Background Defining the quality of HIV T cell responses is a major hurdle in the development of T cell based vaccines. A key determinant of viral control is the affinity of the T Cell Receptor (TCR) for the HLA/epitope complex. We report for the first time in HIV the development of Class I HLA tetramers, which allow detection of CD8 with high TCR affinity that may prove to be invaluable in assessing the quality of T cell immunity. Methods HLA Class I molecules A*0201 and B*0702 were mutated at positions D227K and T228A to nullify CD8 binding and refolded with HIV epitopes: SLYNTVATL (A*0201), ILKEPVHGV (A*0201) and GPGHKARVL (B*0702). BIACORE confirmed abolition of CD8 binding and HLA molecule conformation. Mutated HLA monomers were termed CD8null. Peripheral blood mononuclear cells from HLA-matched acute patients in the SPARTAC trial (n = 30) were stained with A*0201 or B*0702 CD8 wild-type and CD8null tetramers. Real-time Image Flow Cytometry, directly examined the CD8null and CD8 wild-type tetramer/TCR interaction on an individual cell level. Results HLA Class I A*0201 and B*0702 CD8 null monomers had undetectable CD8 binding. Wild-type monomers had comparable CD8 binding capacity for A*0201 and B*0702 (KD = 5.9 × 10-4 and 6.0 × 10-4 M, respectively). Both CD8wild-type and CD8null monomers are bound by the anti-HLA w6/32 antibody with equal affinity (KD = 4.2 × 10-10 M). Ex vivo imaging showed slower internalisation of CD8null, compared to CD8wild-typetetramers, indicating prolonged HLA/TCR interaction. HIV patients stained with CD8null and CD8wild-type had distinct high affinity CD8 populations for A*0201 SLYNTVATL and ILKEPVHGV (p < 0.05) but not for B*0702 GPGHKARVL. Conclusion CD8null tetramers represent a novel technology that allow the direct ex vivo detection and characterisation of high affinity CD8 T responses. This represents a crucial new tool for assessing the quality of T cell responses to vaccination.

ABSTRACT The hypothesis that the intrapatient emergence of cytotoxic T-lymphocyte escape variants contributes to the evolution of human immunodeficiency virus type 1 at the population (interpatient) level was tested using the HLA-A*0201-restricted gag p17 epitope SLYNTVATL. Using a simple experimental design, we investigated the evolutionary processes operating within this epitope among patients while compensating for the confounding influence of intrapatient natural selection. Using this approach, we revealed a pattern of A*0201-driven escape within patients, followed by the sustained transmission of these escape variants among patients irrespective of their HLA type.

The immune-viral dynamics of the transmission of HIV-1 from mother to child are poorly understood, despite 20 years of research. Here we review evidence that the maternal immune response against HIV-1 can select forms of the virus that evade immunity and when transmitted have negative consequences in the child. Moreover, recent studies indicate that when wild-type virus is transmitted, an early immune response in the child can lead to the selection of viral escape forms in the first few months of life. These data suggest that adaptive immune surveillance in both mother and child contributes to the pathogenesis of early perinatal HIV-1. These observations augment our general understanding of the processes that determine the evolution of HIV-1 as it passes from one host to another.

ABSTRACT Antigenic variation inherent in human immunodeficiency virus type 1 (HIV-1) virions that successfully instigate new infections transferred by sex has not been well defined. Yet this is the viral “challenge” which any vaccine-induced immunity must deal with. Closely timed comparisons of the virus circulating in the “donor” and that which initiates new infection are difficult to carry out rigorously, as suitable samples are very hard to get in the face of ethical hurdles. Here we investigate HIV-1 variation in four homosexual couples where we sampled blood from both parties within several weeks of the estimated transmission event. We analyzed variation within highly immunogenic HIV-1 internal proteins encoding epitopes recognized by cytotoxic Tlymphocytes (CTLs). These responses are believed to be crucial as a means of containing viral replication. In the donors we detected virions capable of evading host CTL recognition at several linked epitopes of distinct HLA class I restriction. When a donor transmitted escape variants to a recipient with whom he had HLA class I molecules in common, the recipient's CTL response to those epitopes was prevented, thus impeding adequate viral control. In addition, we show that even when HLA class I alleles are disparate in the transmitting couple, a single polymorphism can abolish CTL recognition of an overlapping epitope of distinct restriction and so confer immune escape properties to the recipient's seroconversion virus. In donors who are themselves controlling an early, acute infection, the precise timing of onward transmission is a crucial determinant of the viral variants available to compose the inoculum.

