Cytotoxic T Lymphocyte Responses to Human Immunodeficiency Virus: Control and Escape

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Cytotoxic T Lymphocyte Responses to Human Immunodeficiency Virus: Control and Escape ANDREW K. SEWELL, DAVID A. PRICE, ANNETTE OXENIUS, ANTHONY D. KELLEHER, RODNEY E. PHILLIPS The Nuffield Department of Medicine, John Radcliffe Hospital, Oxford, UK Key Words. HIV · Cytotoxic T lymphocytes (CTLs) · Immune escape · Epitope · Viral persistence

A BSTRACT Effective preventive and therapeutic intervention in individuals exposed to or infected with human immunodeficiency virus (HIV) depends, in part, on a clear understanding of the interactions between the virus and those elements of the host immune response which control viral replication. Recent advances have provided compelling

INTRODUCTION CD8+ cytotoxic T lymphocytes (CTLs) recognize viral proteins in the form of short peptides comprising 8-11 amino acids presented in association with major histocompatibility (MHC) class I molecules on the surface of infected cells [1] (Fig. 1). These viral peptides are derived from nascent proteins which are cleaved by cytosolic proteases and diverted into the MHC class I antigen processing pathway throughout the process of virion synthesis [2] (Figs. 1, 2). Recognition of viral peptide-MHC class I complexes on the surface of infected cells is a function of the T-cell receptor (TCR), which, in conjunction with the CD8 coreceptor, mediates the translation of antigen engagement events into functional activation of the CTLs through a complex signaling cascade [3-5]. Multiple effector mechanisms are utilized by CTLs to control viral replication [6-7] (Fig. 3). Direct lysis of infected host cells is caused by the release of perforin from lytic granules in a

evidence that cytotoxic T lymphocytes (CTLs) constitute an essential component of protective antiretroviral immunity. Here, we review briefly the significance of this work in the context of previous studies, and outline the mechanisms through which HIV evades CTL activity. Stem Cells 2000;18:230-244

CTL Immune surveillance by cytotoxic T lymphocytes

T-cell receptor (TCR)

Transport to cell surface

HIV-infected cell

ENDOPLASMIC RETICULUM

MHC class I binding

Proteolysis

MHC I TAP

NUCLEUS PROTEASOME

Integrated proviral DNA

Figure 1. The MHC class I antigen presentation pathway. Viral proteins within infected cells are degraded into peptides and transported into the endoplasmic reticulum by the transporter associated with antigen processing. Some of these peptides can bind to MHC class I molecules and are transported to the cell surface for immune surveillance by the TCRs of cytotoxic T lymphocytes.

Viral protein

Correspondence: Andrew Sewell, Ph.D., The Nuffield Department of Medicine, Level 7, John Radcliffe Hospital, Oxford, OX3 9DU, UK. Telephone: 44-1865-228-927; Fax 44-1865-220-993; e-mail: [email protected] Received May 24, 2000; accepted for publication May 25, 2000. ©AlphaMed Press 1066-5099/2000/$5.00/0

STEM CELLS 2000;18:230-244

www.StemCells.com

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HIV-1 gp120 binding to CD4

CD4

Chemokine receptor Uncoating of viral core

Internalization of virus NUCLEUS NUCLEUS

Reverse transcription

Budding of mature infectious virions

Viral genomic RNA

CD4+ T CELL

Integrated Provinal DNA Proviral DNA

Unintegrated proviral DNA

NUCLEUS Integrated Proviral DNA

Processing to mature viral proteins

NUCLEUS

Activation of virus production (TCR stimulus, cytokines)

Synthesis of viral protein precursors

Viral Viral peptide-MHC I mRNAs

PRODUCTIVELY INFECTED CELL (Viral peptides presented to CTL)

Integrated Proviral DNA

Unintegrated proviral DNA

LATENTLY INFECTED CELL (No viral peptides presented to CTL)

