In the online ahead of print section of J. Virology, Arnold Levine from Princeton University (who chaired a well-known, comprehensive 1996 critique of AIDS research at the National Institutes of Health) offers a thoughtful, personal review of a recent meeting that set out to address the question: why do we not yet have an HIV vaccine? Levine covers a range of territory, from the recent failure of Merck’s T cell-based candidate in the STEP trial to concerns regarding how the HIV vaccine research field is currently structured. There follows some selected highlights and commentary, but the article is well worth reading in its entirety.
Beginning with a review of STEP, Levine notes that the grimmest interpretation of the results – which came on the heels of the failure of a prior antibody-based vaccine called AIDSVAX - is that adaptive immunity is insufficient to repel or control HIV infection; he argues, however, that “there is good evidence that this is not correct and that more needs to be learned.” He cites the strong associations between specific class I and II HLA alleles and elite control of HIV replication (such associations have also been reported among exposed, uninfected individuals) and suggests that: “a clinical trial of a vaccine using individuals with this HLA group could be instructive in learning from the few to apply to the many.” Recent analyses of the STEP trial suggesting trends toward better control of viral load in recipients of the Merck vaccine possessing favorable class I HLA alleles (such as HLA B*57 and B*27) may offer additional support for this idea. Levine also stresses the need for a better understanding of the functional readouts that should be captured by immunological assays used in clinical trials, such as CD8 T cell-mediated killing of HIV-infected cells and antibody-mediated neutralization. Citing advances in gene analyses and systems approaches to interpreting data, Levine offers his view that “the modern tools of molecular biology now permit the human to be the best model organism to study biology.”
Addressing advances in understanding innate cellular mechanisms for interfering with DNA and RNA virus replication, Levine laments that attempts to incorporate this knowledge into HIV vaccination strategies remain in their infancy, and suggests “an organized effort in this area of research carried out in human beings is needed.”
Discussing the role of animal models, Levine touches on an area where he may be gratified to learn there has recently been some significant progress. Raising the issue of the relative resistance of HIV-infected chimpanzees to the development of AIDS, Levine argues that the phenomenon should by now be better understood. The recent findings that a selective sweep has occurred at the level of chimpanzee class I MHC and that present-day alleles mirror the specificity of human HLA alleles associated with elite control of HIV offers a compelling explanation of the results obtained in chimpanzee HIV challenge studies, and one that further reinforces Levine’s earlier comments regarding the importance of HLA.
Levine concludes his discussion of the scientific challenges facing the field with a pithy summation: “The fact is we have failed to make some vaccines (HIV, Hepatitis C virus) because we don’t understand the immune system, the virology and the host in sufficient detail. We must carry out the hard work of doing good, even great science; if we continue just taking “shots on goal” in the hope we might get a small response to a vaccine, we will not be able to understand it or even improve it.”
Toward the end of his review, Levine also makes some pointed observations regarding how HIV vaccine research is currently organized. He notes: “the HIV field of basic and translational research has two structural properties that are not optimal for real novelty and progress. Because of the very large funding opportunities that come from several sources, laboratory sizes of some groups are very big. Having one leader and many researches can narrow the direction and questions being asked in a field. A truly original and gifted scientist would not like to spend his or her career working on research problems formulated by others. The large groups compete well for funds, which may tend to drive talented new young researchers into other fields where they will have a greater chance to make an impact. Another consequence of large laboratories dominating a field is that research efforts become stale.” He also points out that advances in virology and immunology that occur outside of the HIV field are often only belatedly acknowledged by researchers working within it, greatly slowing progress – a criticism leveled in the past by many other commentators, including TAG. Levine goes on to conclude: “there is a need to attract smart and interested young scientists into HIV virology, immunology, vaccine research, and systems biology. Not enough effort has been put into the planning of this component of the future of the HIV field. That is the best chance to gain the insights required for a larger group to develop a vaccine against HIV.”
JVI Accepts, published online ahead of print on 1 October 2008
J. Virol. doi:10.1128/JVI.01953-08
"Why do we not yet have an HIV vaccine?"
Arnold J. Levine
Institute for Advanced Study, Princeton N.J. 08540
A two-day meeting to explore why we do not yet have an HIV vaccine was held under the joint sponsorship of The Simons Center for Systems Biology at the Institute for Advanced Study and the International Aids Vaccine Initiative, with additional support from Merck & Co., at the Institute for Advanced Study in Princeton, NJ over the 29th and 30th of May, 2008. ...