viral and cellular dynamics in hiv disease

Viral and Cellular Dynamics in HIV Disease

R. Pat Bucy, MD, PhD

AddressDepartment of Pathology, University of Alabama at Birmingham, P220 West Pavilion, 619 South 19th Street, Birmingham, AL 35233, USA.E-mail: bucy@path.uab.edu

Current HIV/AIDS Reports 2004, 1:40–46Current Science Inc. ISSN 1548–3568Copyright © 2004 by Current Science Inc.

IntroductionA central focus of investigation into the pathophysiologyof HIV-1 infection is determining the interactions betweenthe immune response and viral growth. Similar to all of theother infectious diseases, the dynamic relationshipbetween the host immune response and the growth of theinfectious agent sets the basic pattern for the course of theinfection. Unlike most other viral infections, HIV-1 strikesthe key cell type that orchestrates the immune response (ie,the CD4 T cell). The primary coreceptor used by the virusfor entry into the cells is the CD4 molecule, which is notonly a lineage marker, but it is also intimately involvedwith the mechanism of antigen activation of these cells.Furthermore, activation of CD4 T cells by a specific antigenrenders the cells much more susceptible to infection withHIV-1 and subsequent cell death. This complex two-wayinteraction between the growth of virus and the activationof immune mechanisms that clear infected cells is highlydynamic. Although this cycle of cellular activation, viralinfection, and immune response that inhibits viral infec-tion churns at a fairly rapid rate, the rate of these cycles isrelatively constant within each individual throughoutchronic infection. This review focuses on the specificmechanisms that control the rate of viral replicationduring this prolonged steady state of the clinically latent

phase of disease. The primary experimental tool to eluci-date the mechanisms that operate during steady-stateconditions is to intervene with agents that significantlychange one variable in the dynamic scenario and character-ize the changes that result. Several basic features of viralreplication are reviewed and the available data are consid-ered through the prism of the two alternative models of themechanisms that control viral replication in vivo (ie,target-cell limitation and immune control).

Changes in Viral and Cellular Dynamics with Initiation of Highly Active Antiretroviral TherapyThe advent of effective combinations of antiretroviraldrugs has not only altered the clinical course of HIV infec-tion, but they have also changed our basic understandingof the physiology of HIV replication in vivo. When infectedpatients are started on highly active antiretroviral therapy(HAART), the fall in viremia is initially exponential, with ahalf-life of 1 to 1.5 days [1–3]. Although there is a modestvariation in the rate between individuals, the range of vari-ation is small [3,4]. This initial rate is dependant on thepotency of the regimen, with less potent regimens resultingin slower clearance rates [4]. Because drugs that inhibit theviral reverse transcriptase or protease block new cells frombecoming infected, the rapid decline in viremia when drugtherapy is initiated strongly implies that the replication-active cells have a short half-life. Furthermore, the rate ofviral-load decline slows after the initial first week becauseof mechanisms that are not clearly delineated. The range ofrates between individuals for this second phase is muchmore variable compared to the range during the first phase[3]. One potential explanation for this second phasedecline is that there is heterogeneity in the pool of infectedcells with most of the short-lived cells plus a small pool ofchronically infected cells that inherently die more slowly[5•]. Other possibilities, which are not mutually exclusive,have also been suggested, including an incomplete drugpotency allowing low levels of persistent replication thatsustain a pool of replication-active cells, a decline inimmune clearance of replication-active cells because of adecrease in antigen-stimulated effector-cell activation, aslower decline of cells with unintegrated viral DNA thatcan become activated to produce replication-active cells,and a potentially slow release of free virions from trapped

The control mechanisms that maintain a steady state viral load during chronic HIV-1 infection are critical to understanding the pathophysiology of HIV disease. The conceptual features of the two alternative models of viral control, referred to in this article as target cell limitation and immune control, are compared to the data regarding the viral and cellular dynamics of HIV-1 infection and the pattern of changes induced by effective antiretroviral drug therapy. The available data support the model that an antigen-driven immune response is the primary mechanism that limits viral growth in vivo.

Viral and Cellular Dynamics in HIV Disease • Bucy 41

tissue reservoirs [6,7•,8,9]. However, there is no consensusconcerning the dominant mechanism.