ABSTRACT Genetic diversity of viral isolates in human immunodeficiency virus (HIV)-infected individuals varies substantially. However, it remains unclear whether HIV-related disease progresses more rapidly in patients harboring virus swarms with low or high diversity and, in the same context, whether high or low diversity is required to induce potent humoral and cellular immune responses. To explore whether viral diversity predicts virologic control, we studied HIV-infected patients who received antiretroviral therapy (ART) for years before undergoing structured treatment interruptions (STI). Viral diversity before initiation of ART and the ability of the patients to contain viremia after STI and final cessation of treatment was evaluated. Seven out of 21 patients contained plasma viremia at low levels after the final treatment cessation. Clonal sequences encompassing the envelope C2V3C3 domain derived from plasma prior to treatment, exhibited significantly lower diversity in these patients compared to those derived from patients with poor control of viremia. Viral diversity pre-ART correlated with the viral replication capacity of rebounding virus isolates during STI. Neutralizing antibody activity against autologous virus was significantly higher in patients who controlled viremia and was associated with lower pretreatment diversity. No such association was found with binding antibodies directed to gp120. In summary, lower pretreatment viral diversity was associated with spontaneous control of viremia, reduced viral replication capacity and higher neutralizing antibody titers, suggesting a link between viral diversity, replication capacity, and neutralizing antibody activity.

ABSTRACT The role of cytotoxic T-lymphocyte (CTL) escape in rapidly progressive infant human immunodeficiency virus type 1 (HIV-1) infection is undefined. The data presented here demonstrate that infant HIV-1-specific CTL can select for viral escape variants very early in life. These variants, furthermore, may be selected specifically in the infant, despite the same CTL specificity being present in the mother. Additionally, pediatric CTL activity may be compromised both by the transmission of maternal escape variants and by mother-to-child transmission of escape variants that originally arose in the father. The unique acquisition of these CTL escape forms may help to explain the severe nature of some pediatric HIV infections.

The average time between infection with human immunodeficiency virus (HIV) and development of acquired immune deficiency syndrome is approximately 8 years. However, progression rates vary widely, depending on several determinants, including HIV-specific immunity, host genetic factors, and virulence of the infecting strain. In untreated HIV-infected patients with different progression rates, we examined HIV-specific T cell responses in combination with host genetic markers, such as chemokine/chemokine-receptor (CCR) polymorphisms and human leukocyte antigen (HLA) genotypes. HIV-specific CD4(+) T cell responses and, to a lesser extent, HIV-specific CD8(+) T cell responses were inversely correlated with progression rate. Slower progression was not related to polymorphisms in CCR genes, HLA genotype, or GB virus C coinfection. These data suggest that HIV-specific T cell responses are involved in protecting the host from disease progression.

There are significant associations between possession of certain HLA class I alleles and rate of progression to AIDS. Immunological data provide an explanatory mechanism for this relationship. Patients with HLA types associated with rapid disease progression recognize a significantly smaller fraction of their known repertoire of viral epitopes than do patients with HLA types associated with slow progression. Population frequency of HLA types (or supertypes) and their capacity to elicit cytotoxic T lymphocyte responses are also negatively correlated. These data provide an immunological mechanism to explain HLA-related risk of progression to AIDS and emphasize the central role of viral evolution in the pathogenesis of HIV.

