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Posted: 11 Aug 2011
30 years in 30 weeks, 1995

Two years before the publication of the paper featured this week, Pantaleo et al. (see 1993, this series) showed that HIV damages the lymphoid tissue of an infected person even before the onset of symptoms of AIDS. Ho et al. expanded on that finding by showing that in asymptomatic patients the virus is actively replicating, new cells are continuously being infected and large numbers of virions are produced every day. The immediate implication of this discovery was the appreciation of HIV’s ability to evolve and escape both the immune system and the antiretroviral drugs.

Rapid turnover of plasma virions and CD4 lymphocytes in HIV-1 infection.
Nature. 1995 Jan 12;373(6510):123-6.
Ho DD, Neumann AU, Perelson AS, Chen W, Leonard JM, Markowitz M.

Article PDF

View the rest of the series:
1994 < All years > 1996

Commentary by Drs. Markowitz and Ho

199
Dr. Martin Markowitz
What inspired your research?
In 1994 the prevailing view of HIV infection was that it entered a phase of both virologic and clinical latency once established. Prior to the publication of our results there were hints that HIV infection was not necessarily latent virologically. For example, the rapidity with which viral populations became resistant to select agents suggested that the dynamics of viral replication were underappreciated. Our small team, which included a virologist (Ho), modelers (Perelson and Neuman), and a clinician (Markowitz), was able to use data generated from a clinical trial of a novel protease inhibitor (provided by Dr. Leonard and colleagues at Abbott) to generate the results published in this paper.

How did these findings influence the HIV field?
The finding that HIV replication was dynamic from the moment of infection was a critical step in establishing the scientific basis for combination antiretroviral therapy. Based on these data, it was predicted that resistance would emerge to monotherapy and dual therapy with the agents available for treatment at that time. In essence, it marked the birth of triple combination antiretroviral therapy – an approach that has not only dramatically reduced HIV related morbidity and mortality worldwide, but remains the current approach to effective treatment.
We also believe that the importance of viral replication as driving the pathogenesis of HIV infection was reinforced.

200
Dr. David Ho
Were you surprised by the results?
The study team was not surprised by the results – actually the results confirmed the hypotheses we put forward going into the project.

In your opinion, why did your paper become one of the most cited papers in the field? Did you expect this when submitting for publication?
The study team knew that this was an important finding in the field, as it redefined the current understanding of HIV viral dynamics. It also set the stage for a series of experiments in which we aimed to more clearly understand the various cell populations and viral reservoirs responsible for the different decay rates observed when effective therapy was applied.

What was the most challenging about this project?
The viral load assay was in its infancy at the time… and the lower limit of detection was 10,000 copies per ml plasma. This was a major issue early on and with advances in technology subsequent papers were more precise in defining viral dynamics and reservoirs.
In addition, the response to the paper in the treating community was mixed. Though we believed we had established the scientific basis for combination therapy, there were many clinicians and biostatisticians who refused to accept measurements of viral load as a surrogate for disease. This was most frustrating. Seeing trials with clinical endpoints and mono- and dual therapy arms continue well into the late 1990s was most difficult to accept.


Did this paper “age well”?  Was anything new discovered since its publication that paints these findings in a different light?
The viral dynamics story has aged well. There has been a lot of discussion subsequently as to what is responsible for the loss of CD4+ T cells during HIV infection. It is clear that this aspect of our paper suffered from a bit of oversimplification. This is a complex issue and clearly T cell activation and proliferation are major drivers of CD4 depletion in addition to direct HIV infection of susceptible T cells.

In all, the story has held up well… and perhaps most importantly HIV infection has been transformed from a near uniformly fatal disease to one that is manageable.


About the authors:
Dr. Markowitz is a Professor at the Aaron Diamond AIDS Research Center.
Dr. Ho is the Scientific Director
at the Aaron Diamond AIDS Research Center.

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