SIX years ago, Dr. Julie McElrath attended the World AIDS Conference in Durban, South Africa, with her 8-year-old son. What she saw there opened her eyes. "Seeing how it affected the families - the parents dying, orphans cared for by grandmothers," she says, "it really made me realize the importance of our work."

McElrath steps away from her computer with its detailed diagram of the human cell, its various parts exposed for her analysis, and leans forward to greet a visitor. Looking comfortable and chic in a loose-fitting sweater and slacks, more like the working mom she is, and not at all like the image of the mad scientist with thick glasses and white lab coat propagated by the movies, she takes a moment to talk about the work she's engaged in as associate head of the infectious disease program at the Fred Hutchinson Cancer Research Center (FHCRC) in Seattle. She also serves as a principal investigator of the HIV Vaccine Trials Network (HVTN), a six-year-old international collaboration of scientists and educators.

"We know more about the HIV virus than any other virus,"? she says. "But up to now we haven't been able to find a vaccine that works. With a shake of her thick, shoulder-length hair, she adds, "But now I think we're on the right road."

The media spotlight has been shining of late on the HVTN program, where she's in charge of analyzing the results of experiments with a prototype HIV vaccine that has shown greater promise than anything scientists have come across in the past two decades. The Merck candidate (Merck & Co. Inc. is sponsoring the trial) is in a Phase 2b trial, just short of the typical Phase 3 efficacy trial that leads to licensure, which means it did well enough in the first clinical trials to warrant expanding the tests. She and her colleagues can point to a number of candidates with potential that didn't pan out, which explains why McElrath is remarkably sanguine and low-key, preferring understatement to a primal beating of the chest. "We're trying to elicit an immune memory response to HIV. So far it looks promising. Now we need to do the work."? The Merck adenovirus vaccine is one of 15 vaccines now in trial within the network.

AIDS research is littered with failures. More than 100 different vaccines have been studied on humans and animals. Some successfully induced antibodies, but they all proved incapable against the disease.
 
"These other products taught us a few lessons," says Dr. Jorge Flores, deputy director of the vaccine and prevention program with the National Institute of Allergy and Infectious Diseases' (NIAID) AIDS division, which oversees the vaccine trials that McElrath's group is part of. "We know better now how to design these products."
 
THE IDEA BEHIND IT
Specifically, this trial is testing a vaccine Merck constructed that abandons the classic approach. Instead of attempting to engage the gene for the surface protein, the company has focused on eliciting T-cell responses by playing the same sneaky game as the virus, putting pieces of three synthetically produced HIV genes (not the entire virus, so it can't cause anyone to contract HIV) inside a deactivated cold virus, called an adenovirus, and injecting this in the human body, thus tricking the immune system into thinking the real virus is attacking.

HIV is not an easy virus to outfox. Most vaccines work to trigger effective antibodies against the surface protein of a virus. But HIV is smarter than most other diseases, masking its outside coat so completely the body can't mount a defense.

HIV quickly moves into bodily tissues with an assassin's eye, killing CD4 cells critical for immunity while navigating the body in its search for the lymph nodes. There it hides out and lies latent, integrating itself into the human genes, sometimes for years, waiting. The virus knows that the minute it starts reproducing itself, the defensive cells will mount an attack, so it waits until it has eliminated enough CD4 cells before it moves in for the kill.

In vitro, the T-cells produced by the deactivated cold virus, with its payload of HIV genes, know to target the HIV and are capable of killing the virus. But the question facing researchers is: Will sufficient numbers be produced and react in the same way in real-life conditions? "We're currently doing studies that lead to proof-of-concept," says Flores. "What Julie [McElrath] is doing in Seattle is a new type of research. We don't know how to test how T-cells combat the virus. She is among a few people you can count on your hands, four or five labs, that are leading in the field of cellular immunity with respect to viral infections. She's been in the forefront, especially with respect to humans."

The National Institutes of Health (NIH) and FHCRC have joint responsibility for the science, with all the blood being processed in the Seattle hub. Merck provides data management, and NIAID funds the research. "We've many other studies with different companies but nothing of this magnitude," adds Flores. "The payoff will be more valuable than anything you can think of in dollars - priceless."