Coincident with the rapid fall in plasma viremia withHAART, there is a rise in the number of circulating CD4 Tcells that also occurs in distinct phases. Although the initialrapid increase was originally attributed to cessation of HIV-specific cell death after blockade of de-novo infection, it isclear that the first phase is simply the result of redistribu-tion of lymphocytes into the blood from tissue sites inwhich they had previously been relatively sequestered.Several lines of evidence support this concept of redistri-bution. The increase is largely caused by changes in thenumber of total lymphocytes, rather than changes specifi-cally in CD4 T cells [10]. In other physiologic circum-stances, such as chemotherapy-mediated ablation ofmature T cells, the net generation of new CD4 T cells inadults is an inherently slower process [11]. A decrease inthe inflammatory state of lymphoid tissue associated withactive viral replication, particularly the decreased expres-sion of adhesion molecules that mediate lymphocytetrafficking, is consistent with lymphocyte redistribution[12]. The explanation for the net rise in blood lymphocytesimmediately after starting HAART does not imply that T-cell turnover is not increased during active viral replication.The concept of lymphocyte redistribution implies thatactive HIV replication drives immune activation thatremains in steady state with viral antigen during chronicdisease. After the initiation of therapy, the viral loaddecreases and, consequently, the immune stimulation sub-sides, allowing T cells that were sequestered in lymphoidtissues to migrate into the blood stream. Over the nextseveral years, a slower rise in CD4 T cells occurs, which islikely caused by a combination of new T cells from thymicproduction and expansion of existing peripheral T cells.The numbers of circulating T cells also change dramaticallywhen patients receiving HAART undergo a therapy inter-ruption, but the CD4 count returns to the baseline levelafter reinitiation of therapy [13]. These observationssuggest that active viral replication induces a relativesequestration of lymphocytes in tissue sites, and short-term rapid changes in the CD4 count with initiation orcessation of therapy should not be interpreted as changesin the total body number of T cells.

Several studies have demonstrated that the amount ofplasma viral RNA (vRNA) is directly proportional to thenumber of vRNA+ cells identified in lymphoid tissue [14–16]. This concept has been formalized in several mathe-matical models, which posit that plasma viremia and thefrequency of activated T cells are the key variables thatdetermine the rate of new cellular infection [7•,17,18].Furthermore, the clearance of virions in the blood is veryquick, with an estimated half-life of approximately 90minutes in steady-state conditions as determined by thekinetics of rebound after plasma pheresis [19]. Clearanceof free virions is most likely mediated by the formation ofimmune complexes between virions and host antibodies,

which are removed by FcR+ phagocytes of the reticuloen-dothelial system primarily in the liver and spleen, similarto other immune complexes. Because it is difficult to con-ceive how the induction of HAART could induce changesin the clearance rate of free virions or the production rateof virions from infected cells, it is widely accepted that thisfall represents rapid death of replication-active cells duringthe steady state of chronic infection.

Plasma Viremia is Directly Related to the Net Loss of CD4 T Cells and Disease ProgressionAnother strong contributor to the standard understanding ofHIV-1 infection is the relationship of viral load to diseaseprogression. Not only do drugs that block viral replicationresult in a rapid fall in plasma vRNA and significant clinicalimprovement, but the specific level of plasma vRNA shortlyafter infection is highly correlated with the rate of diseaseprogression [20]. Many subsequent analyses have shown thatthe amount of vRNA in plasma remains remarkably constantover many years during chronic infection, despite the highdaily turnover of individual infected cells. In a large longitu-dinal study of HIV disease progression in the completeabsence of antiretroviral therapy, the average rate of changeof viral load was only 0.03 log10 cells/mL per year before anytherapeutic interventions, which was not statistically signifi-cant from no rise in the 218 patients analyzed [21•]. How-ever, there was a significant decline in CD4 count ofapproximately 110 cells/mm3 per year within this samegroup. When subjects with different rates of disease progres-sion (time to AIDS diagnosis) were stratified, not only didsubjects with rapid disease progression have higher initialviral loads, but the rate of rise with time was also faster.When these subjects were analyzed during the 3 years preced-ing the diagnosis of AIDS, they had similar viral loads(median of approximately 200,000 cells/mL) and rates ofincrease of viral load (approximately 0.21 log10 cells/mL peryear or 60% per year), independent of how long they hadbeen infected [21•]. Therefore, the overall situation is therapid turnover of individual infected cells at a steady-statelevel that results in the progressive loss of CD4 T cells overseveral years.

