Thirty years in review, and a look toward the future
Today, World AIDS Day, marks the conclusion of our HIVe series, "30 years in 30 weeks," a compilation of perspectives behind some of the most interesting and influential HIV/AIDS research in the last 30 years. To commemorate World AIDS Day and acknowledge the extraordinary efforts to combat HIV/AIDS in the 30 years since the virus was first discovered, Drs. José Esparza and Bonnie J. Mathieson review the series with a look toward the future. Please let us know what you thought of "30 years in 30 weeks," we hope you enjoyed the series. Email: HIVe@vaccineenterprise.org.
View the rest of the series:
2010 < All years >
As its name indicates, the series “30 years in 30 weeks” compresses in seven months the incredible scientific progress in understanding, treating and ultimately trying to prevent HIV/AIDS since it was first identified as a new disease in 1981 - thirty years ago.
This series is not a comprehensive historical record of the past: It is rather a reminder that the search for better HIV prevention and treatment is a dynamic continuum that provides critical scientific bases on which to build the successes of the future.
The editors of the series selected one emblematic paper for each year from 1981 to 2010, and the process was guided, in part, by the number of citations that each paper received, although ultimately decisions were made to truly represent the diverse approaches to address and solve one of the greatest public health challenges of all time. The volume of important information that the scientific community was producing in response to the global HIV/AIDS health crisis made the selection process increasingly more difficult.
The inspiring commentaries by the authors of the papers, in which they discuss their personal motivations, anxieties, excitement, mistakes, frustrations, etc., capture the human side of science, not usually found in anthologies or review papers.
We do not intend to revisit every paper and comment posted over the last thirty weeks. Instead, we prefer to provide a high level summary of scientific progress, and we very much encourage you to go back and read each one of the postings, so that you can extract your own conclusions and lessons.
Many of us still remember vividly the 1981 CDC Morbidity and Mortality Weekly Report (MMWR) that reported the cases of Pneumocystis carinii pneumonia and Kaposi’s Sarcoma (KS) among homosexual men in California and, later, in New York City. Initially those cases were an immunological curiosity and until reports of KS and “slim disease” were reported in Africa, few people recognized that they were the first descriptions of what became one of the most serious global epidemics of modern times.
Within three years of these initial reports, cohorts of gay men in the US were established to study the disease and cases of transmission via blood and from mother to infant were documented. HIV was isolated and convincingly identified as the cause of AIDS. The ability to grow large amounts of virus in the laboratory allowed the development of diagnostic assays in 1985, which both ensured the safety of the blood supply and provided the early tools to begin understanding the clinical and epidemiological significance of this newly identified disease.
The unprecedented speed with which these initial discoveries were made took advantage of investments made during the previous decade in retrovirology and immunology as part of the “War on Cancer” program, proving once again that investments in one area of science can have profound and unforeseeable benefits in other areas.
The next few years were of rapid scientific advances. By 1985 we had the first nucleotide sequences of HIV, the identification of the CD4 molecule as the main receptor of the virus, and the demonstration that a compound previously studied as a potential cancer drug (AZT or Zidovudine) could inhibit the replication of HIV in cultured cells.
“Bench” science was rapidly translated into “Bedside” medicine, and in 1987, the clinical efficacy of AZT to slow disease progression was demonstrated. Although monotherapy with AZT proved to be an inefficient treatment for AIDS, the clinical trial demonstrated the power of science to impact a virus that integrates into the host cell chromosome. Despite the limited efficacy of AZT for treatment, in 1994 it proved to be highly effective in preventing mother to infant transmission in the ACTG 076 trial and subsequent trials. The power of science and human ingenuity has been proven many times since then, and today we have more than 30 effective anti-retroviral drugs that can suppress the replication of the virus, allowing a more normal life for people living with HIV. The rapid development of drug resistance with any monotherapy was ameliorated in the clinic with the use of combination therapy by 1996.
Parallel to critical advances in the clinical management of HIV/AIDS, major efforts were mounted to better understand the pathogenesis of the disease and the potential correlates of immune protection, with the ultimate goal of developing better treatments or even a cure, and eventually a preventive vaccine. In the 1990s we learned about the function of the non-structural genes of HIV, the mechanisms of latency and persistence, and the humoral and cellular immune responses elicited by the infection. Those were sobering years, when we slowly learned what a formidable enemy we had in HIV. We learned that there was no true virological latency of HIV and that the elicited immune responses were not able to control the inexorable progression to disease and eventual death.
By the end of the 1990s and the beginning of the 2000s, new technology and new approaches were engaged in our scientific response to HIV/AIDS. In 1998 the molecular structure of the core of HIV gp120 envelope protein was elucidated, providing new insights into the mechanism of early interactions of HIV with the CD4 cell receptor, as well as new understanding of the antibody response to HIV. Our knowledge of HIV pathogenesis, cell biology and immunology was enriched with additional in vitro and in vivo studies and through the use of non-human primate (NHP) experimentation.
