Research Initiative Treatment Action (RITA!); Vol 5, No. 3 July 1999
L. Joel Martinez
By now those who follow HIV/AIDS know the theory of eradication of HIV like the back of their hand. Stopping ongoing HIV replication with highly active antiretroviral therapies would result in a quick and steep decline in productively infected CD4 T cells. With the passage of time chronically infected cells with a longer half-life, such as macrophages, would die out and be replaced with new uninfected cells. It was estimated that the half-life of the chronically infected cell was about two weeks. Scientists calculated that eradication would occur with 2 to 3 years of effective antiviral treatment.
The theory was met with instant skepticism, but its simplicity had appeal and the end result was desired fiercely. There were early concerns about so-called "sanctuary" sites&mdas;places like the brain, testes, guts, etc.—places the drugs might not reach. It was thought that the virus might be harbored in such sites and reemerge at the first opportunity. This early concern was dwarfed by the discovery in 1997 of the existence of a pool of long-lived, latently infected CD4 T cells.
How does this pool of latently infected cells get created? CD4 T cells that are activated to fight an antigen are also the primary target of infection of HIV. Sometimes these cells die through one of various mechanisms, but sometimes they retreat from battle and become resting memory cells. These cells persist for a long time; their purpose is to remember the invader if it should ever present itself again. The problem is that these memory cells have the genetic sequence of HIV incorporated in their DNA and if these cells become activated will begin to produce virus once more. (See, "Recent Progress in the Clearing of the HIV Reservoirs," on page 20 of this issue and Figure 1.)
The nature and life span of this pool of latently infected cells has been described recently in several scientific articles, but most prominently in articles appearing in The New England Journal of Medicine and in Nature Medicine.
One article in The New England Journal of Medicine ("Quantifying residual HIV-1 replication in patients receiving combination antiretroviral therapy," 1999 May 27;340(21):1605-13) reported research conducted at the Aaron Diamond AIDS Research Center. In short the research posed the following questions. In patients who are fully suppressed (i.e., below 50 copies by viral load tests) are there changes in the HIV-1 proviral genetic sequences that would indicate residual replication? And, are there cells actively expressing HIV-1 RNA?
The scientists studied eight patients who began treatment within 90 days after acute infection. The patients had viral loads below the limits of quantification. Four samples of blood were taken over time and each was examined for changes in the proviral genetic sequences. Two patients showed substantial divergence in the DNA sequences indicating the presence of ongoing replication despite the fact that their viral loads were unquantifiable. In another patient who underwent multiple lymph biopsies there was evidence of HIV-1 expressing cells throughout the tissue specimens. This group of researchers estimated the half-life of these latently infected cells to be approximately six months. Given this half-life, eradication was estimated to take 7 to 10 years of "continuous, truly effective therapy."
These scientists suggest that there is good news and bad news. The good news is that if there is ongoing HIV-1 replication, then the size of the pool has been overestimated. The bad news is that residual replication also indicates that highly active antiretroviral therapy may not be "active" enough.
The second article in The New England Journal of Medicine ("Persistence of HIV-1 transcription in peripheral-blood mononuclear cells in patients receiving potent antiretroviral therapy," 1999 May 27;340(21):1614-22) reached similar conclusions with regard to the persistence of this pool of latently infected, resting CD4 T cells. Further, it added that given the quasi-steady state of proviral DNA and messenger RNA that was found "HIV-1 infection cannot be eradicated with current treatments."
The article appearing in Nature Medicine ("Latent infection of CD4+ T cells provides a mechanism for lifelong persistence of HIV-1, even in patients on effective combination therapy," 1999 May;5(5):512-7) suggests that eradication of the latent reservoir may take as long as 60 years. A general description of this study can be found in "Recent Progress in the Clearing of HIV Reservoirs" on page 20 of this issue.
What do these gloomy predictions of HIV persistence and replication mean? In a sense they only confirm what many have suspected for some time.
They do, however, provide some new insights. First, that the latent reservoir is not truly "latent." These studies demonstrate that some viral replication is taking place, although none of the studies found any evidence of genetic mutations that would be suggestive of resistance. The fact that these reservoirs seemed to be replenished or exist in some quasi-steady state in the presence of highly active antiretroviral therapy poses a question of how this can happen. Are these sites not reached because of some kinetics of the drugs or because of some cellular mechanism? Further, in contrast to previous theories about discreet anatomical sanctuary sites, scientists from the Aaron Diamond AIDS Research Center suggest that these latently infected cells seem to be circulating readily throughout the body.
Does this mean the end of the dream of eradication? One thing is certain. Waiting for the virus to snuff itself out while it is being controlled with antivirals will be an exercise in futility. The permanency of eradication has much appeal, but if it is to happen it will require a greater creativity and imagination. Now is not the time to rest.
Antigen: a foreign substance, usually a protein that stimulates an immune response.
Proviral sequence: HIV DNA that has fused with and become a permanent part of a chromosome in a cell.
HIV-1 RNA: the genetic sequence of HIV before it is transcribed into DNA and incorporated in to the chromosome of a cell.
Messenger RNA: a copy of a gene involved in the assembly and synthesis of protein.
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Copyright © 1999 - Research Initiative Treatment Action (RITA!). Reproduced with permission. RITA! is published by The Center for AIDS. Contact Thomas Gegeny, MS, ELS, Editor, RITA! for permission to reproduce RITA!. tom@centerforaids.org. http://www.centerforaids.org
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