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Posted: 4 Aug 2011
30 years in 30 weeks, 1994

Many viral infections resolve and leave the individual immune to the repeated viral challenges. Such cases can serve as a guide and a model for vaccine development. However, HIV infection is chronic and no cases of the complete clearance of the virus are known. Nevertheless, the evidence for immune control of virus replication existed in 1994: after acute infection the amount of virus in the blood decreased, presumably due to immune pressure.Dr. Koup et al. expected that by discovering the immune mechanisms responsible for this reduction in viral load, they would be able to develop a vaccine to effectively control viral replication in infected individuals.

Temporal association of cellular immune responses with the initial control of viremia in primary human immunodeficiency virus type 1 syndrome.
Koup RA, Safrit JT, Cao Y, Andrews CA, McLeod G, Borkowsky W, Farthing C, Ho DD.
J Virol. 1994 Jul;68(7):4650-5.

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1993 < All years > 1995

Commentary by Dr. Richard Koup

This paper described the timing of the antibody and cytotoxic T lymphocyte (CTL) responses, in comparison to virus loads, during acute HIV infection.  It showed that virus loads decline at a time when the CTL response is expanding, and well before any neutralizing antibody response is detectable.  The importance of this finding is that it indicates that CTL, not antibodies, are primarily responsible for controlling virus replication in HIV infection.  Inherent in this conclusion is that the human immune system, while unable to fully clear HIV, does have the capacity to negatively impact upon virus replication, thereby providing initial evidence that inducing such a response by vaccination could lead to improved outcomes.  Development of CTL-based vaccines was a natural byproduct of this finding, enthusiasm for which was greatly diminished when no efficacy was shown for just such a vaccine in a randomized phase IIb clinical trial.

Generating the T cell results for this paper was no small feat.  The only quantitative cellular immune assay that was available to us at the time was the limiting dilution precursor frequency assay.  This required 184 individual wells of PBMC be stimulated, cultured for several days, split into multiple wells, mixed with different targets, and tested in 736 individual chromium-release assays to derive the CTL data for each time point on each subject.  These draconian methods, known only to a dwindling population of aging immunologists, have now been replaced by more robust methods such as peptide/MHC tetramer staining, ELISpot assays, and intracellular cytokine staining, which have allowed the results to be confirmed in subsequent studies using much more sophisticated methods.

While controversial at the time, the findings of this paper should not have been a surprise, and certainly weren’t to me or Jeff Safrit, the post-doctoral fellow responsible for the study.  Multiple elegant studies of immunologic control of viral infections in mice had demonstrated that antibodies have little effect on the course of a chronic virus infection, while CTL can have a great impact.  Immunology textbooks had figures of the immune responses in mice to acute and chronic viral infections that clearly mirrored our findings in humans.  Despite what we considered to be expected results and obvious conclusions, many virologists and antibody-based immunologists disagreed, asserting that the drop in viral load was a consequence of the depletion of CD4 T cells thereby starving the virus of adequate targets in which to produce large numbers of virions, or that the antibodies were really involved but we couldn’t measure them in plasma because they were bound to the virus in immune complexes.

Despite the protestations of a few, the general conclusions of this paper became accepted and have stood the test of time.  This is mostly because multiple other approaches have been used to independently show that CTL are intimately involved in the control of HIV or SIV replication in vivo, and the authors of those other studies have been kind enough to cite us.  At the time that we published this paper, we thought that we had mastered quantitative T cell immunology, and it would be only a matter of a few years before we had unraveled all of the mysteries of HIV-specific T cell immunology.  Jeff Safrit, Bruce Walker and I actually lamented the fact that we would have to move onto other avenues of discovery, since we would soon have nothing left to study in HIV.  How wrong we were.

About the author: Richard Koup is a Senior Investigator at the Vaccine Research Center of the National Institute of Allergy and Infectious Diseases, NIH

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