Although it is clear that viremia correlates with thenumber of replication-active cells that are rapidly killed, itis unclear that the death of directly infected CD4 T cells isthe primary mechanism for the net loss of CD4 T cells dur-ing disease progression. The absolute frequency of replica-tion-active cells is quite low and seems insufficient toaccount for the net loss of CD4 T cells. For example, a viralload of 30,000 cells/mL was associated with approximately60 vRNA+ cells per million lymph node cells [16]. Assum-ing that the half-life of these infected cells is 1 day, correct-ing for the frequency of CD4 T cells per lymph node cell inthis data set (17%), and assuming that there is no netgeneration of new CD4 T cells from thymic or peripheralsources, it would take approximately 12 years to result in a

42 The Science of HIV Medicine

depletion of 80% of the CD4 T-cell pool (1000 cells/µL to200 cells/µL). Because there is most likely some net pro-duction of CD4 T cells from the thymus and mean diseaseprogression is somewhat faster than 12 years, the dataimply that some form of bystander mechanism in whichthe presence of HIV causes death of uninfected CD4 T cellsmay be operative. Variations in the viral envelope that aredirectly associated with the extent of viral cytopathicity,but not as directly related to the growth rate or number ofinfected cells in vivo, may contribute to this bystandermechanism of CD4 death. Perhaps the variation betweenindividuals in the rate of CD4 T-cell loss beyond what isaccounted for by viral load is caused by varying efficiencyof this indirect mechanism of CD4 T-cell death. Therefore,direct and indirect mechanisms of CD4 T-cell death com-bine to result in net depletion of CD4 T cells and operate ata rate proportional to the number of replication-activecells present at steady state.

Latent Infection and the Reservoir in Patients Receiving Highly Active Antiretroviral TherapyAlthough HAART regimens can routinely suppress viral rep-lication below the limits of detection, it is clear that theinfection is not eradicated. One of the major obstacles toeradication is the presence of a small number of latentlyinfected CD4 T cells. Patients that are started on HAART veryearly during the acute infection syndrome or after manyyears of sustained high-level viral replication have similarnumbers of latently infected cells and similar total amountsof total proviral DNA [22–24]. These data indicate that thelatent pool develops very quickly during the early phase ofinfection, but it accumulates much more slowly throughoutchronic infection, despite multiple rounds of de-novo infec-tion. Furthermore, the latent pool is cleared very slowlywhen potent antiretroviral drugs substantially suppress viralreplication [25,26•,27,28]. Therefore, there are significantconstraints on potential conceptual models of viral replica-tion to account for the highly dynamic nature of chronicinfection and unusual generation and clearance of this poolof latently infected cells.

The mechanisms operative after prolonged effectiveHAART, in which many subjects have undetectable virus inplasma, is also an area of intense study but not completeconsensus. The source of this persistent infectious viruslikely involves incomplete potency (at least during intermit-tent episodes) of the drugs, which allows some viral replica-tion and the presence of resting latently infected cells thatpersist for long periods of time [9]. Several groups havefound extremely rare vRNA+ cells (< one per 106 lympho-cytes) in lymphoid tissue and blood [16,23,26•,28].Furthermore, circular unintegrated viral DNA has beendetected in effectively treated patients, indicating persistentde-novo infection [29]. Based on the relationship of plasmaviral load to the frequency of infected cells, there could be asmany as 105 replication-active cells in lymphoid tissue

throughout the body and the virus would be cleared quicklyenough so that a steady state above 50 cells/mL would notbe achieved [16]. The existence of these rare vRNA+ cells issufficient to ignite renewed high-level replication if HAARTis discontinued, but there is no consensus concerning themechanism that accounts for the persistence of these cells atroughly stable frequencies.

Immune Response to HIV-specific AntigensAlthough many investigators initially concluded that anormal host immune response was incapable of control-ling HIV infection, multiple lines of evidence indicate thatan active immune response is primarily responsible forcontrolling viral replication in vivo [30]. The developmentof active cytotoxic T lymphocyte (CTL) is temporallyrelated to the resolution of the acute retroviral syndrome.HIV-specific CTL activity is detectable during chronic infec-tion in untreated subjects using several different methodol-ogies, and antigen-specific CD8 T cells that produceinterferon-γ can be detected by Elispot assay, intracellularcytokine staining, or binding of HIV peptide/major histo-compatibility complex tetramers. Viral persistence and dis-ease progression may be associated with the selection ofspecific CTL escape mutants. Some patients who beganHAART very early in the disease maintained very low viralload associated with in-vitro evidence of enhanced CD4and CD8 immune response with discontinuing HAART[31]. No viral-specific or host-genetic factors have beenidentified that distinguish these individuals from the typi-cal chronically infected person, suggesting that effectiveimmune responses may maintain the low levels of viralreplication. Therefore, cellular immune responses thatoccur very quickly could conceivably eliminate infection,and CTL that are consistently associated with chronic infec-tion may exert ongoing inhibition of viral growth.