Although candidate HIV vaccines had first entered human clinical trials in 1987, experimental vaccines that showed some promise in NHP did not progress to advanced clinical trials in humans until the late 1990s. Results from four efficacy trials have now been reported. In 2003 we learned of the disappointing results from the VaxGen trials that tested the efficacy of related bivalent gp120 vaccines aimed at inducing antibodies. Trials conducted in Thailand (VAX003) and in the US/Canada/Netherlands (VAX004) showed that the vaccines were not effective. Those results came as no surprise to many members of the scientific community who had learned that antibodies elicited by those vaccines were able to neutralize only a small subset of the clinical isolates of HIV using CCR5 as the co-receptor.
The prevailing paradigm shifted to vaccine candidates that elicited cytotoxic CD8+ T cells (CTL) based on information obtained from “elite” controllers and NHP experiments. The results from the “STEP” trial, that used an adenovirus-5 vector to induce CTL to three HIV genes (gag/pol/nef) were announced in 2007.The vaccine not only failed to provide protection, but it showed a surprising and disturbing trend towards an increased risk of HIV infection shortly after vaccination particularly in uncircumcised male volunteers with preexisting immunity against the adenovirus vector. These unexpected results provided a strong incentive for soul searching, planning, and intensified collaboration. Once again the field went into a downward curve of what has been a roller coaster of successes and failures. However, as in the past, the scientific community showed its resilience and commitment to finding an HIV vaccine.
In 2009 we had the results from the RV144 (the Thai HIV vaccine trial) that showed a modest and short-lived ̶ but real ̶ efficacy signal bringing renewed optimism to the field. Moreover, in the last couple of years we have also learned of the great potential of microbicides, PrEP and earlier antiretroviral treatment of infected persons to help prevent infection, particularly in monogamous sero-discordant couples. We also saw a multitude of vaccine advances including the discovery of additional broadly neutralizing antibodies and new collaborations in the post-RV144 correlates analysis.
Scientifically, 2011 has been an extremely rewarding year and we want to list a few examples among many excellent papers published this year. After many years of work a high resolution structure of the envelope trimer was solved (Sodroski et al., in preparation), and this information is being used for the design of new generations of vaccines aimed at inducing protective antibodies. The team at the NIH Vaccine Research Center (VRC), lead by Gary Nabel, John Mascola and Peter Kwong, reported how deep sequencing of antibody genes allows reconstruction of their unmutated ancestors, which opens a potential new path to eliciting broadly neutralizing antibodies by tailoring immunogens to intermediate antibody variants and, thus, guiding affinity maturation of these antibodies to specific targets (Wu et al., Science 333:1593-602). An unprecedented effort to find immune correlates of protection in RV144 identified a set of immune responses, particularly antibodies against the V2 loop of the gp120 envelope protein, as a potential correlate of risk (Haynes, Kim, et al., in preparation). This result is informing the design and implementation of future trials that build on RV144. Recent work by the team of Louis Picker provided proof of principle that by using a cytomegalovirus vector, a vaccine-induced CTL response can gain profound and sustainable control of HIV (Hansen et al., Nature 473:523-7, 2011). Further building on the success of the poxvirus vectors, the team led by Harriet Robinson and Rao Amara have demonstrated that pox and DNA vectors with new adjuvants can induce antibodies without protein boosts (Lai et al., J. Infect. Dis. 204:164-73, 2011). Renewed interest in DNA vaccines has come as the result of recent improvements in constructs, delivery via electroporation and better adjuvants. Both antibodies and cellular immunity have been induced in NHP studies and clinical trials by the team led by David Weiner. And there is significant progress in other fields, such as the use of mosaic gene inserts and alternative viral vectors.
Today, as we commemorate World AIDS Day 30 years after the disease was first identified, the future of HIV prevention looks brighter than ever. Different proven interventions used in combination might considerably reduce the burden of infection worldwide. But we remain convinced that only a vaccine will break the back of the epidemic and will eventually control HIV/AIDS. Science has made enormous progress over the last 30 years, and the scientific community should be proud that its findings were rapidly harnessed to develop clinical and public health interventions. Vaccine research will not be the exception, but we need to pursue it with an even stronger sense of urgency. How soon we will have an HIV vaccine will depend on the decisions we make today.
About the authors:
Dr. José Esparza is Senior Advisor, Vaccines, at the Bill & Melinda Gates Foundation, Seattle, WA, USA and is also the interim Board President of the Global HIV Vaccine Enterprise.
Dr. Bonnie J. Mathieson is the Chair of the HIV/AIDS Vaccine Coordinating Committee at the Office of AIDS Research (OAR), National Institutes of Health, Bethesda, MD, USA.