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Posted: 21 Jul 2011
30 years in 30 weeks, 1992

Categories: careers, comment, opinion piece

Soon after the discovery of HIV, a whole family of related viruses were found to naturally infect a variety of African nonhuman primates. The simian immunodeficiency viruses (SIVs) became useful models for HIV. The SIV models allow study of viral transmission, pathogenesis and vaccine concepts under well-controlled laboratory conditions. In his commentary, Dr. Desrosiers recalls the development of a vaccine which protected monkeys from SIV infection.

Protective Effects of a Live Attenuated SIV Vaccine with a Deletion in the nef Gene
Muthiah D. Daniel, Frank Kirchhoff, Susan C. Czajak, Prabhat K. Sehgal, Ronald C. Desrosiers
Science vol. 258, 18 December 1992.

Article PDF

Commentary by Dr. Ronald C. Desrosiers

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 I vividly remember our former Director, Dr. Ronald D. Hunt, walking through the halls of Harvard’s New England Primate Research Center (NEPRC) in early 1982 waiving the Gottlieb et al New England Journal of Medicine publication saying: “This looks like what our monkeys have! This looks like what our monkeys have!”  Indeed, macaque monkeys at NEPRC as well as several other national primate centers were suffering from some sort of acquired immunodeficiency syndrome. I was working exclusively on gamma herpesviruses at the time but decided to allocate a portion of my effort to searching for what the cause in monkeys might be. Little did I know how that decision would affect the path of my professional life for decades to come.

Initial efforts from my group led to the description in Science in 1984 of a new group of type D retroviruses from immunodeficient macaque monkeys.  It turned out that this type D retrovirus was the major cause of the immunodeficiency syndrome that we were seeing and it has now been weeded out of most macaque breeding colonies in the U.S.  However, Dr. Norval King at the NEPRC had generated electron microscope pictures of viral particles from lymph nodes of a small sub-group of these immunodeficient macaques that he knew to be distinctive for the lentivirus subfamily of retroviruses. So we kept hunting. This led to the discovery of the simian immunodeficiency virus, first published in Science in June 1985 almost exactly one year after the publication in Science of the four seminal papers from the Gallo laboratory.

In 1990, my lab described an infectious molecular clone for SIVmac239. Not only was virus derived from this clone replication competent, it was fully capable of inducing CD4+  T cell declines and AIDS in rhesus monkeys. At the time, this was the first infectious, pathogenic molecular clone that had been defined for any lentivirus.  This and subsequently other such cloned DNAs became incredibly powerful tools for performing well-controlled experimental infections of monkeys and for dissecting the contribution of individual genes and of individual genetic elements to pathogenic processes. Any nucleotide or combination of nucleotides of the 10,279 present in the SIVmac239 clone can be changed at will to determine the effects on the ability of the virus to do what it does. Many questions were being raised at the time regarding the so-called “non-essential” genes: vif, vpr, nef, and vpu for HIV-1 and vif, vpr, nef, and vpx for SIVmac.  So we deleted these genes individually and in combinations from the SIVmac239 clone and began examining their relative importance and functional role through experimental monkey infections. Viruses deleted in nef, vpr, or vpx, alone or in any combination, replicated in monkeys, persisted in monkeys, but exhibited varying degrees of attenuation based on viral loads, stability of CD4 counts, and absence of clinical signs.

Around this time, it was beginning to come clear to many in the field that development of an effective vaccine against HIV-1 was going to be a very difficult struggle.  It was also becoming clear that one of the most important uses of the SIV-macaque model was for vaccine development efforts, in particular what vaccine approaches may work best in providing protection against SIV challenge. My lab had been trying whole killed virus approaches and, with Dennis Panicali, poxvirus recombinants without much success. We soon realized that the SIVmac239 gene deletion mutants that we had been studying for pathogenesis reasons also had applicability as experimental live attenuated vaccine strains.  This 1992 publication, as well as subsequent publications from my lab and other laboratories, demonstrated the powerful protective capacity of live attenuated nef-deleted strains of SIV, in most cases yielding apparent sterilizing immunity.  To this day, live attenuated nef-deleted SIV remains the gold standard to which other vaccine approaches are compared.

Because of concerns for long-term safety, it is not likely that live attenuated strains of HIV-1 will be considered for use in humans, at least in my lifetime.  There was a period of considerable controversy after this publication appeared when small groups were advocating for its use and volunteering themselves to be the guinea pigs.  Such thinking has passed but the research has fortunately continued.  Most research with live attenuated strains of SIV is currently directed to defining the key factors responsible for the protective immunity.  If we can figure out why live-attenuated SIV protects as well as it does, the thinking goes, then perhaps we can figure out some other safer way to do it. It should be noted that even live attenuated SIV does not protect so well when heterologous strains of SIV are used for challenge, paralleling what one would expect in field trials of an HIV vaccine. This observation highlights yet again the enormous obstacles we are facing in the development of a safe and effective vaccine against HIV/AIDS.

About the author: Dr. Ronald C. Desrosiers is Professor of Microbiology and Immunobiology at Harvard Medical School and Director of Harvard’s New England Primate Research Center.

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