Further support for the critical role of effective cellularimmunity in controlling retrovirus infection comes fromstudies of the simian immunodeficiency virus (SIV) modelin rhesus macaques. Strong CTL responses are associatedwith the control of initial viremia in SIV infection, such asin human infection with HIV [32–34]. Infection with a liveattenuated SIV strain induces a vigorous immune responseand protection from subsequent infection with a virulentstrain [35,36]. Furthermore, vaccination of rhesusmacaques with a glycoprotein-120 subunit preparationthat primarily stimulates CD4 T cells resulted in a lowerviral load set point after infection compared to nonimmu-nized controls [37]. Two groups have independentlyshown that depletion of CD8 T cells with a cytotoxic anti-CD8 monoclonal antibody in SIV-infected rhesusmacaques caused rapid increases in plasma viral load[38••,39••]. Even in SIV-infected animals with undetect-able plasma HIV RNA, depletion of CD8 T cells (withoutan appreciable change in the number of target CD4 T cells)results in a 2- to 4-log–fold rise in viral load within several

Viral and Cellular Dynamics in HIV Disease • Bucy 43

days. Therefore, CD8 T cells (presumably continuouslyactivated by viral antigen) are required to maintain thesteady-state level of viral replication.

Conceptual Models of Viral ReplicationAlthough many parameters of viral dynamics are wellestablished, there is no consensus on the mechanisms thatcontrol the steady-state level of replication characteristic ofchronic HIV infection. There are two basic ideas of howthis control is mediated, which are referred to as the targetcell-limited and the immune-control models. The centralfeature of the target cell-limited model is that the availabil-ity of activated CD4 T cells (or susceptible macrophages) isthe critical host factor that limits replication at the set-point level. The alternative view is that the immuneresponse is constantly active and limits viral replication atthe steady state. Both of these models can be formulated inmathematical terms, which take the form of predator-preymodels [40]. In target cell-limited models, the virus preyson infectable CD4 T cells, whereas infected cells are theprey for an active immune clearance predator in immune-control models. Although both types of models can cometo an equilibrium level of infected cells and viral load, thespecific mechanisms are quite different.

Target cell-limited modelThe target cell-limited model was originally proposed as amechanism that could account for the limitation of viralgrowth during primary infection, without the need to invokethe participation of an active immune response [41]. Theprimary evidence for limitation of viral replication by theavailable target cells is that immune activation by interleukin(IL)-2 or vaccination leads to transient elevation in the viralload [42–44]. This concept is also supported by the observa-tion that HIV infection of CD4 T cells in vitro is greatlyamplified by stimulation with strong mitogens and IL-2.Upregulation of the coreceptors for viral entry and integra-tion of proviral DNA appear to be enhanced by T-cell activa-tion, but which step is rate limiting during in-vivo growthhas not been conclusively determined.

Although there is likely some role for target cell limita-tion as one factor in determining viral replication, there aremultiple lines of reasoning that argue that this factor is notthe primary mechanism that controls the steady-state levelof viral replication during chronic infection. The density ofCD4 T cells in lymphoid tissue (the site of viral replica-tion) does not vary by the same wide degree as the differ-ent set-point levels of viremia during chronic infection. Inaddition, the absolute number of productively infected Tcells in lymph nodes at steady-state infection is severalhundred fold less than the number of activated CD4 Tcells, which was measured by standard activation markers,such as expression of CD25 (IL-2R) or HLA-DR. Therelative density of CD4 T cells in lymphoid tissue does notcorrelate with the kinetics of viral replication during acute

disease or at the end stage of disease. In addition, a kineticanalysis of viral load data during the acute infection syn-drome is not compatible with a pure target cell-limitedmodel [45]. Furthermore, the density of CD4 T cells is low-est during late-stage disease when viral load tends to behighest. This concept does not directly account for thelarge body of data that indicate a critical role for an activeimmune response in controlling infection. Perhaps thestrongest single result indicating a central role for immuneresponses is that deletion CD8 T cells from SIV-infectedrhesus macaques results in a rapid increase in viral loadwithout significant changes in the number of CD4 T cells[38••,39••]. Therefore, there may be a minor contributionof the availability of target cells to the equilibrium level ofviral replication, but there is no substantial evidence thatthe rate of viral replication is primarily limited by targetcell availability during steady-state chronic infection.

