via reverse transcription in the nucleus, creating both the structural and regulatory proteins it requires to construct new virions. Essentially it turns infected cells into HIV virus factories, providing an ever-increasing number of new viruses that enter other T-cells and spread the infection throughout the body, co-opting and crippling the immune system in the process. A small (only 9700 base pairs) but hardy virus, HIV-1 mutates at a high rate, enabling it to evade both the body’s natural defenses and, over time, the various drugs that have been developed to combat it.
Prevalence and Cost to Society
According to the UN AIDS figures for December, 2004, the total number of cases of HIV/AIDS in the world today is estimated at 39.4 million (9). 3.1 million people died of AIDS in 2004, including 510,000 children under the age of 15. New infections acquired worldwide in 2004 total 4.9 million. In the
Although AIDS was first identified among the gay male population in the US and Europe, it has been known for a long time that HIV-1 can be transmitted heterosexually; in fact, the heterosexual transmission route is by far the most common way to acquire the virus. Women are increasingly the victims of AIDS; in fact nearly 50 percent of the total number of individuals currently infected with AIDS are women. In Sub-Saharan Africa close to 60 percent of those infected are women, and 75 percent of infected young adults are females aged 15 to 24. The same situation is increasingly true in
The costs of the AIDS pandemic, both in terms of the resources that must be spent on behalf of infected patients and in terms of human suffering, are vast. Because the medical needs of infected patients are long-lasting and expensive, AIDS increases the demand for medicine and health care. HIV also tends to infect adults in their most productive years. In countries like South Africa, where a large percentage of the work force is already infected, lower productivity reduces exports, while sickness forces an increase in the importation of medical equipment and supplies (4). It has been estimated that by 2010
Historic Breakthrough for Treatment of AIDS
The most significant breakthrough in the treatment of HIV/AIDS was the development of two types of drugs, which when used together in combination therapy (the so-called AIDS cocktail), can slow the progression of the disease for years. The nucleoside analogs (example: Zidovudine or AZT) and the non-nucleoside reverse transcriptase inhibitors (example: Nevirapine) prevent HIV replication by interfering with the process by which a strand of HIV RNA adds nucleotides to form double stranded DNA chains in the infected cell (8). The so-called “nukes” cause chain termination during DNA replication, and the “non-nukes” have elements that bind competitively to HIV RNA, also preventing viral RNA from generating infected DNA.
The second type of drug, the protease inhibitors, interfere with HIV replication at a different point in the viral life cycle. By inhibiting the action of the protease enzyme that cleaves the HIV structural proteins GAG and POL, these agents prevent the production of mature virions by the HIV-infected cell (8). HIV replication is thus stopped in its tracks.
When these drugs were first developed, they were so successful at raising T-cell counts and banishing other symptoms of AIDS that many people thought the disease had been conquered. Although the drugs can cause serious side effects, many people were willing to live with these in order to get their immune systems operating effectively again. But because the HIV retrovirus is quick to mutate, the “nukes” and “non-nukes” eventually fail to stop DNA replication (8). Adding protease inhibitors to the mix lengthens the time period during which the disease responds to drug therapy. But HIV’s ability to mutate and thus evade every drug that has yet been devised makes it a formidable opponent. Sooner or later, even combination therapy fails; without new treatments, HIV will eventually kill nearly everyone it infects (8).
Potential Treatment for AIDS
Previous efforts to stop AIDS have focused on attempts to develop a vaccine (so far this has failed) or to devise agents that stop the virus from replicating inside infected cells. More recent efforts, however, are focusing on preventing the virus from actually gaining entry to target cells, like T-lymphocytes and macrophages, by interfering with the binding of the HIV envelope proteins gp120 and gp41 to the CD4 receptor and its co-factor, CCR5 (7).
In macrophages, which are the immune system cells most likely to be found in the mucous membranes that line the vagina and anus, HIV uses CD4 for viral entry (3) but it also requires the cytokine CCR5 as a co-factor (5). People who lack CCR5 (due to a mutation that is more common in Caucasians than in people of other ethnicities) show a far greater resistance to HIV when exposed (10). Therefore Lederman et al. theorized that if the expression of CCR5 could be downregulated on the surface of macrophages, HIV entry could be inhibited (7).