Figure 2. The HIV-1 life cycle. Binding of the envelope proteins (gp120/gp41) on the surface of the HIV-1 virion to both CD4 and a chemokine coreceptor facilitates viral entry. Once internalized, the viral core is uncoated and the RNA genome is reverse-transcribed by HIV-1 RT to a DNA copy. This preintegration stage can last for several days [105]. The preintegrated provirus can insert itself into the host cell genome where it can either remain dormant (latently infected cell) or replicate (productively infected cell). CTLs are only able to recognize productively infected cells. The rapid replication rates of HIV-1 [175] combine with its error-prone reverse transcriptase [176] to produce a swarm of related but genetically distinct viruses within an infected individual [177]. Such viral quasispecies are subject to natural selection within the host environment and exhibit dynamics consistent with adaptive evolution [80].

calcium-dependent process. Integration of perforin, a 70kD glycoprotein resembling the membrane attack complex of the complement system, within the plasma membrane results in the formation of pores with an internal diameter of up to 16 nm and target cell death through osmotic lysis. This appears to be the critical effector mechanism in the control of noncytopathic viruses such as lymphocytic choriomeningitis virus (LCMV) in the mouse [8]. Proteases cosecreted with perforin by lytic granule exocytosis enter the target cell and induce apoptosis. Granzyme B, which shares with the interleukin-1βconverting enzyme family cysteine proteases the unusual property of substrate cleavage after aspartate residues, appears to be the major mediator of target cell DNA fragmentation in this perforin-dependent pathway of cytotoxicity [9]. Calcium-independent cytotoxicity is mediated through specific ligands, such as Fas-Ligand (FasL), which trigger

apoptosis following the engagement of receptors on the target cell surface. Fas (CD95) is a member of the tumor necrosis factor receptor superfamily; crosslinking of Fas by FasL, which is expressed on activated CTLs, leads to apoptotic target cell death [10-12]. In addition to cytotoxic activity, activated CTLs release soluble factors, including interferon-γ (IFN-γ), tumor necrosis factor-α, and chemokines which have diverse antiviral and immunological effects [13-17]. These cytokines appear to be essential for the control of cytopathic viruses [18, 19]. Non-lytic control of HIV-1 infection by CTLs involves CC chemokine-mediated blockade of virus entry through ligand competition with the V3 domain of the gp120 envelope glycoprotein for coreceptor binding sites [20, 21], and suppression of replication in CD4+ cells at the level of transcription by a poorly characterized soluble agent called CD8+ T-cell antiviral factor (CAF) [22, 23].

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KEY Apoptosis-inducing molecules (e.g. Fas ligand) Apoptosis-inducing receptors (e.g. Fas) Granzymes

Activation signal HIV-specific

CTL

Figure 3. CTL recognition. Recognition of viral peptideMHC complexes on the infected cell surface leads to an activation signal which in turn initiates the effector functions of the CTLs. CTLs kill the infected target cell through both lytic and apoptotic pathways. They also release soluble factors, including proinflammatory cytokines such as IFN-γ and CC-chemokines.

peptideMHC

TCR

Perforin

Release of soluble cytokines and chemokines

Release of lytic granules

HIV-infected target cell

DNA fragmentation CONTROL OF HIV-1 INFECTION BY CTLS With the exception of some enteroviruses, most viral infections are controlled even in humans with genetic deficiencies in antibody production [24, 25]. In contrast, the frequency and severity of viral infections are enhanced in humans exhibiting impaired T-cell responses [25]. However, since the initial description of virus-specific CTLs in HIV-1-infected individuals, the significance of these effector cells in vivo has remained uncertain [26, 27]. In this section, we review the evidence that CTLs are important mediators of protective immunity against HIV infection. The virus-specific humoral response is not considered; this aspect of adaptive immunity to HIV has recently been reviewed in detail elsewhere [28]. Animal Models of Viral Infection Much of the evidence supporting the proposal that protective antiviral immunity in general is mediated primarily by CTLs has necessarily originated from studies of animal models of infection [29]. Multiple experimental approaches, including the adoptive transfer of virus-specific CTLs and vaccination strategies designed to induce specific cellular immune reactivity in the absence of humoral responses, have

confirmed the importance of these effector cells in antiviral immunity (Table 1). These observations provide a precedent for the human studies described below. The Simian Immunodeficiency Virus (SIV) Model of AIDS SIV infection of rhesus macaques is currently the favored animal model for the study of AIDS pathogenesis and candidate vaccines [30]. Attempts to correlate postvaccination CTL levels with outcome following virus challenge have provided conflicting results. In one study, macaques were vaccinated with an attenuated (nef-defective) SIV prior to challenge with the pathogenic J5 strain.