Immune-control modelThe alternative concept that an immune response is primarilyresponsible for controlling viral load has many attractivefeatures, but it also presents some conceptual problems. A keyidea required to understand the implications of an immune-control model is to distinguish immune responsiveness (ratioof response magnitude to stimulating antigen dose) from themagnitude of the immune response at a particular instant intime. The fundamental concept of an immune-control modelthat comes to dynamic equilibrium is that the immuneresponse is controlled in magnitude by the production ofviral antigen from replication-active cells. The mathematicaldescription of this idea leads to some nonintuitive conclu-sions. For instance, at equilibrium, the level of viremia isrelated to the immune responsiveness, but the magnitude ofthe response is equivalent among individuals [7•,46•]. Indi-viduals with high responsiveness (significant response at lowantigen level) will come to equilibrium at a low viral loadlevel, whereas individuals with a low responsiveness willcome to equilibrium at high viral load level. The modesttrend for an inverse relationship of indices of CTL responsemagnitude (HIV-specific tetramer-positive cells in blood) toviral load set point can be accounted for by the effects ofunequal distribution of activated effector cells betweenlymphoid tissue and blood [47]. In individuals with higherviral loads, the level of general immune activation is higherand more of the antigen-specific cells may be localized in tis-sue at the site of antigenic stimulation. This unequal distribu-tion superimposed on a basically equivalent magnitude ofimmune response is consistent with the observed inverse rela-tionship (ie, a higher precursor frequency in the blood forindividuals with lower viral load).

The hypothesis that an active antigen-driven immuneclearance mechanism is the primary rate-controlling step forviral replication at equilibrium also can explain the relativelyuniform rapid rate of decline of viral load when patients atequilibrium are started on HAART [7•]. Because equilibriumis achieved when replication-active cells are cleared as

44 The Science of HIV Medicine

quickly as they are produced, when viral infectivity issuddenly dramatically reduced, the initial rate of clearance ofinfected cells and plasma virus is predicted to be uniform.Because there is a time delay of several days between antigen-induced activation of immune-effector cells and decay ofthese effectors back to resting T cells, the rate of clearance ofinfected cells is initially rapid, but it gradually falls as theimmune response subsides because of the decreasingnumber of infected cells producing viral antigen. The declinein various indices of CTL response with HAART has beendocumented by several groups [48,49].

The immune-control model also assumes that the lifespan of infected cells is controlled primarily by the immuneresponse, not controlled by a direct cytopathic effect.Although it has been widely assumed that the rapid and rela-tively uniform rate of viral load decline implies a rapid invivo direct cytopathic effect, an antigen-driven immuneclearance model also accounts for this result without invok-ing rapid direct cytopathicity. This concept does not implythat the virus is not cytopathic, but it merely implies that therate of direct viral cytopathic effect is significantly slowerthan the rate of immune clearance at equilibrium. Althougha direct cytopathic effect of HIV exists in vitro, the rate of thisprocess is inconsistent with a uniform half-life of 1 to 1.5days [50,51]. Furthermore, this model leads to a naturalexplanation of the rapid generation of latent infection earlyin disease because, before activation of an effective immuneresponse, replication-active cells would have a longer lifetimeand a higher fraction of the cells would revert to a restingstate before cell death. Therefore, the pool of productivelyinfected CD4 T cells that survive long enough to silence HIVtranscription (long-lived latent infection) develops quicklyin the first several weeks of infection. Once the effectorimmune response initiates, the life span of replication-activecells drastically shortened, thus few additional latentlyinfected cells accumulate. If rapid replication with the atten-dant high level of antigen-driven immune response isblocked by initiation of HAART, a new dynamic steady statedevelops [7•]. The rare latently infected cells can occasionallyactivate viral transcription but, unlike the circumstances inthe absence of HAART, there is insufficient antigen derivedfrom these extremely rare cells to activate effector cells tomediate rapid clearance of these replication-active cells.Therefore, most of these cells can return to a resting state,thus the net frequency of cells with functional provirus is sta-ble. This scenario of viral persistence does not require postu-lation of a discrete lineage of cells in which HIV infection isnot blocked by HAART or a sequestered anatomic site tomaintain the reservoir of infectious HIV in subjects main-tained on effective antiretroviral therapy [7•,16,26•].

