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Editor—As Yamey et al highlighted, HIV will have killed 55 million people by the year 2010.1 Now, 20 years since the first appearance of the virus, is a good time to review the advances to date and identify promising avenues for future research.
To estimate the amount of money spent on research on HIV and, within that, the amount spent on animal studies is difficult. Assessments of the efficacy of animal studies in HIV research are, however, easier to come by.
Thomas Insel, former director of the Yerkes Regional Primate Center in Georgia, said: “[An animal model] that takes 12-14 years to develop doesn't sound to me to be ideal . . . I can't tell you what it is that those studies [with chimpanzees] have given us that has really made a difference in the way we approach people with this disease.”2 Animal models of HIV have been notoriously inaccurate for two reasons.
Firstly, the immune response is intensely complicated and there are many disparities between the human immune response and those of other animals. Secondly, viruses are usually species specific.
In terms of treatment, the efficacy of zidovudine—originally an anticancer drug—was shown in 1985 from the results of in vitro studies rather than animal research. Similarly, combination antiretroviral therapy was developed using in vitro methods, rational drug design, and clinical research.
In vitro research has also enabled other advances in understanding and potentially treating HIV. These include elucidating the structure of the virus (and recently the rare b12 antibody), finding that an HIV-1 entry inhibitor could prevent HIV from fusing with the cell membrane,3 and discovering that certain strains of HIV do not use the normal 2-receptor binding process but bind directly to T helper cells via the CD8 receptor.4 Epidemiological studies determined the routes of HIV transmission. Gene variants that influence HIV progression were identified using longitudinal epidemiological cohort studies, high throughput genotyping and polymorphism discovery methods, and computational algorithms to detect gene associations in cohorts with the disease.5
The fact that 20 years on there is still no cure or vaccine for HIV is surely partly because too much money, time, and effort have been invested in animal research which has produced little, if nothing, in return. To make any impact on this global pandemic during the next 20 years, funding needs to be concentrated on research methods that have come up with the goods.
Footnotes
Competing interests: None declared.
References
1.Yamey G, Rankin W, Feacham R. Twenty years of AIDS and no end in sight. BMJ. 2001;322:1440. doi: 10.1136/bmj.322.7300.1440. [DOI] [PMC free article] [PubMed] [Google Scholar]
2.Smaglik AIDS vaccine researchers turn from chimps to monkeys. Scientist. 1999;13:7. [Google Scholar]
3.Root MJ, Kay MS, Kim PS. Protein design of an HIV-1 entry inhibitor. Science. 2001;229:884–888. doi: 10.1126/science.1057453. [DOI] [PubMed] [Google Scholar]
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BMJ. 2002 Jan 26;324(7331):236.
Reply: Animal models for HIV advance and complement clinical studies
Editor—Overcoming the HIV/AIDS epidemic has presented an unprecedented challenge to the scientific and medical communities. Despite years of research and the development of antiviral drugs, death from AIDS remains a certainty. A safe and effective vaccine is widely acknowledged as the only means to stem the pandemic. The rate of progress to date has underscored the need for multifaceted scientific approaches. In their letter above Greek and Pound discount the value and results gained from using animal models, in conjunction with in vitro and epidemiological studies, for HIV research. Such discounting is unwarranted.
In fact, animal models have provided key advances. Animal studies on HIV allow us to gather information, compare approaches, and perfect strategies to maximise the potential for clinical success. Work in chimpanzees showed that chimpanzees and humans have a similarly long time frame between HIV infection and the development of AIDS. This led to a switch to using macaques, in which AIDS develops sooner, to expedite the testing of new, risky concepts without putting humans in danger.
Before studies were conducted in non-human primates short term treatment of newly infected, symptom-free patients immediately after exposure with antiviral drugs was considered to be risky and unlikely to result in long term benefit. Then short term treatment with the antiviral PMPA was found to prevent infection in macaques infected with SIV, clearly showing a benefit from stopping treatment.1-1 Subsequently, many of the critical parameters and limitations of interrupting treatment have been discovered using these models. Further studies in macaques have shown that monoclonal antibodies can block vaginal infection, offering hope for non-toxic treatments.1-2
Innovative strategies for vaccine development, such as DNA vaccines, have also been facilitated by research in macaques. Live attenuated SIV, genetically engineered to eliminate pathogenicity, protects adult macaques from lethal challenge.1-3 While an attenuated HIV vaccine was under consideration for humans, this same highly attenuated SIV vaccine was found to cause AIDS in newborn macaques.1-4 Without these studies, the need for additional safeguards might have been missed—with dire consequences.
The delays in making more effective HIV drugs or vaccines should be blamed on this formidable and elusive virus. Animal models must be used to complement epidemiological and clinical studies in humans. Answers will come faster and the research will cost less if the clinical work is focused on strategies that have been pretested in models. Funding in all arenas is critical to evaluate and accelerate progress—and to prevent disasters.
Footnotes
Competing interests: NLH is president of the board of trustees of the Washington Association for Biomedical Research, a non-profit educational organisation whose mission is to advance biomedical research for humans and animals through public education and service to the scientific community.
References
1-1.Tsai C-C, Follis KE, Sabo A, Beck TW, Grant RF, Bischofberger N, et al. Prevention of SIV infection in macaques by (R)-9-(2-phosphonylmethoxypropyl) adenine. Science. 1995;270:1197–1199. doi: 10.1126/science.270.5239.1197. [DOI] [PubMed] [Google Scholar]
1-2.Mascola JR, Stiegler G, VanCott TC, Katinger H, Carpenter CB, Hanson CE, et al. Protection of macaques against vaginal transmission of a pathogenic HIV-1/SIV chimeric virus by passive infusion of neutralizing antibodies. Nat Med. 2000;6:207–210. doi: 10.1038/72318. [DOI] [PubMed] [Google Scholar]
1-3.Wyand MS, Manson KH, Garcia-Moll M, Montefiori D, Desrosiers RC. Vaccine protection by a triple deletion mutant of simian immunodeficiency virus. Journal of Virology. 1996;70:3724–3733. doi: 10.1128/jvi.70.6.3724-3733.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