Apoptosis

Table 1. Protective antiviral immunity is mediated by CTL. Animal

Virus

References

Mouse

Influenza A

[150-155]

Mouse

Cas murine leukemia virus

[156, 157]

Mouse

Hepatitis virus strain JHM

[158]

Mouse

Herpes simplex virus type 1

[159]

Mouse

Japanese encephalitis virus

Mouse

Lymphocytic choriomeningitis virus

Mouse

Moloney murine sarcoma virus

Mouse

Murine cytomegalovirus

Mouse

Rabies virus

[167]

Mouse

Sendai virus

[168]

Mouse

Theiler’s murine encephalomyelitis virus

[169]

Sheep

Bluetongue virus

[170]

[160] [161-163] [164] [165, 166]

Animal models in which the role of CTL in antiviral immunity has been demonstrated.

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233

Human Studies Evidence for a protective role of CTLs in human viral infections is largely circumstantial. However, data analogous to that from the adoptive transfer experiments described above have emerged from human studies involving therapeutic lymphocyte infusions following bone marrow transplantation. For example, suppression of cellular immunity in individuals with persistent Epstein-Barr virus (EBV) infection is associated with lymphoproliferation and the development of B-cell lymphomas [40]. Transfer of enriched T-lymphocyte populations or virus-specific CTLs prevented or ameliorated post-bone marrow transplant EBV-associated lymphoproliferative disease [41-43]. Similarly, protection 1,250 from the complications of 1,000

Cells (x106/l plasma)

Figure 4. HIV disease progression. The initial rise in plasma virus load during primary infection is followed by an increase in CD8+ CTLs. Much of this increase in CTLs is due to an expansion of HIV-specific CTLs, which then bring the viral load under control. The initial drop in CD4+ lymphocytes (T helpers), due to the combined effects of viral infection and antiviral CTLs, recovers as the disease enters the lengthy asymptomatic period. Progression to AIDS sees a fall in both CD4+ and CD8+ lymphocytes with an increase in virus load.

human cytomegalovirus (CMV) reactivation was conferred by the infusion of CMV-specific CTLs into bone marrow recipients [44, 45]. Human studies of HIV-specific CTLs are complicated by ethical and technical difficulties. However, there is now substantial evidence that CTLs are central determinants of outcome in HIV infection. Temporal Variations in CTL Activity with Disease Course It is established that HIV-1-specific CTLs appear early in the course of infection and are temporally associated with the clearance of culturable virus from blood [46, 47]. In addition, such CTLs are commonly found in high numbers during the asymptomatic phase of infection [48-52] and decline with progression to AIDS [53-57] (Fig. 4). Transverse Studies of CTL Activity and HIV Plasma Virus Load Direct ex vivo quantification of antigen-specific CD8+ lymphocyte frequencies using specific peptide-MHC class I tetrameric complexes in a cross-sectional study of donors in the quasi-equilibrium phase of HIV-1 infection has demonstrated an inverse correlation with plasma virus RNA load [50, 57]. Assuming that HLA A2-restricted CTLs specific for the SLYNTVATL epitope in HIV-1 p17 Gag are broadly representative of the host virus-specific cytolytic T-cell response, these data provide experimental confirmation of a relationship predicted from mathematical models based on the assumption that CTLs are the key antiviral effectors in HIV infection [58]. Additional data from other studies utilizing different methods of CTL quantification tend to support these results [59, 60]. However, it is worth noting that a similar inverse relationship with 107

