Eradication or Immune Control: New Research, Issue of Focus
Four separate publications in the current New England Journal of Medicine1,2,3,4 and research papers published this month in Nature Medicine5,6,7 and Journal of Experimental Medicine8 have brought attention to issue of how much AIDS research should focus on attempting to eradicate HIV by antiretrovirals, vs. seeking long-term immune control even without eradication.The New England Journal reports have received the most public attention. Two research papers1,2 and an editorial3 discussing them, are again illustrating the difficulty of completely eradicating HIV from the body with current drugs. Two years ago it was hoped that if the virus were continually suppressed to undetectable levels with antiretrovirals, maybe the infection would die out by itself within a few years, as infected cells died and were not replaced. Today this hope seems unlikely, at least with current treatments, for two reasons: some cells can live for a long time, and there is evidence of some ongoing viral replication or activity (at least in many patients) despite very good control of viral load with the drugs.
Zhang and others1 studies eight patients who began treatment soon after infection, and had undetectable viral load for two to three years. They looked for evidence that the virus had changed during this time--an indication that viral replication was continuing. They did find such evidence in two of the patients, but not in the other six. And even in those two who had low-level replication, drug resistance did not develop.
But this team of 18 scientists at the Aaron Diamond AIDS Research Center and other institutions also estimated the half life of the virus in resting CD4 cells as six months--meaning that complete eradication in these cells would take many years.
Furtado and others2 studied five patients with long-standing HIV infection who had undetectable plasma viral load for at least 20 months on antiretroviral treatment. They measured HIV DNA and RNA within CD4 cells, and found that both of these decreased, but then seemed to reach a steady level and not go lower, suggesting that some very low level of viral replication was continuing. They concluded that it might not be possible to eradicate HIV with current treatments.
One benefit of these studies is that they have developed new tools to study very low levels of HIV activity, even in patients whose viral load is completely undetectable.
Another Approach
The letter4 reports on the well-known "Berlin patient"--who started treatment soon after acute HIV infection with a regimen which included hydroxyurea, interrupted treatment temporarily on two occasions, and then was able to stop treatment without a rebound in his viral load. While most of the information was already presented at the Retroviruses conference (see "Restoring HIV-Specific Immunity," AIDS Treatment News #312, February 11, 1999), this report after 19 months of treatment notes that very low levels of live virus have been detected by special tests, so the HIV has not been eradicated and it is possible that this patient could have a viral rebound in the future. The importance of this case is that it shows the possibility of immune control of this virus, even in a patient who previously had a high viral load and needed antiretroviral treatment to suppress it.
Comment
Treatment activists are increasingly questioning whether there is too much research emphasis on eradication with antiretrovirals, vs. studies on how to maintain or repair the body's initial ability to control the virus. When HIV infection first occurs, the immune system suppresses the virus very well, much better than any known drugs--but then this ability is usually lost. Since almost everybody can control this virus for a time--and some long-term nonprogressors may be able to control it permanently--and chimpanzees can be infected with HIV, but almost always control the virus and do not become ill--all of which suggests that immune control of this infection is biologically plausible--it seems that there should be more research focus on immune responses to HIV, how immune control is lost, and what can be done to maintain or restore it.
Is the research balance is being distorted by the existence of a huge market in antiretrovirals, vs. almost none in immune-based therapies? Or are we only seeing the effects of ongoing progress, as studies planned years ago based on the information of that time are now being reported?
References
1. Zhang L, Ramratnam B, Tenner-Racz K, and others. Quantifying residual HIV-1 replication in patients receiving combination antiretroviral therapy. The New England Journal of Medicine. May 27, 1999; volume 340, number 21, pages 1605-1613.
2. Furtado MR, Callaway DS, Phair JP, and others. Persistence of HIV-1 transcription in peripheral-blood mononuclear cells in patients receiving potent antiretroviral therapy. The New England Journal of Medicine. May 27, 1999; volume 340, number 21, pages 1614-1622.
3. Pomeranatz RJ. Residual HIV-1 disease in the era of highly active antiretroviral therapy. The New England Journal of Medicine. May 27, 1999; volume 340, number 21, pages 1672-1674.
4. Lisziewicz J, Rosenberg E, Lieberman J, and others. Control of HIV despite the discontinuation of antiretroviral therapy. The New England Journal of Medicine. May 27, 1999; volume 340, number 21, pages 1683-1684.
5. Finzi D, Blankson J, Siliciano JD, and others. Latent infection of CD4+ T cells provides a mechanism for lifelong persistence of HIV-1, even in patients on effective combination therapy. Nature Medicine. May 1999; volume 5, number 5, pages 512-517.
6. Pitcher CJ, Quittner C, and Peterson DM. HIV-1-specific CD4+ T cells are detectable in most individuals with active HIV-1 infection, but decline with prolonged viral suppression. Nature Medicine. May 1999; volume 5, number 5, pages 518-525.
7. Robinson HL, Montefiori DC, Johnson RP, and others. Neutralizing antibody-independent containment of immunodeficiency virus challenges by DNA priming and recombinant pox virus booster immunizations. Nature Medicine. May 1999; volume 5, number 5, pages 526-534.
8. Hockett RD, Kilby JM, Derdeyn CA, and others. Constant mean viral copy number per infected cell in tissues regardless of high, low, or undetectable plasma HIV RNA. Journal of Experimental Medicine. May 17, 1999; volume 189, number 10, pages 1545-1554.