The cytokine, RANTES, has been shown in many experiments to inhibit HIV entry (7). Using a more potent analog of RANTES, PSC-RANTES, Lederman et al. created a microbiocide that could be applied to vaginal tissues. They then challenged rhesus macaques with a chimeric HIV-SIV virus. Their results indicated that PSC-RANTES decreases the expression of the co-factor CCR5. Animals who received with large doses of PSC-RANTES were able to successfully resist infection when challenged intravaginally with SHIV. Although macaques provide the best animal model for testing possible AIDS therapies, the researchers were only able to offer proof of concept at this point in time; much more research needs to be done before their approach can be tested and approved for use in humans.
Reasons to Fund This Research
According to the Joint UN/World Health Organization, a microbiocide, even if only 60 % effective, could result in a major reduction of new HIV infections among women (9). If applied vaginally prior to intercourse by 20 percent of women in 73 low income countries, it could prevent 2.5 million new infections over a three year period.
Such an approach is urgently needed. During sexual intercourse, the receptive partner is more susceptible to the virus than the penetrative partner; thus women are more likely to acquire the virus from men than vice versa. Since power dynamics in relationships often make it difficult for women to insist upon the use of condoms, the development of a topical agent that women could apply prior to intercourse is vital. Past (and, unfortunately, current US) strategies for dealing with AIDS suggest that infection can be avoided by the same “just say no” approach (abstinence) that was once promulgated, unsuccessfully, for drug abuse. In the rest of the world, too, there has been a failure by public health officials to recognize that gender inequality all too often deprives women of the right either to decline sex or to insist upon the use of condoms (9).
When young women of reproductive age are infected with HIV, they can pass along the virus to their children. Although this happens less frequently than was originally feared, 97 percent of infants infected between 1993 and 2003 acquired the virus from their mothers (8).
Initiatives are underway to produce the AIDS “cocktail” in cheap, easy to use pills for distribution in areas where the prevalence of the disease is high (6), but these drugs do not cure the disease. If effective microbiocides can be researched and developed, and if women can be taught to use them regularly, the viral entry inhibitor approach of Lederman et al. could prevent millions of new infections in the years to come. The potential benefits of such research are great enough to call for generous funding.
References
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2. Barre-Sinoussi, F., Chermann, J. C., Rey, F., Nugeyre, M. T., Chamaret, S., Gruest, J., et al. (1983). Isolation of a T-lymphotropic retrovirus from a patient at risk for acquired immune deficiency syndrome (AIDS). Science, 220(4599), 868-871.
3. Bour, S., Geleziunas, R., & Wainberg, M. A. (1995). The human immunodeficiency virus type 1 (HIV-1) CD4 receptor and its central role in promotion of HIV-1 infection. Microbiol Rev, 59(1), 63-93.
4. Dixon, S., McDonald, S., & Roberts, J. (2002). The impact of HIV and AIDS on Africa’s economic development. Bmj, 324(7331), 232-234.
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6. Laurent, C., Kouanfack, C., Koulla-Shiro, S., Nkoue, N., Bourgeois, A., Calmy, A., et al. (2004). Effectiveness and safety of a generic fixed-dose combination of nevirapine, stavudine, and lamivudine in HIV-1-infected adults in Cameroon: open-label multicentre trial. Lancet, 364(9428), 29-34.
7. Lederman, M. M., Veazey, R. S., Offord, R., Mosier, D. E., Dufour, J., Mefford, M., et al. (2004). Prevention of vaginal SHIV transmission in rhesus macaques through inhibition of CCR5. Science, 306(5695), 485-487.
8. Stine, G. J. (2004). AIDS Update (2004). Englewood Cliffs, N.J.: Prentice Hall.
9. UNAIDS AIDS Epidemic Update: 2004 (December, 2004). Joint United Nations Programme on HIV/AIDS (UNAIDS) and World Health Organization, 2004, p. 8-17.
10. Zimmerman, P. A., Buckler-White, A., Alkhatib, G., Spalding, T., Kubofcik, J., Combadiere, C., et al. (1997). Inherited resistance to HIV-1 conferred by an inactivating mutation in CC chemokine receptor 5: studies in populations with contrasting clinical phenotypes, defined racial background, and quantified risk. Mol Med, 3(1), 23-36.