Perhaps the greatest conceptual problem for an activeimmune-control model is the nonintuitive character of theimplication that immune responsiveness controls the equi-librium level of viremia but, at equilibrium, the instanta-neous magnitude of the response is equivalent among allindividuals at various absolute viral load levels. However, the

concept that the immune response is balanced by the inten-sity of antigen-driven immune activation is the fundamentalfeature of models that allow the immune response to controlviral load at a steady state of viral replication. This principledoes not directly determine the precise mechanism by whichthe antigen-driven immune response limits the overall levelof viral replication. The most straightforward mechanism isimmune-mediated lysis of infected cells, thus the lifetime ofthe antigen-producing cells is shortened. Therefore, cytolyticactivity could account for the rapid and relatively uniformrate of viral decline with the initiation of HAART in naïvepatients, the early development of latently infected cellsbefore the initiation of an immune response, and the relativeslowness of in-vitro direct viral cytopathicity. Alternatively,the antigen-driven production of cytokines inhibits viralinfectivity, rather than the survival of replication-active cells.Both of these immune mechanisms may be simultaneouslyinvolved, but the cytokine mechanism fails to account for therapid development of latent infection and slow accumula-tion of these cells after the induction of an effective immuneresponse. The nonintuitive features of antigen-drivenimmune response as the primary control of viral replicationremain if cytokine production is substituted for lytic activityas the dominant antigen-driven effector mechanism. It ispossible to contend that the immune responses is failingbecause the virus is not completely eliminated and stillmaintain that the immune response is responsible for viralclearance at steady state. This idea is the same as the conceptthat the heart is failing in congestive heart failure and leftventricular output still maintains blood pressure.

The distinction between the target cell-limited andimmune-control models of HIV replication is not merely oftheoretical interest, but it has a substantial practical impact. Iftarget cell limitation is the primary control mechanism, thereis little hope for effective therapeutic intervention beyondantiretroviral drugs. If the efficiency of viral antigen-specificimmune responses is the primary control of steady-state viralreplication, then therapeutic interventions to increase the effi-ciency of the immune response should have an impact onviral load and disease progression. Potential approachesinclude therapeutic immunization with HIV vaccines andmodulation of the rate of viral rebound and immune statusduring supervised therapy interruption. The substantiation ofthe concept of immune control of viral replication leads notonly to the prospect for new therapeutic interventions, but itprovides a strong rationale for an effective clinical trial endpoint to assess these interventions (eg, a decreased steady-state viral load after antiretroviral drug interruption). Thisresult would be meaningful without the conceptual under-pinning of an immune-control model, but it would makelittle sense interpreted in the context of a target cell-limitedmodel of HIV replication. If a new steady-state level of replica-tion below a threshold associated with disease progression(eg, 5000 cells/mL) can be achieved, then an immune inter-vention could replace continual antiretroviral drug therapy asthe optimal treatment for chronic HIV infection.

Viral and Cellular Dynamics in HIV Disease • Bucy 45

ConclusionsThe consensus understanding of the basic pathophysiology ofHIV infection has undergone several substantial changes in thealmost two decades since the first isolation of HIV-1. Theinitial conception of a long dormant phase of infection beforesymptomatic disease has given way to the view that thisclinically latent phase of disease is actually a highly dynamicactive infection with rapid turnover of infected cells. Evidenceis accumulating to support the hypothesis that an activeimmune response is primarily responsible for maintaining thesteady-state level of viral replication throughout this longasymptomatic phase of the infection. Variable levels ofimmune response efficiency may determine the variablesteady state level of viral replication, which is reflected inplasma viral load. This conceptual paradigm suggests thattherapeutic intervention designed to increase the efficiency ofthe antiviral immune response is a feasible goal. Induction ofefficient immune control may be a superior strategy for long-term control compared to sole reliance on tight control of viralreplication by combination antiretroviral drugs with the atten-dant risks of drug toxicity and viral resistance development.

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