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From The AIDS Reader®
Editorial Jeffrey Laurence, MD [The AIDS Reader 9(8):512-513, 518, 1999. © 1999 Cliggott Publishing Co., Division of SCP/Cliggott Communications, Inc.]
The West Nile-like encephalitis virus had never been seen in North America before it was identified in birds and humans in New York City 2 months ago.[1] An outbreak of the virus is occurring simultaneously in Russia, another part of the world where it has been seen very rarely.[1] According to Dr Andrew Spielman, a professor of public health at Harvard, at this moment it's impossible to evaluate completely its threat to us.[2] This virus has shocked New York City, Westchester County, and most of the surrounding counties in New York, as well as Fairfield County in Connecticut, with the simple fact that a single mosquito bite can be fatal. Just as shocking is the fact that this outbreak of an encephalitis virus rare to the Western Hemisphere but prominent in central Africa was preventable. The outbreak not having been prevented, birds are now migrating long distances, perhaps carrying that West Nile-like virus across the United States. Of course, HIV is a lot like this. A single infectious particle can be fatal. And, as with the West Nile-like virus, it doesn't respect geographic borders. But in contrast to the West Nile-like virus, HIV changes rapidly. The potential consequences of more than 40 million people worldwide now incubating a virus that mutates every time it replicates -- and it replicates every 8 hours -- is staggering. If we don't stop HIV everywhere in the world, we've stopped it nowhere. Women are at particular risk worldwide. In the United States, one in three new cases of HIV infection now occurs in a woman. This was the underlying theme of a conference held on October 6, 1999, at The Rockefeller University entitled, "Under a woman's control: biomedical means for preventing sexual transmission of HIV." It is also the topic of an article in this issue by Dr Tracy Wilson. "Amplified perversity" is the term public health experts are using to explain these new trends in the spread of HIV. Simply put, there is a tendency for bad things in an epidemic to get worse, increasing the range and severity of that outbreak. For the West Nile-like virus, it may have been the drenching we had in August, the proliferation of stagnant ponds in the suburbs, and the lack of adequate monitoring for disease-carrying insects. For HIV, there are complacent attitudes among those infected with HIV or at high risk for its acquisition; the complacency of much of the general public, who believe that with all those new drugs, the AIDS epidemic is over; the rapid development of mutant viral strains and drug-resistant viruses; and the profound difficulties many patients have in complying with complex drug regimens and drug side effects. We know that these are important issues because the rate of HIV infection, which had been declining markedly in the United States for several years, is no longer declining at such a rate. The risk for becoming infected is particularly high among adolescents. By the age of 19, at least 50% of American girls and 60% of boys have had sex. More than 1 in 10 teenage girls has been pregnant, and 1 in 6 sexually experienced teens has had a sexually transmitted disease (STD).[3] The United States also has the highest rate of curable STDs of any developed country. Yet, for every dollar spent by federal STD prevention programs, $43 needs to be spent on STD treatment. We're obviously doing a very poor job of prevention.[4] Until recently, AIDS vaccine development was given a woefully insufficient priority, and the biology of HIV transmission prevention in general remains a very young discipline. One conclusion from this symposium was the recognition that many factors, social and political as well as biologic, enhance the sexual acquisition and transmission of HIV. And a coordinated effort between prevention and molecular biology is needed to stop it cold. Other STDs are also important in facilitating transmission of the AIDS virus. Improved treatment of STDs in Tanzania, using only pennies worth of antibiotics, led to a 42% reduction in the incidence of HIV infection.[5] Gonadal hormones may also influence HIV infection. Hormonal changes during the menstrual cycle regulate the character of genital tissues and the function of immune cells throughout the female reproductive tract. They can also alter levels of critical membrane co-receptors for HIV, CXCR4 and CCR5, enabling the virus to better enter and infect cells. Macaques given progesterone implants, equivalent to what a woman might get in one of those progestin-containing "mini-pills," are eight times more susceptible to infection by the simian AIDS virus, SIV, introduced vaginally.