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Posted: 8 Sep 2011
30 years in 30 weeks, 1999

Historically, a robust humoral antibody response to a pathogen has been viewed as key to the control of viral replication and, hence, to an effective vaccine. The role of cell-based immune responses has been unclear, at best. The paper presented this week uncovered some of the very first evidence that T-cells – in this case CD8+ T cells – play a critical role in controlling SIV replication in macaques.

Control of viremia in simian immunodeficiency virus infection by CD8+ lymphocytes.
Science. 1999 Feb 5;283(5403):857-60.
Schmitz JE, Kuroda MJ, Santra S, Sasseville VG, Simon MA, Lifton MA, Racz P, Tenner-Racz K, Dalesandro M, Scallon BJ, Ghrayeb J, Forman MA, Montefiori DC, Rieber EP, Letvin NL, Reimann KA.

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View the rest of the series:
1998 < All years > 2000

Commentary by Dr. Joern Schmitz

Dr. Schmitz
Shortly after the discovery of HIV, a number of prominent scientists predicted that an AIDS vaccine would be rapidly developed and, like most other vaccines, provide protection by eliciting humoral immune responses. However, it soon became clear that this prediction was premature. When I entered the HIV field in the early 1990s, it was already apparent that antigenic drift of viral genes was one of the major reasons for the failure of vaccine candidates. In fact, at that time virologists and immunologists were struggling to show that adaptive immune responses played any role in HIV containment. Some clinical observations provided circumstantial evidence that CD8+ T cell responses were involved in early viral containment. However, definitive proof was elusive.

When I first met Norman Letvin in 1993, I became convinced that SIV-infected rhesus macaques were an excellent model for studying AIDS. While working at the Bernhard Nocht Institute in Hamburg, Germany in the year before joining Norman’s lab, I thought about an interesting project:  the field would gain significantly if the role of adaptive immune responses in HIV control could be proven.  In particular, I was very keen on obtaining definitive proof of the importance of virus-specific CD8+ T cells.  While this type of study would have been easily performed in mouse models using gene knock outs, the nonhuman primate model is more challenging.  I reasoned that the easiest method to eliminate CD8+ lymphocytes in vivo would be administering a cell-depleting antibody. After spending over half a year searching the literature and making numerous phone calls, I had almost given up hope of finding such an antibody reagent. However, just by chance, I hit gold when I mentioned my search for an anti-CD8 antibody to the director of the Bernhard Nocht Institute as we were riding together on an elevator. He referred me to a team of immunologists at the University in Munich who had developed an antibody to eliminate CD8+ lymphocytes in hepatitis virus-infected humans. A few phone calls and faxes later, I had several grams of this humanized anti-CD8 antibody for my proposed studies in rhesus macaques.

When I performed the first pilot experiment in naive rhesus monkeys, my colleagues in the Letvin lab voiced polite skepticism as to the ability of this antibody to induce adequate CD8+ lymphocyte depletion. The results not only blew me away, but also convinced the skeptics that we had a very powerful tool: CD8+ lymphocytes were nearly undetectable in blood within 30 min after the first injection. We now could design a study that would directly address the role of CD8+ T cells in AIDS virus containment. The advent of the T cell tetramer technology for detection of SIV-specific CD8+ T cells was developed in the Letvin lab at the same time and provided a crucial tool for these studies. After an observation period that challenged my patience, we observed that eliminating CD8+ lymphocytes during primary SIV infection rendered monkeys incapable of controlling primary viremia. Moreover, CD8+ lymphocyte depletion during chronic infection resulted in an immediate and massive increase in SIV replication that was again controlled when the CD8+ lymphocytes reappeared.

Since our observation, we have provided this antibody to more than 90 colleagues who have used the CD8+ lymphocyte depletion model in hundreds of studies of AIDS pathogenesis and vaccine development, as well as in more than a dozen other primate models of infectious diseases. 

About the author:
Dr. Schmitz is an Associate Professor of Medicine at Harvard Medical School.

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