Asymptomatic phase

AIDS 106

CD8+ lymphocytes

105

750

CD4+ lymphocytes 104

500

Plasma virus loads

250

103

Primary infection 6

12

Time (weeks)

2

4

6

8

Time (years)

10

12

Virus RNA load (copies/ml plasma)

Although six of seven monkeys were not protected from infection, prechallenge Nef-specific CTL precursor frequencies were inversely correlated with postinfection virus loads; the uninfected animal had the highest levels of CTL precursors prior to challenge [31]. However, other studies in which SIV-specific CTLs were induced by immunization prior to challenge with pathogenic virus have failed to demonstrate protection [32, 33]. Despite these conflicting data, recent convincing evidence supporting a role for CTLs has come from CD8 depletion experiments in this model [34-36]. Viral replication during primary infection was shown to be poorly controlled in monkeys depleted of CD8+ lymphocytes. Similarly, dramatic rises in plasma viremia were demonstrated following depletion of this lymphocyte subset in established infection. These studies are supported by observations that the emergence of SIV-specific CTLs in primary infection correlate with suppression of viremia [37, 38], and that CTL activity is inversely correlated with virus load and disease progression [39].

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plasma virus load could arise from an HIV-induced impairment of CTLs; this may result, for example, from HIV-1 infection of CD4+ T helper cells. Further, the direction of correlation between virus load and HIV-specific CTL frequency may be influenced by multiple variables and therefore inconstant. In Vitro Studies of Human HIV-Specific CTLs Experiments with HIV-specific CTLs have shown that antigen-sensitized target cell lysis is efficient and sufficiently rapid to kill HIV-infected lymphocytes before maximal virus production is attained [23, 61-64]. Further, viral suppression through non-lytic mechanisms has been demonstrated in vitro [22, 23, 65]. This latter activity correlates with the clinical staging of disease, although the identity of the putative virostatic agent, CAF, and its relationship to antigen-specific recognition remain ill-defined [22, 66, 67]. HLA Class I Associations with Disease Progression The rate of disease progression in HIV-1 seropositive individuals has been linked with the HLA class I genotype [68-72]. These relationships are complex, but certain class I molecules, such as HLA B27 and HLA B57, are consistently linked with slow progression while others, such as HLA B35 and the extended haplotype HLA A1/B8/DR3, are linked with rapid progression. Despite associations in some cases with gene variants encoding for transporters associated with antigen processing, these observations suggest the involvement of HLA class I-restricted systems in determining the course of HIV-1 infection. This may relate to qualitative differences in the CTL response between individuals and the relative biological constraints on viral antigens presented by these HLA molecules.

Protection Against Disease Transmission HIV-specific CTLs have been documented in HIVexposed but uninfected infants [73], the uninfected heterosexual partners of HIV seropositive individuals [74, 75], and in repeatedly exposed but persistently seronegative female prostitutes in West Africa [76]. These studies suggest that CTLs may have the capacity to prevent transmission of HIV-1. Viral Evolution and Immune Evasion Perhaps the strongest evidence that CTLs are important in the control of HIV-1 infection in vivo has come from combined longitudinal studies of viral evolution and cytolytic activity within individual seropositive individuals. If CTLs exert a significant antiretroviral force in vivo, then “resistant” viruses should possess a selection advantage in evolutionary terms. These issues are discussed below. CTL ESCAPE IN HIV-1 INFECTION Multiple mechanisms of immune evasion have been described for HIV-1. In broad terms, these strategies can be considered as mutational or constitutive. This approach is adopted below with reference to analogous escape mechanisms in other viruses. Mutational Escape Genetically unstable RNA viruses possess the ability to interfere with antigen presentation and recognition by a number of mechanisms. Viral mutation can lead to epitope deletion, failure of antigen processing, loss of MHC class I binding, and impaired recognition by the TCR (Fig. 5). We have reviewed these mechanisms extensively elsewhere [77].