CD4+ T lymphocyte responses are thought to play a major role in control of the hepatitis C virus (HCV). Few, however, have been mapped down to the level of peptide and HLA restriction. Furthermore, the ability of such T cells to respond to viruses which differ in genotype has not been addressed in detail. In most cases of persistent infection with HCV, CD4 proliferative responses are weak or absent. From a large cohort of persistently infected patients, we identified an individual with unusually robust and persistent responses in the face of chronic infection. We firstly mapped two peptide epitopes to regions of the nonstructural protein NS4 (aa1686-1705 and aa 1746-1765). However, in contrast to the genotype 1a derived antigens used for mapping, the infecting virus was identified as genotype 3a. Strikingly, the patient's CD4 response to these epitopes were specific only for the genotype 1a sequence, and did not recognize genotype 3a synthetic peptides. Serologic assays indicated that prior exposure to HCV of genotype 1 had occurred. This patient therefore maintains strong CD4 proliferative responses which are genotype specific and not cross-reactive. The apparent 'misdirection' of these nonprotective responses has important implications for the role of natural and vaccine induced CD4 responses in the face of variable viruses.

Cytotoxic T lymphocytes (CTLs) play a key role in the control of persistent viral infections. Differences in the quality of this cellular immune response influence the long-term outcome of such infections, but the factors that determine which virus-derived peptide epitopes are targeted by CTLs remain poorly understood. Here, we examine the antigen-processing requirements of three human leukocyte antigen (HLA) A*0201-restricted HIV-1 CTL epitopes. Each of these three peptides appears to be generated by a distinct proteolytic pathway, despite presentation on the cell surface in association with the same HLA class I molecule. Presentation of the commonly immunodominant SLYNTVATL (HIV-1 p17 Gag; residues 77-85) epitope was unaffected by inhibition of the proteasome with lactacystin, but was dependent on the presence of the beta-subunit LMP7. These findings are consistent with emerging data on the complexity of peptide epitope generation, and suggest that differences in antigen processing might contribute to patterns of CTL recognition in vivo.

ABSTRACT There is a continuing search for better ways to use existing drugs against human immunodeficiency virus (HIV). One idea is to use short therapy interruptions to “autovaccinate” HIV-infected patients. A group of 13 chronically HIV-infected patients enrolled in a trial of such so-called structured treatment interruptions (STIs) were intensively studied with respect to their viral load (VL) and HIV-specific CD8 + T-cell (cytotoxic T-lymphocyte [CTL]) responses. We found that 10 of the 13 patients had plateau VLs after STIs that were lower than their pretreatment VLs. While viral rebound rates became lower over STIs, there were no changes in clearance rates. Although numbers of CTLs did increase over the same time that viral rebounds decreased, there was no correlation between CTL count and either viral rebound rates or clearance rates. Finally, we asked whether absolute numbers of or changes in numbers of CTLs predict plateau VLs after STIs. No measure of CTLs was able to predict plateau VLs. Thus, there was no signature in these data of an important contribution to virological control from HIV-specific CD8 + T lymphocytes.

Impairment of CD4(+) T lymphocyte responses to human immunodeficiency virus (HIV)-derived antigens is the classic immunological defect observed during the chronic phase of HIV-1 infection. Early intervention with potent antiretroviral therapy (ART) can preserve HIV-specific CD4(+) T lymphocyte reactivity, providing indirect evidence that such responses are mounted during primary infection and subsequently lost in the majority of infected individuals. Here, we demonstrate early and dramatic expansions of functional HIV-specific CD4(+) T lymphocyte frequencies directly ex vivo. These responses are initially of broad specificity, and can disappear rapidly during the natural course of primary infection. This process of loss is variable, such that the rapidity and extent of functional compromise differs between individuals. Institution of ART during these early phases of HIV-1 infection preserves patterns of functional reactivity within the HIV-specific CD4(+) T lymphocyte population. However, there was no evidence for the restoration of deleted responses. These findings indicate that, in some individuals at least, ART must be administered within a narrow window of opportunity during primary HIV-1 infection to effect substantial immune preservation.

