amfAR, The Foundation for AIDS Research

Their First Year: Young amfAR Scientists Publish “Spectacular” Work

by Jeffrey Laurence, M.D.

February 19, 2009—Just one year ago, amfAR announced awards of more than $1 million for the inaugural round of the Mathilde Krim Fellowships in Basic Biomedical Research. This new initiative was created to support young scientists seeking innovative solutions to HIV/AIDS.

The first nine Krim Fellows have already achieved some outstanding results. In January alone, three of the awardees authored papers in key journals describing novel strategies for vaccine development, drug design, and prevention of heterosexual transmission.

Writing in the Journal of Virology, Dr. Rogier Sanders of the University of Amsterdam, hoping to devise new ways of designing an AIDS vaccine, uses the process of evolution itself to force HIV into yielding up some of its secrets. Antibodies, as well as other methods employed by the immune system to kill pathogens, form the mainstay of immunizations we’re all familiar with, and, as with most viruses, the outer envelope or coat of HIV is the principal focus of efforts directed at generating a vaccine. But these products have uniformly failed in several large AIDS vaccine trials worldwide. One problem has been that production of isolated pieces of virus envelope do not resemble the AIDS virus itself. In addition, vulnerable parts of HIV are normally shielded in the intact virus by sugar molecules, electric charges, and fat-avoiding regions that further impede protective antibody activity.

The first nine Krim Fellows have already achieved some outstanding results.

Scientists have already tested the straightforward vaccine strategies that have worked for other viruses, but to no avail with HIV. And although tweaking some of the details of vaccine design has increased the potency of vaccine candidates undergoing testing, these changes have not helped enough. So, Sanders reasoned, why not let the virus do this work for us?

HIV mutates extremely rapidly because of its high rate of growth and the genetic errors it makes in the course of that growth. The vast majority of those mutated viruses are effete. But every so often a virus appears with a greater or slower growth rate, accompanied by changes in its envelope that may render it more exposed or malleable, and thus more likely to be a better vaccine candidate. Sanders and associates created sets of mutated envelopes by growing them in Petri dishes with human T cells for up to 18 weeks, thus “forcing” them to evolve by applying environmental pressure. Now Sanders’s team has begun testing their putative vaccine products. As the authors conclude, this innovative strategy—“optimization by virus evolution”—may also “provide a powerful tool to optimize [any] vaccine antigens.”

Continuing with the theme of HIV evolution, amfAR Fellow Dr. Richard Haaland, of Emory University in Atlanta, collaborating with amfAR Krim Fellow Brandon Keele at the University of Alabama-Birmingham, sought to define the number and types of viruses transmitted through penile-vaginal intercourse. Writing in the journal PloS Pathogens, they sought to relate this information to the function of genital mucosal barriers in blocking viral transmission. This information is critical to designing the means—be it a vaccine or microbicide—to block such passage.

Haaland and Keele examined over 1,750 HIV genetic sequences derived from very early infections in Africa. Despite the great diversity of HIV types that they discovered in a typical infected partner, some nine in 10 HIV transmissions involved a single strain of HIV. But what characterized the one out of 10 people who became infected with multiple types of HIV? Virtually all suffered genital infections leading to an inflammation that compromised their genital mucosa. This lends further support to the concept, which continues to be evaluated in clinical trials, that prevention and treatment of common sexually transmitted infections, perhaps facilitated by male circumcision, should be part of a comprehensive AIDS prevention program.

Finally, Krim Fellow Dr. Bruno Marchand of the University of Missouri, writing in the Journal of Molecular Biology, reviewed the state of the art of anti-HIV drug therapy, focusing on reverse transcriptase inhibitors. Marchand and colleagues concluded that a more comprehensive examination of the structure of this enzyme, alone and in its interactions with existing drugs, “can be used to generate better drugs; in particular drugs that are effective against the current drug-resistant strains of HIV-1.”  This area of investigation—new drug targets—continues to be a primary focus of amfAR’s research program.

These three reports from a single month represent just a sampling of the spectacular work coming out of the labs of Krim fellows. And this is just the first year of what could be three full years of Krim-funded research for each young researcher. The first phase of the Krim awards provides fellowship funds for two years in a senior mentor’s lab. Successful completion of that training and promotion to a tenure track position makes a recipient eligible for the fellowship’s second phase, which adds additional funding for a third year of research. Given the rapid success of the Krim Fellows thus far, the blossoming of these young scientists into independent AIDS researchers seems all but assured.

Dr. Laurence is amfAR’s  senior scientific consultant.