Research Initiative Treatment Action (RITA!); Vol 5, No. 5 December 1999
L. Joel Martinez
Theoretically, any regimen that does not fully suppress viral suppression will allow evolution of drug resistance, resulting eventually in viral rebound, CD4 T-cell depletion, and ultimately disease progression. Therefore, drug failure is said to occur in any patient who has persistent viral replication while taking combination therapy.
–Deeks, et al.
Our study demonstrates that some cell-free virion production may be quite common in patients taking suppressive HAART with fewer than 50 copies/mL of viral RNA in peripheral blood.
–Pomerantz, et al.
The war against HIV in sanctuary sites—places where the virus might hide from the inhibiting effects of highly active antiretroviral therapies (HAART)—was over before it was officially declared. The hope that drugs would reach these sites and that HIV might slowly dissipate and finally disappear, collapsed with the discovery that even outside these privileged sites HIV persists in quiescent latently infected memory CD4 T cells that live for a long time and are not easily inhibited by HAART.
So even if these sanctuary sites could be cleared of HIV with effective drug therapy, the presence of latently infected quiescent memory cells outside these sites represent a relatively untouched reservoir of HIV. The existence of the reservoir has the effect of increasing the time to potential eradication from the early estimate of two to 3 years to a more pessimistic 10 to 60 years. Undeterred by that dismal news, proponents of interleukin-2 (IL-2) pressed on with experiments to purge these reservoirs with the activating qualities of the cytokine in combination with HAART.
Millions of cells of a small group of patients at the National Institutes of Health were scrutinized to see if any were still harboring HIV. Despite the apparent absence of HIV or the extremely low levels of the virus, all patients had virological rebound when taken off drug regimens.1 This tiny residual ember of HIV seems to represent a major obstacle to putting out the viral fire. Scientists have confirmed that some low level of HIV replication may indeed be replenishing this remaining pool of infected cells.2
As if that were not gloomy enough, a recent article published in the journal Nature Medicine further complicates this scenario by calling into question some of the basic premises that underlie the theories of eradication and more importantly, some of the assumptions of what occurs during viral suppression with HAART.
In an article entitled "Ongoing HIV dissemination during HAART"3 the authors question the generally accepted model of treatment response. Under their proposed model viral replication continues even after so-called "complete" suppression with HAART and this ongoing replication is not "insubstantial." Furthermore, this replication, according to the scientists, is not limited to "isolated tissue domains."
If this is true, it follows that highly active antiretroviral therapy may be only be "fairly active antiretroviral therapy" after all. The overestimation of the potency of current drug regimens indeed could be the proverbial "last nail in the coffin" of the eradication theory, at least with current therapies. Scarier still is the possibility that continuing low levels of HIV replication will eventually result in resistance to medications and that all the advances of combination therapy will be undone with time. At this time there is no evidence that such low levels of HIV replication lead to resistance. The model proposed by these authors may have clinical applications that may influence therapy choices for the patient and future drug design for industry.
The old Ho model. In the treatment kinetics model proposed by David Ho, MD, and others, the introduction of combination therapy does not result in the direct killing of HIV, but rather in the protection of new cells from infection. As such, cells that are actively producing HIV at the time that HAART is administered continue to produce HIV and it is only as these cells die and are replaced by new cells that the decline in HIV levels is seen. That decline in HIV levels occurs quickly because the vast majority of the virus (over 99%) is produced by cells that survive for only a day to a day and a half.
As the theory goes, introduction of HAART results in a steep decline in the HIV levels (phase I) that is followed by a slower decline which is reflective of another pool of cells, like macrophages and monocytes, that generally live longer (phase II). Ho postulates these cells, too, will die and be replaced by uninfected cells and that eventually the HIV will disappear from the body. Discovery of the latent infection of memory cells that live even longer than this second group of cells dampened further the prospect of eradication and creates the possibility of yet another slower rate of HIV decline (phase III).
Nonetheless, scientists have speculated that it might be possible to activate these quiescent cells, thereby shortening their lives and hastening the purge of latently-infected cells. Thus, under this model of HIV treatment, HIV decline is reflective of the half-lives of these different cell populations: productively infected CD4 T cells, longer-lived cell and latently infected memory cells. The shorter the life of the cell, the more quickly it is replaced by an uninfected cell and the steeper the decline in HIV levels. Conversely, the longer the life of the cell, the longer HIV will persist and the less steep its level of decline. Once all three phases of decline are complete (through natural cell death or by artificial stimulation as in the use of IL-2) eradication would occur.
While the lengthening of the time to eradication seemed to make the objective less and less accessible, the hope of some mechanism of speeding up the last two phases of decline still loomed as a real, albeit, remote possibility.