Cytotoxic T lymphocytes (CTL) play a central role in containment of HIV infection. Evasion of the immune response by CTL escape is associated with progression to disease. It is therefore hypothesised that transmitted viruses encode escape mutations within epitopes that are required for successful control of viraemia. In order to test this hypothesis, escape through the dominant HLA-A2-restricted CTL epitope SLYNTVATL (p17 Gag residues 77–85 SL9) in the setting of mother-to-child-transmission (MTCT) was investigated. Initial data from two families in which the HIV-infected mother expressed HLA-A*0201 and had transmitted the virus to other family members were consistent with this hypothesis. In addition, analysis of the gag sequence phylogeny in one family demonstrated that CTL escape variants can be successfully transmitted both horizontally and vertically. To test the hypothesis further, a larger cohort of transmitting mothers (n=8) and non-transmitters (n=14) were studied. Variation within the SL9 epitope was associated with expression of HLA-A2 (P=0.04) but overall no clear link between variation from the SL9 consensus sequence and MTCT was established. However, the high level of background diversity within p17 Gag served to obscure any possible association between escape and MTCT. In conclusion, these studies highlighted the obstacles to demonstrating CTL escape arising at this particular epitope. Alternative strategies likely to be more definitive are discussed.

Objectives To assess whether drug-induced suppression of the plasma viral load is associated with selective differential distribution of virus-specific CD8 T cells between the blood and secondary lymphoid organs. Methods HIV-specific CD8 T lymphocyte responses were quantified in matched peripheral blood and lymph node samples from seven patients starting treatment shortly after infection, who received antiretroviral theray (ART) for a median of 14 months. Cells recovered from samples were subjected to IFN-γ ELISPOT analysis. A series of synthetic peptides corresponding to previously characterized cytotoxic T lymphocyte epitopes restricted by HLA I molecules present in each patient were used as antigens, together with appropriate positive and negative controls. Results HIV-specific CD8 T lymphocyte responses were found in six of the seven patients. The observed frequencies of HIV-specific CD8 T lymphocytes and the pattern of epitope recognition was identical within the two compartments. These results also confirm the observation that functional HIV-specific CD8 T cells are preserved on ART in most patients initiating treatment at the time of primary HIV-1 infection. Conclusion This investigation demonstrated that patterns of antigenic immunodominance as well as frequencies of HIV-specific CD8 T lymphocytes are similar in blood and lymphoid tissue compartments in HIV-infected individuals. These findings support current approaches to the identification of HIV-specific CD8 T lymphocyte reactivity based on leukocytes isolated from blood even in patients with ART-induced suppression of viral load.

