July 26, 2005
In this interesting format, two experts debated whether highly active antiretroviral therapy (HAART) can result in the eradication of HIV in HIV-infected people. Dr. Mario Stevenson from the University of Massachusetts, Worchester, was the pro argument respondent and Dr. Tae-Wook Chun from the U.S. National Institutes of Health gave the con argument.
What was remarkable was that they both concluded with somewhat similar logic and justification that currently available HAART was not capable of HIV eradication.
Dr. Stevenson was up first. He gave a brief overview of HIV's life cycle inside cells and listed the types of cells that could become infected. He then spoke generally about the fact that many of the CD4+ cells, macrophages and resting T cells are relatively long-lived, including some of those that might be HIV infected.
He presented an example of a patient who had started HAART, had a fully suppressed plasma viral load, and then stopped treatment. This resulted in plasma viral load rebound, something most providers have seen repeatedly. Why does this happen? What might be sustaining HIV survival even while someone is taking HAART? Dr. Stevenson noted that one of the major reasons for HIV survival is that memory CD4+ cells have provirus, which could rekindle HIV replication in the absence of HIV treatment.
In addition, HIV treatment doesn't really stop 100% of HIV replication. The evidence for ongoing replication in patients who are receiving HAART and have undetectable plasma viral loads includes:
Episomes are HIV nucleic acid strands that can persist within the nucleus and thus point to a cryptic reservoir that could sustain viral replication in patients who have suppressed plasma viral load while receiving HAART.
Dr. Stevenson concluded by saying it is possible that HIV could be eradicated by HAART, but HAART would have to be intensified with drugs attacking new targets such as the gag and vif genes, RNase H or integrase enzymes. If we could control cryptic replication, we would be in a better position to answer this critical question.
Next up was Dr. Chun for the rebuttal. However, he pretty much agreed with Dr. Stevenson. He listed the following 3 impediments to HIV eradication in the presence of HAART:
He also presented a schematic of the HIV life cycle, but emphasized the fact that there can be pre- and post-integration latency. This means there are several forms HIV can take once it gets inside a cell, and it can exist as circular DNA forms in the cytoplasm or can be integrated into the host cell genomic DNA. The decay or longevity of replication-competent latently infected cells can be years, he noted.
People who have been virologically suppressed on HAART for several years, he added, still had relatively high levels of HIV-infected T cells in their blood. What then is the evidence that HIV can be replicating while patients are on HAART and have an undetectable viral load? Dr. Chun gave some data in which patients with suppressed viral load had their CD4+ cells analyzed. He found varying levels of replication-competent HIV and when the cells were activated from a resting state, he found an increase in proviral levels. He then presented some sequencing data from these patients, which revealed that HIV sequences from these patients could also be shown to be changing and moving between cells over time. This again demonstrates the dynamic nature of HIV infection and replication during the presence of HAART.
Dr. Chun concluded by saying what Dr. Stevenson had said -- we cannot eradicate HIV with current HAART treatment because of the persistence of a latent reservoir. Some possibilities to enhance current treatment might include:
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