CTL 3

Figure 5. Mutational escape from CTL by HIV-1. The propensity of HIV-1 for variation allows it to avoid CTL recognition by a number of mechanisms. CTL selective pressure can select for epitope deletion [86, 89]. 1) Changes in the amino acid residues which flank an epitope can lead to altered proteolysis and epitope loss. 2) Mutations which change MHC “anchor” residues can lead to reduced binding to MHC class I molecules [55, 84, 85, 178] and loss of cell surface presentation. 3) Variation in the peptide-MHC class I surface recognized by the TCR can lead to escape from CTL recognition by a number of mechanisms. These include TCR antagonism [5, 179-181], CTL anergy [77], distortion of the CTL repertoire [77], and CTL decoy activity [77].

Changes in TCR contact residues can lead to loss of recognition or altered recognition by the TCR.

Proteolysis ENDOPLASMIC RETICULUM

MHC class I binding

MHC I

2

Changes in MHC-anchor residues can lead to loss of MHC-binding.

1 TAP

Changes in epitope amino acid residues or residues “flanking” the epitope can lead to altered proteolysis and loss of the epitope.

Viral protein

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between rapid and slow progression could be conferred by a single MHC molecule [79].

Table Table 2.2. Animal Animal models models of of mutational mutational escape escape from from CTLs CTLs Animal

Virus

Mouse

Friend/Moloney/Rausher virus

Mouse

Lymphocytic choriomeningitis virus

Mouse

Mouse hepatitis virus

Chimpanzee Hepatitis C Macaque

SIV

References [171] [88, 91] [172] [173, 174] [78, 79]

Selection of CTL escape variants is dependent on several parameters. For example, only infection with high doses of LCMV results in the generation of CTL escape variants, suggesting that a high viral turnover is a prerequisite for the generation of spontaneous mutant viruses that can be subsequently positively selected for by CTL-exerted pressure [88].

Animal Models of Viral Escape Through Mutation—Proof of Principle The demonstration that replication-competent CTL escape mutants can provide a mechanism of immune evasion in animal models of viral infection provides important evidence to suggest that this phenomenon may be applicable to other genetically unstable viruses. Although a comprehensive survey of these experiments is beyond the scope of this review, some key studies and citations are listed in Table 2. Evidence from the SIV Model of AIDS A recent study in SIV-infected macaques elegantly demonstrated the selection of viral escape mutants under immune pressure [78, 79]. Virus was carefully monitored in five closely related macaques infected with an identical inoculum. These macaques shared some, but not all, MHC class 1 molecules, thereby allowing epitope variation to be compared in animals with and without the presenting MHC. Since the macaques all shared identical MHC class II alleles, this controlled for the possible confounding influence of differing CD4+ lymphocyte-mediated responses. Two of the monkeys with identical MHC class I types died rapidly from aggressive SIV infection. Neither developed a detectable CTL response. The other monkeys all developed CTL responses to a range of epitopes in the Env and Nef proteins. The rate of nonsynonymous mutations in the regions of the presented CTL epitopes was higher than elsewhere in the proteins. The mutation rate of epitopes was considerably lower in monkeys that lacked the restricting MHC class I molecule. Epitope variation was consistent with positive selection and tended to result in epitopes that exhibited decreased binding to MHC class I or reduced recognition by CTLs. Where CTLs were detected, viruses harboring escape mutations in the CTL epitopes dominated the plasma pool of viruses at the time of disease progression [78]. Furthermore, the difference