Multimeric soluble peptide-MHC class I complexes bind to T cell receptors (TCR) on the surface of CD8 cytotoxic T lymphocytes (CTL) with sufficient avidity to enable the labelling of CTL according to their antigen specificity [1]. Visualization of antigen-specific CD8+T lymphocytes with fluorogen-conjugated peptide-MHC class I multimers enables both the physical quantification and the phenotypic characterization of CTL responses directly ex vivo, and these properties have led to the widespread adoption of this technique throughout the field of experimental immunology. However, it is well documented that TCR can exhibit a degree of promiscuity in terms of ligand recognition [2]. We recently demonstrated that the multimerization of peptide-MHC class I can allow binding to TCR with affinities that are too low to generate ligand-induced physiological responses, and result in crossreactive staining of HIV-specific CTL lines and clones by unrecognized natural variant antigens [3]. These results suggest that crossreactivity between peptide-MHC class I multimers and low avidity CTL could be relevant to the interpretation of direct ex-vivo staining. The possibility of such cross-staining is likely to be considerably greater when using peptide-MHC class I multimers to stain CTL specific for epitopes derived from antigenically variable pathogens such as HIV-1 [4]. Here we extend our previous study with the demonstration that the cross-staining of CTL populations with peptide-MHC class I multimers can complicate analyses performed directly ex vivo. In a detailed analysis of virus-specific T cell responses during primary HIV-1 infection, we defined a substantial population of CD8 T lymphocytes in donor SC21 that stained with phycoerythrin-conjugated tetramers of human leukocyte antigen (HLA) B7, folded around the HIV-1 Nef epitope RPMTYKAAL (residues 75–83; reference strain HIV-IIIB) (Fig. 1a) [5]. However, the tetramer-positive population consisted of a smear of CD8+T lymphocytes with different staining intensities. This suggested either that a spectrum of TCR expression densities was present within the tetramer-positive population of CD8+T lymphocytes, or that the RPMTYKAAL-specific response was polyclonal and comprised TCR with variable affinities for the peptide-HLA B7 ligand. Consistent with the former possibility, extensive staining of the population with a monoclonal antibody panel recognizing individual Vβ TCR chain determinants revealed that more than 95% of the antigen-specific CD8+T lymphocytes expressed Vβ14 TCR at three separate time-points (Fig. 1a and data not shown). Similar antigen-specific oligoclonal expansions within the CD8+T lymphocyte population have been reported previously in acute primary HIV-1 infection, and appear to typify the early cellular immune response to virus infection [6]. Furthermore, there was a large discrepancy between the number of antigen-specific CD8+T cells determined physically with the RPMTYKAAL-HLA B7 tetramer compared with functional measurements based on IFN-γ release in ELISpot assays. These incongruities prompted the sequencing of plasma virus from donor SC21, which revealed that 39/40 Nef clones isolated from two separate time-points encoded the variant epitope RPMTYKGAL (data not shown). We therefore performed both peptide-MHC class I tetramer staining and ELISpot analysis using the autologous virus epitope sequence. Although the total number of antigen-specific CD8 T lymphocytes determined with the RPMTYKGAL-HLA B7 tetramer was similar in magnitude to that measured with the RPMTYKAAL-HLA B7 tetramer, staining with tetramer folded around the autologous epitope improved both the intensity and uniformity of staining (Fig. 1a and b). In contrast to staining with the RPMTYKGAL-HLA B7 tetramer, staining with the non-autologous tetramer was abrogated at lower concentrations (Fig. 1b); this observation is consistent with the generation of a high affinity response to the autologous viral epitope, and indicates that the naturally dominant Vβ14 TCR had a lower affinity for the RPMTYKAAL-HLA B7 antigen. In addition, IFN-γ ELISpot analysis demonstrated that the autologous peptide epitope activated a substantially higher proportion of CD8+T lymphocytes, which were stimulated to produce spots that were larger both in size and intensity, compared with the RPMTYKAAL sequence (Fig. 1c). Quantitative differences between the epitopes were also seen in direct ex-vivo chromium release lysis assays (data not shown). The ‘wild-type’ sequence RPMTYKAAL therefore acted as a poor or weak agonist for SC21 CTL.Fig. 1.: Ex-vivo physical and functional characterization of CD8 T lymphocytes specific for the HIV-1 Nef-derived epitope RPMTYK(A/G)AL. (a) Staining profile of peripheral blood lymphocytes (PBL) from SC21 with tetrameric complexes of human leukocyte antigen (HLA)-B7 folded around RPMTYKAAL (RPMA) or RPMTYKGAL (RPMG). PBL were stained for 20 min at 37°C with 10 μg/ml phycoerythrin-labelled tetrameric complexes [3], washed and incubated for 20 min at 4°C with Tricolor-labelled anti CD8 antibody (Caltag, USA). Numbers in the upper right corners represent percentages of tetramer-positive CD8+PBL. Inserted flow cytometry profiles show the T cell receptor (TCR) Vβ usage of RPM-specific CD8+T lymphocytes. CD8+ tetramer-positive cells were co-stained individually with a panel of fluorescein-isothiocyanate-labelled TCR Vβ-specific antibodies; 94 or 95% of the CD8+ tetramer-positive cells stained with a Vβ14-specific antibody [7]. Inserted flow cytometry profiles are gated on CD8+T cells. (b) PBL were stained as described in (a), but with tetramer at 1 μg/ml. (c) Functional characterization by IFN-γ ELISpot analysis. PBL of SC21 were incubated overnight with serial 10-fold dilutions (20, 2 and 0.2 μM) of the RPMA and RPMG peptide epitopes, and specific IFN-γ secretion was determined as described previously [8]. Spot-forming cells (SFC) per million PBL were calculated as (no. of spots in the presence of antigen) − (no. of spots in the absence of antigen) normalized to 106 PBL.These findings demonstrate that crossreactivity can complicate direct ex-vivo peptide-MHC class I multimer-based analyses of CTL populations responding to pathogens with variable antigenicity. Marked discrepancies between physical and functional measurements of antigen-specific CTL, together with non-uniform staining of low intensity in oligoclonal CD8+T lymphocyte populations, should alert investigators to the possibility that individual CTL responses are directed against variant epitopes. Acknowledgements The authors would like to thank Anele Waters and the donor SC21 for excellent collaboration. Annette Oxeniusa* David A. Priceb* Sara J. Dawsona Tin Tuna Philippa J. Easterbrookc Rodney E. Phillipsa Andrew K. Sewella

