Heterosexual Transmission
Harvard AIDS Institute researchers have found that subtypes C and E grow far more readily in Langerhans cells-which line the cervix, the vagina, and the foreskin of the penis-than does subtype B, which appears to spread primarily through blood and blood products. Essex contends that these subtypes are spread more efficiently through vaginal intercourse, which helps explain why the U.S. epidemic of subtype B has spread most quickly among homosexual men and injection drug users, while in Africa and Asia, subtypes C and E have spread rapidly among heterosexuals.

In Thailand, subtype B was present before subtype E, yet it was E that subsequently had the explosive spread through the heterosexual population, to the extent that the overwhelming majority of HIV infections in Thailand are now of subtype E. The same pattern has occurred in such countries as India, where subtype C has overtaken subtype B, and Tanzania, where subtype C has overtaken subtypes A and D.

A New U.S. Epidemic?
In 1995, fearing that subtypes originating outside the United States would make their way to North America, Essex had recommended nationwide screening to determine whether these other HIV subtypes were present in the United States. The blood screening tests currently used can detect the subtypes but cannot distinguish among them.

Later that year, routine testing of American servicemen in a San Diego naval medical center found three men with subtype E and two with subtype A.

The following year, screening conducted by the Centers for Disease Control and Prevention (CDC) at a Bronx, New York hospital found two people infected with HIV subtypes that are new to the United States. Whether these subtypes have spread further is unknown, but if they do take hold in the United States, Essex believes, a new, more diverse pattern of HIV infections may be imminent.

The CDC chose the Bronx to begin its search for new subtypes because of the high levels of HIV infection and populations with risky behaviors such as injection drug use and commercial sex work. Of the 22 infected patients at Bronx Lebanon Hospital Center who underwent genetic typing, two were infected with subtype A and the rest were infected with subtype B.

While most of the variant subtypes found in the United States were contracted abroad, one of the Bronx study participants infected with subtype A contracted the virus in this country. The participant reported having had sexual partners who had spent time in the Caribbean, Latin America, or Africa.

"Cases of U.S. residents infected with non-subtype B viruses indicate that several introductions of HIV have occurred in North America and will probably continue to occur," says Kathleen Irwin, one of the CDC researchers who directed the Bronx study. "The strain diversity in our Bronx study population may be due to either recent introduction of new strains from outside the United States or local transmission of non-subtype B strains established in the community. Because the two patients with non-subtype B strains had recently practiced unprotected sex, local transmission of these variants may be ongoing."

In the CDC's follow-up study at the same Bronx hospital, 3 of 250 HIV-infected people were infected with subtypes that are new to the United States: one with subtype A, one with subtype F, and one with a possible F/B recombinant. CDC researchers also are conducting a cross-sectional review of recently diagnosed individuals at testing sites and early intervention clinics in 10 U.S. cities. They hope to enroll 1,000 people per year in the study.

Emerging Viruses
Essex notes that the fear of previously unknown infectious agents being introduced into the population has been the inspiration for many popular books and movies. "We should think of HIV, which entered our population 20 to 25 years ago, not only as the first of these infectious agents," Essex says. "We should also think of its subtypes as new, emerging viruses in new, emerging epidemics." The appearance of these non-B subtypes in the United States is cause for concern, Essex adds, because they could be far more dramatic in their rapid spread.

"That doesn't mean we're certain to have an epidemic from subtypes C and E yet," Essex says. "What it would require is more time for it to get established in some high-risk heterosexual group. All infectious agents must reach a certain level of saturation in a population before an epidemic becomes inevitable. My fear is that we are not monitoring that well enough."

Implications for a Vaccine
The predominance of non-B subtypes has serious implications, Essex says, for the current direction of vaccine development. Most vaccine research has used antigens from subtype B, even though the vast majority of infections worldwide are of non-B subtypes.

"For preventive vaccines to be effective in Africa and Asia, they must be made with the subtypes that are prevalent in those areas," Essex says. "Yet the trial vaccines have all been made with subtype B, rather than with the subtypes that dominate Asia and Africa. Beyond the ethical mandate of protecting the millions of people at risk in developing countries, the threat of new, more fearsome epidemics of HIV should shake us.

"At least four other subtypes in Asia and Africa are more easily spread between men and women than is the subtype in the U.S.," Essex adds. "When these more easily transmissible subtypes come to this country and gain force, will we be prepared with a preventive vaccine?"

Essex warns that an epidemic of non-B subtypes could develop in the United States before we know it. "So far we've been lucky," he says. "But we know that these more easily transmissible subtypes have already arrived."