Evidence from Human Studies It is well established that HIV-1 variants with impaired CTL recognition properties occur during the natural course of infection (Fig. 5, [80-84]). However, it has been more difficult to determine whether this observed variation results from selection pressure exerted by CTLs or represents merely a passive consequence of random sequence variation. Here, we outline the evidence in favor of the former proposition. There are several examples where escape mutations occur in HIV-1 and eventually represent nearly 100% of the viral populations [55, 85, 86]. In the case of an immunodominant HLA-B8-restricted epitope in Nef and an immunodominant HLA-B44-restricted epitope in Env, escape can occur during primary infection. Variation appears to be specific for the CTL epitope. Price et al. demonstrated the selection of escape variants over time in a dominant CTL epitope during primary infection [86]. This study further determined that the nonsynonymous-to-synonymous mutation ratio was higher in the region of the epitope, suggesting that the mutations were driven by CTL-mediated selection [86]. Additional data showing the selection of an escape mutant in a dominant HLA B27-restricted epitope, which correlated with progression to AIDS [55], supports the argument for CTL-mediated selection. These well-documented examples of positive selection for CTL escape mutants occurred under conditions of high viral turnover; escape may be less evident at lower levels of viral replication [87, 88]. Further evidence that CTLs can select for epitope mutations in HIV-1 is provided by a study that showed rapid growth of a variant virus accompanied by disease progression following the re-infusion of ex vivo expansions of an autologous CTL clone [89]. Immediately following the infusion, a mutation emerged in the viral population that resulted in the deletion of the epitope to which the clone responded [89]. These observations support the hypothesis that viral variation might eventually outstrip the capacity of the immune system to develop alternative and effective CTL responses, thereby leading to disease progression [58]. Models of CTL-driven antigenic variation predict that, if escape from immunodominant responses results in a shift of the immune response to weaker secondary epitopes, then escape eventually reduces the capacity of CTLs to control the pathogen, thus leading to increases in viral load [58]. With the advent of increasingly sensitive methods for studying antigen-specific CD8+ T cells, it has become apparent that antiviral CTL responses in chronic infection are often much broader than previously thought. As more and more

Sewell, Price, Oxenius et al. CTL epitopes are described, it is becoming clear that many epitopes, restricted by different HLA class I alleles, overlap [90]. Thus, there may be pressure from several sources on a given region of the virus. The breadth of response may make it difficult for the virus to escape as it has multiple selection pressures applied simultaneously [83, 87, 91]. However, the apparent breadth of HIV-specific CTL responses could reflect multiple previous escape events leading to responses directed at further epitopes [58]. Two HLA-identical brothers infected by the same batch of HIV-contaminated factor VIII provide an excellent example [92]. The virus in one sibling contained a mutation preventing recognition of the normally dominant Gag epitope. This led to a response directed against a different spectrum of CTL epitopes, while in the other brother, the Gag response remained dominant. It is notable that in the brother who developed the escape mutant, memory cells specific for the index epitope were detectable at low frequencies, indicating that CTL responses were, at some previous time, directed against the immunodominant epitope [92]. Transmission studies demonstrating that babies born to HIV-1 seropositive mothers are more likely to become infected when the dominant CTL response is impaired by an epitope mutation provide additional evidence to support the role of mutational escape as a mechanism employed to overcome CTL control of viral replication [93]. Further evidence supporting the CTL mutational escape hypothesis comes from a recent analysis of several pooled large studies in which the length of disease-free survival in HIV-1-infected individuals increased as the level of HLA class I heterozygosity increased [72]. Multiplex genotyping of microsatellites around the HLA locus demonstrated no effect on heterozygosity, thereby confirming that the effect on HIV1 disease progression is not simply due to HLA linkage to other effector genes. Conversely, HLA class I homozygosity accelerates disease progression in HIV-1 infection [94]. These results can be interpreted in light of the potential for antigen presentation to CTLs. The number of viral epitopes which can be presented will increase in proportion to the number of available HLA class I molecules. Thus, one can envisage a broader repertoire of CTL specificities in heterozygous individuals which might correlate with more effective control of virus replication due to the proportionately larger number of mutations required to escape host immune control [91]. Observations that individual MHC class I molecules are associated with prognosis are also relevant. Escape mutation within some CTL epitopes may not be selected due to biological constraints. Thus, CTL epitopes vary in their “quality”—high-quality epitopes being those in regions of HIV with a limited capacity to tolerate mutation. Since different MHC class I molecules are able to present different