The vaccine is currently being tested on men who have multiple same-sex partners and have not yet contracted HIV. In Seattle, 115 have been recruited, doubling the number of volunteers from the onset of the study. More than 20 test sites have been set up in the United States, the Caribbean, South Africa, Australia and Peru. Internationally, the consortium has enrolled two-thirds of the target 3,000 volunteers.

"We want to look at larger cohorts,"? says McElrath, "with more diverse populations."? McElrath says it may take as long as seven years to reach any solid conclusions. She would like to see results sooner; as she speaks, her frustration is clear. Now that her son is a teenager, the realization that she is in a race against time hits close to home. "I want to do something for his generation and his future,"? she says. "It makes my work that much more important to me."

HOW THE VIRUS WORKS
In addition to her investigation of the role of HIV-1-specific memory T-cells in protecting HIV-1-seronegative persons with multiple high-risk exposures to HIV-1, McElrath and her team of 70 are studying other pieces of the puzzle, hoping to shed light on how this virus works. They ask such questions as: Why do some people experience unusual control of HIV-1 infection? They study individuals with acute infection who typically demonstrate a rapid decline in plasma viremia (the presence of virus) with the onset of T-cell responses. They study individuals with long-term nonprogressive disease who control infection for more than a decade without antiretroviral treatment.
 
And more recently, they study patients from Senegal who have HIV-2 infection, which leads to a more attenuated infection than HIV-1 and appears to reduce the virulence of HIV-1 infection if co-infected. Initial studies demonstrated that broad suppression of T-helper function occurs during acute infection, followed by a progressive recovery as the virus-load stabilizes. If someone with the disease is in the very early stages, the researchers have been able to detect HIV-1-specific CD4+T-cells. Later on, these cells are difficult to trace.

McElrath is hoping to determine if low-level infection is a common feature among this study group, if the viruses are replication-incompetent and if T-cells contribute to the containment of infection. She is also studying the local T-cell response at the initial sites of infection.

The goal is to either contain the virus or completely wipe it out. McElrath says she'd be happy with either outcome. She is cautiously optimistic: "A lot of infrastructure has been established; hopefully the big effort pays off."

Time is important. No longer is the disease confined in this country to the gay population. Worldwide, AIDS is the third-leading cause of death for females, and the number of women in the United States getting infected is on the rise. Of the more than 40,000 new HIV infections yearly in the United States, women now make up an estimated 30 percent. In minority communities, black women account for 64 percent of new infections, and Latino women, 18 percent.

The majority of females become infected from having sex with an HIV-infected man or using a contaminated syringe. There's speculation that black men in prison have sex with each other, and some may contract the disease there. Once out, they resume their heterosexual lifestyles. Frank Chaffee, head of the King County HIV prevention unit, calls prisons "an HIV incubator."

The King County Board of Health has noticed an increase in the number of women with HIV, although the percentage is still tiny - 90 percent of infected persons in the county continue to be male and primarily gay. Due to the county's free exchange program, the number of drug users getting HIV from contaminated needles has fallen, currently flat at 2 percent to 3 percent (compared with 50 percent in some parts of the country).

In one worrisome trend, during the past decade King County recorded a 30 percent spike in the number of males who engage in unprotected sex with males, "playing Russian roulette," as McElrath puts it. And they're contracting other STDs, which increases their chances of getting HIV, when exposed, by two to five times. At the clinic, McElrath and her team counsel volunteers on safe sex practices, such as carrying a condom with them rather than leaving it behind in the nightstand, but no one is following them around to make sure they remember.

Why this relapse into the old ways exists is something doctors have been grappling with. "We need to understand the context,"? says Chaffee. "In the mid-80s, getting HIV was a certain death sentence. Now they live with complicated drug regimens that for many people cancel [one another] out and stop working. Treatment reduces but does not eliminate the possibility of transmission."

Chaffee blames the tendency for people to relapse into their old, high-risk ways on "message fatigue." Adds McElrath, who has noticed a similar trend in her volunteers, "The drugs lower the viral load and they think they're less likely to transmit. The way they see it, when they do get infected, the virus is pretty well controlled by the drugs."