The new "viral bursts" model. The new model that is proposed in the Nature Medicine article undermines one of the central premises of the Ho theory in that it postulates that HAART does not completely halt infection of new cells. Rather it asserts that viral infection of new cells continues after the introduction of therapy and it is only the amplitude and frequency of the infection events that are affected.
According to this new model HIV is produced in intermittent local bursts in the lymphoid tissue during immune response episodes. During an encounter with an antigen, infected CD4 T cells or antigen presenting cells (APC) become activated in order to fight the antigen. It is during this process that HIV is produced in local bursts by the activated cells and in the process the newly produced HIV infects other activated and bystander cells. Eventually the bursts subside as the immune response subsides. According to these authors HIV production is local and transient but continuous because the local bursts are multiple, overlapping and occurring at different times.
When anti-HIV therapies are introduced there is a rapid decline in HIV. This decay of viral levels within the first two weeks (corresponding to the phase I decline) is reflective of strong, but incomplete suppression of the viral replication. Antiretroviral drugs reduce the size of the local viral bursts and diminish their frequency but according to this model the virus continues to replicate and infect new cells.
A second slower phase of decline follows as antiretroviral therapies reduce the size of the viral bursts and consequently the number of infected memory cells that are created. This slower decline would correspond to the phase II described above. The authors also note that this slower second decline attenuates with time, that is to say, the rate of decline of levels of HIV gets slower and slower until it may stop completely. At such time a new steady state of HIV production that is not detectable by current methods may be established.
What accounts for this attenuating of the decline? One reason may be that as activation events decrease with HAART the pool of memory cells also contracts. With fewer immune response events, the smaller pool of memory cells is activated at a lower rate. Other factors that may contribute to this attenuation may include a progressively increasing proportion of drug resistant particles and a non-uniform distribution of antiretroviral drugs in infected lymphoid tissue.
While some scientists have thought of residual replication in the context of sequestered sites such as the brain, where viral production might continue while being blocked everywhere else, this model proposes that because viral transmission may be primarily a local event (directly from one cell to another). Drugs only partially block transmission and drug tissue distribution may be non-uniform so that persistent viral replication may vary considerably across tissues.
Consequences of the new model? Because cells continue to produce HIV even after the introduction of HAART and because the virus is produced in multiple, hard to abolish, local bursts, the authors of this article postulate that eradicating HIV with drugs alone will be a "formidable task." They believe the efficacy of available drugs has been overestimated and most surprisingly, they question the wisdom of the strategy of stimulating latently infected cells under cover of HAART. Under their model such stimulation may result in HIV transmission to new cells.
Grossman, et al., envision that finding ways of enhancing the anti-HIV activity of cytotoxic (killer) T lymphocytes, or generating neutralizing antibodies or perhaps developing drugs with greater efficiency and greater, more uniform tissue penetration to all domains may be part of the answer.
Questions posed. This new model of viral dynamics during HAART poses many questions for further investigation. If HAART merely establishes a new steady-state of viral replication that is below the current levels of quantification, what is a truly "safe" steady-state that does not run the risk of developing drug resistance? Below 50 copies? Below 20 copies? Further, does this safe steady-state vary from person to person? The aberrant phenomenon of "disconnect"4 and the experience of patients who do not progress clinically despite receiving suboptimal therapies (e.g., dual nucleosides) seem to argue for a steady-state of viral load above detection that does not automatically predict clinical progression.
In any case, this model argues in favor of drugs with the best pharmacokinetics. Drugs such as ABT-378/r, with its high trough, efavirenz (Sustiva) with its long half-life and apparent ability to reach tissue efficiently and the combination of indinavir (Crixivan) and ritonavir (Norvir), with its high and even distribution of therapy are seemingly favored candidates if this model proves true.
Of interest, too, is the question of the use of interleukin 2 (IL-2) as a method to purge HIV infection. This article implies that use of IL-2 might be counterproductive, but evidence from the field appears to contradict such an assertion. Finally, the possible use of immunosuppressive agents as a method to further diminish the size and frequency of viral bursts is intriguing.
As with the many rounds of viral bursts described in this article, it is safe to assume that this proposal will soon stimulate many new "bursts" of discussion about viral dynamics.
1 Nature Medicine, 1999 Jun;5(6):651-5.
2 New England Journal of Medicine, 1999 May 27;340(21):1614-22 and more recently, Journal of the American Medical Association, 1999 Nov 3;282(17):1668-9.
3 Nature Medicine, 1999 Oct;5(10):1099-104.
4 "Disconnect" refers to patients who never reach unquantifiable levels of viral load on HAART or who rebound from unquantifiable levels to a detectable level and still maintain their CD4 T cell gains.
Antigen: a foreign substance, usually a protein that stimulates an immune response.
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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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