[6] Those hormones naturally thin vaginal walls. Use of HAART may lessen, but does not prevent, sexual transmission of HIV. This is not surprising, given the fact that levels of HIV in vaginal fluid and in semen are often independent of levels of virus in the blood. Prevention, not treatment, is the least expensive and most effective method of blunting the spread of AIDS. Making condoms freely available to adolescents does not affect their decision to initiate sexual activity, nor does it impact on its frequency. And the least effective condoms afford a protection factor against HIV of over 10,000 compared with unprotected intercourse. Of course, condoms and many other HIV control efforts are predicated on the need to reduce personal risk behaviors, but that approach does not adequately reflect the complicated interplay between personal behaviors and the social setting in which they occur. In many instances, in many cultures and countries, women may not have the power to define sexual vocabularies and boundaries. Relationships in which there are many sexual partners apart from a primary relationship are of particularly great danger. Poverty; inequality; lack of educational opportunities; and social, religious, and cultural biases and demands, including female genital mutilation, used to decrease a woman's sexual pleasure and thus attempt to enforce faithfulness -- the "structural violence" encountered by women in much of the developing world -- further exacerbate these conditions. While the need for women to take control of preventing HIV infection and other STDs may seem to be just another burden organized by men to be carried by women, their taking control is one of the most effective means of reducing HIV spread. This is particularly true for those with the highest rates of partner change. There is further disturbing news even with adherence to "safer sex" guidelines. The San Francisco Department of Public Health followed more than 1,500 HIV-seronegative, sexually active homosexual and bisexual men for 3 years. Only 15% of all new HIV infections among these men appeared to involve unprotected anal intercourse.[7] What were thought to be "lower-risk" activities, such as unprotected oral sex and condom-protected receptive anal intercourse, were major risks for HIV transmission among this highly educated population.[7] Physical and chemical barriers under the control of the woman, or any susceptible partner, are critical gaps in our AIDS prevention arsenal. Female condoms are one possibility. Although female condoms are rarely used in the developed world, some 7 million have been distributed throughout Africa, Asia, and Latin America. One commercial sex worker in South Africa interviewed recently in the New York Times noted that when men refuse to use a standard condom with her, she inserts a female one into herself. "They never know," she said. "And they think that they got flesh-to-flesh, so I charge them double."[8] The cost of female condoms -- about $2.75 (US) per sheath at retail and $0.62 in government distribution programs -- is a major problem. There is also the concern that some women will not replace these condoms between sexual encounters with different partners. This could facilitate spread of HIV to men, by their coming into contact with HIV-positive semen from the woman's last partner still retained in the old condom sheath. But scientists are always coming up with new ideas. Gels and foams containing nonoxynol-9, or N-9, which can kill HIV in the test tube, have been advocated by some to block HIV. Unfortunately, they don't. N-9 is a detergentlike chemical that irritates both viral and cell membranes, can increase genital ulceration in men and women, and may even enhance rather than block sexual spread of HIV. The "stealth condom," now in phase I clinical trials, may help. It's a liquid at room temperature but gels at body temperature. Introduced into the vagina as a liquid, it solidifies rapidly like plastic, preventing viruses, sperm, or anything else from touching genital tissues. It could be used along with otherwise irritating virus-killing chemicals. Natural products for the treatment and prevention of HIV infection and other STDs are being developed. For example, the bacterium Lactobacillus crispatus, part of the normal vaginal flora and a species distinct from those in active yogurt cultures, produces hydrogen peroxide, helping to maintain an acid environment in the vagina, which suppresses bacterial and HIV growth.[9] A gelatin suppository containing dessicated lactobacilli, referred to as a "vaginal vitamin," could help restore this natural defense. In the absence of an effective systemic HIV vaccine that also elicits mucosal immune responses, rapid development of methods for the biomedical prevention of sexual transmission of HIV under the susceptible partner's control is critical. A variety of chemical and biologic substances capable of killing HIV directly or blocking its infectivity when used locally -- the definition of a microbicide -- are in development for vaginal and rectal use. More than 60 products are in pre-phase I through phase II studies. But only 8 are in phase III studies, and all of these products include N-9 or N-9 variants. It is clear from this symposium that there are critical gaps in our knowledge of how HIV is transmitted sexually. The major site in the female appears to be the transition zone of the cervix, not the vagina. Vaginal tissues are susceptible, at least in the hysterectomized macaque model using SIV, but only when 10,000-fold more virus than is normally present in an ejaculate is introduced. The target cells for initial infection are also unclear. Possible hosts include the dendritic cell, CD4+ T cells and macrophages, and perhaps the mucosal epithelial cells themselves. Finally, discerning whether cell-free virions or cell-associated virus is the major source for heterosexual transmission will be critical to the design and preclinical evaluation of potential products.
References
Dr Laurence is associate professor of medicine and director of the Laboratory for AIDS Virus Research, New York Presbyterian Hospital -- Weill Medical College of Cornell University, New York; senior scientific consultant for programs, American Foundation for AIDS Research (AmFAR); and editor-in-chief of The AIDS Reader.
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