236

parts of HIV, the argument of “quality” can be extended to HLA type. Both HLA-B8 and -B35 usually present multiple HIV-1 epitopes. However, the “quality” of these epitopes, in terms of the ability of the virus to tolerate mutations in these areas, appears to be different from the quality of epitopes presented by MHC molecules that confer survival advantage. The initial immunodominant HLAB8 response during primary infection is to an epitope in a variable region of the regulatory protein Nef [86]. Escape from this epitope has been described during primary infection [86]. The CTL response must then depend on secondarily evolved HLA-B8 restricted responses. In turn, several of these secondary immunodominant epitopes also appear to be in areas of the virus where escape mutations are tolerated [58, 81]. In contrast, the dominant HLA-B27restricted response is to a p24 Gag epitope in a conserved region of the virus, tolerant to only a narrow range of engineered mutations [95]. Despite the immunodominance of this epitope throughout infection, escape often takes years to occur ([55, 96], ADK unpublished observations). Observations showing that biological constraints on p24 require escape mutation to occur in the context of two other compensatory mutations outside the epitope (ADK, unpublished observations) may provide an explanation for the delay. Constitutive Escape Strategies Antigenic variation occurs in the context of viral fitness within the host environment. There are biological constraints on the permissible sequence variation in HIV at both the RNA and protein levels; in each case, function depends on the secondary structure of the macromolecule, which, in turn, is dependent on primary sequence. Thus, although changes in antigenic structure can lead to loss of CTL recognition, additional evasion strategies have evolved to counter host immune responses directed against relatively conserved regions of the virus. Much previous work has addressed nonmutational escape in other persistent viral infections; the mechanisms involved include concealment in immunologically privileged sites, viral latency without antigen manufacture, interference with leukocyte trafficking, subversion of antigen processing, and downregulation of MHC class I molecules [15, 97-104]. Here, we review the evidence that similar mechanisms operate in HIV-1 infection. Viral Latency Although HIV replication is continuous within HIV-1infected individuals, cells carrying latent genomes are also found (Fig. 2, [105]). Studies of HIV in chimpanzees which show that transcriptionally silent, but inducible, HIV genomes circulate in the peripheral blood [106] best

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demonstrate this point. Two latent forms of the virus are known to exist [105]. Unintegrated viral DNA (preintegration latency) has been documented within quiescent peripheral blood T cells [107]. These genomes retain the ability to integrate after activation of the host cell [107]; however, preintegration latent forms of the virus have a short half-life, and the stable integration of such genomes in vivo is likely to be a rare event [105]. Postintegration latency, where the HIV genome is integrated into the host cell genome and lies dormant, could represent the virus’ most effective form of immune escape. Integrated latent forms of HIV are insensitive to both antiretroviral drugs and sequestered from immune surveillance by CTLs. These latent viral forms, the half-life of which has been estimated to be at least six months, may prove to be important obstacles to effective antiretroviral therapy [108-113]. Destruction of CD4+ Lymphocyte Help Virus-specific CD4+ lymphocyte help is required not only for the induction of humoral responses but also for the maintenance of long-term CTL activity [114-119]. Depletion of CD4+ lymphocytes is a hallmark of HIV-1 infection [120]. However, the mechanisms through which this occurs are uncertain. Direct cytopathic destruction by HIV-1 or immune-mediated clearance of HIV-1-infected cells is thought to be central to the observed loss of CD4+ lymphocytes, although mechanisms unrelated to cellular infection by the virus may also be significant [121]. Preferential targeting of HIV-1-specific CD4+ lymphocytes could effectively sabotage the virus-specific CTL response during the course of natural infection; this could result from preferential infection of activated lymphocytes or from selective interaction between specific lymphocytes and productively infected, antigen-bearing dendritic cells (DCs) [122]. The recent discovery that the DC cell surface protein DC-SIGN can capture HIV-1 at low external titers and deliver it to CD4+ T lymphocytes may also be relevant [123, 124]. Evidence that early intervention with antiretroviral therapy during primary HIV-1 infection preserves HIV-1-specific CD4+ lymphocyte responses is consistent with these ideas [125, 126]. The demonstration that HIV-1specific help correlates with sustained CTL responses supports the notion that selective destruction of antigen-specific lymphocytes provides a potent means of immune sabotage [126, 127]. Inhibition of Antigen Processing A recent report suggests that the HIV Tat protein inhibits the 20S proteasome and its 11S regulator [128]. This may lead to the defective presentation of some, but not all [129], HIV epitopes, and thus aid escape from CTLs.

CTL Responses to HIV: Control and Escape Downregulation of MHC Class I Expression In addition to its role in the surface downregulation of CD4, the HIV accessory protein Nef has been shown to downregulate expression of MHC class I molecules [130132]. Further studies showed that this downregulation exhibits allele specificity and does not include HLA C and E [133, 134]. Natural killer (NK) cell lysis is predominantly inhibited by HLA C and HLA E [135-138]. Thus, this selective downregulation may allow HIV to escape from CTLs while allowing infected cells to maintain a resistance to NK cell regulation [134]. Small populations of NK cells expressing the NKB1 receptor may be ideally suited for the elimination of HIV-1-infected cells. NKB1 is an NK inhibitory receptor specific for the Bw4 subset of HLA B molecules [139, 140]. The HIV-specific downregulation of surface HLA B molecules in Bw4 individuals with an NKB1-expressing NK cell population should lead to NK-mediated lysis. It is interesting to note that the influence of HLA type on disease progression appears to be most strongly linked to HLA B [68]. HLA molecules associated with slow progression to AIDS [68] belong to the family of NKB1-recognized Bw4 subset of HLA B molecules. By contrast, those HLA B alleles associated with rapid disease progression [68] belong to the Bw6 subset of HLA B alleles that are not recognized by NKB1 [134, 139, 140]. NK cell activity may be a determinant in HIV disease progression [141], and the role of NK cells during HIV infection warrants further study. In HIV infection, the benefits afforded by HLA molecules such as HLA B27 may therefore arise from a combination of their recognition by NKB1 and their ability to present conserved regions of HIV-1 to CTLs. Back-Killing of CTL by Infected Target Cells Both SIV [142] and HIV [143] upregulate surface expression of FasL (CD95L) via a signaling mechanism involving Nef and the TCR. If HIV-infected cells express FasL in vivo, this may lead to the destruction of HIV-specific CTLs via Fas/FasL-induced apoptosis. Inhibition of CTL-Mediated Apoptosis Viral modulation of apoptosis is well described [144]. In several cases, direct inhibition of CTL-mediated apoptosis by viral proteins has been demonstrated [145-147]. It is possible that certain HIV-encoded proteins may perform a similar function within infected CD4+ lymphocytes. Likely candidates include Nef and Vpr [148, 149], although experimental confirmation is currently lacking, partly due to technical difficulties in separating perforinmediated target cell lysis from the apoptotic effects of CTL in vitro.

Sewell, Price, Oxenius et al. Figure 6. Constitutive escape from CTL by HIV-1. HIV-1 has a number of constitutive mechanisms to counteract the antiviral effects of CTLs. These include downregulation of MHC class I (1)[130133], destruction of T help for HIV-specific CTLs, interference with antigen processing [128], upregulation of Fas Ligand to “back-kill” antiviral CTLs [143] (2), and both pre- and postintegration latency (3 and 4) [105].

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CTL Nef-mediated down regulation of MHC class I

1

Apoptosis

Upregulation of Fas ligand

2

CONCLUDING REMARKS Pre-integration From the evidence outviral latency 3 lined above, it can be conENDOPLASMIC RETICULUM cluded that CTLs are crucial MHC class I binding elements of the antiretroviral NUCLEUS MHC I immune response and that viral Integrated TAP proviral DNA escape from these effector cells is a determinant of disease progression in HIV-1-infected 4 Post-integration viral latency individuals. The next big chalACKNOWLEDGMENTS lenge in AIDS research is to utilize these key biological We thank Charles Bangham for helpful discussions and insights to optimize vaccination protocols and therapeutic critical review of the manuscript. interventions.

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