Recognition of antigen by cytotoxic T lymphocytes (CTL) is determined by interaction of both the T cell receptor and its CD8 coreceptor with peptide-major histocompatibility complex (pMHC) class I molecules. We examine the relative roles of these receptors in the activation of human CTL using mutations in MHC class I designed to diminish or abrogate the CD8/pMHC interaction. We use surface plasmon resonance to determine that point mutation of the alpha3 loop of HLA A2 abrogates the CD8/pMHC interaction without affecting the affinity of the T cell receptor/pMHC interaction. Antigen-presenting cells expressing HLA A2 which does not bind to CD8 fail to activate CTL at any peptide concentration. Comparison of CTL activation by targets expressing HLA A2 with normal, abrogated, or diminished CD8/pMHC interaction show that the CD8/pMHC interaction enhances sensitivity to antigen. We determine that the biochemical basis for coreceptor dependence is the activation of the 23-kDa phosphoform of the CD3 zeta chain. In addition, we produce mutant MHC class I multimers that specifically stain but do not activate CTL. These reagents may prove useful in circumventing undesirable activation-related perturbation of intracellular processes when pMHC multimers are used to phenotype antigen-specific CD8+ lymphocytes.

Therapeutic intervention with antiretroviral therapy (ART) enables the modulation of HIV virus load and hence provides a unique opportunity to study the consequences of varying antigen load on the phenotype of virus-specific CD8(+) T lymphocytes in a persistent human viral infection. The recent advent of tetrameric peptide / HLA class I complexes has enabled the direct phenotypic characterization of antigen-specific T cell populations ex vivo. Here, we use this technology to examine directly ex vivo the consequences of therapeutic manipulation of HIV virus load on the phenotype of HIV-specific CTL. Our observations show that: (1) distinct sequential activation patterns of CD8(+) T cells are associated with increasing virus load; (2) T cell receptor (TCR) down-regulation without apoptosis represents an early event during the generation of a T cell response in a natural infection and precedes the emergence of two distinct antigen-specific CD8(+) T cell populations which differ in TCR and CD8 expression levels. Clear differences in surface Annexin V staining were observed between these populations. The observation that CTL activation, demonstrated by TCR and CD8 down-regulation, in response to rising levels of virus load, co-segregates with apoptosis only during later stages of the response indicates that antigen-associated cell death is restricted to distinct subpopulations of CTL.

Human cytomegalovirus (CMV) is a ubiquitous pathogen which sets up a lifelong persistent infection and which can lead to significant disease in the immunosuppressed. The immunological mechanisms controlling CMV in the long term are not defined completely, but CD8+ T lymphocytes are thought to play an important role. Antiviral CD8+ T lymphocytes may exist in very large pools in healthy individuals. Although the detailed composition of these pools is not completely understood, there is known to be heterogeneity, in particular of CD45 isoform expression. We have therefore investigated the CD8+ T-lymphocyte response against CMV directly ex vivo using Class I tetramers combined with stains for a range of phenotypic markers followed by four-colour flow cytometric analysis. In particular, we examined expression of these phenotypic markers in relation to the expression of CD45 isoforms. We found that a spectrum of phenotypes exists stably, from CD45R0(high)/RA(low) through CD45RA(high)/R0(low), and that expression of other surface markers such as CD28 and CD62L, and also TCR usage, may vary in parallel with CD45 isoform expression. In some individuals, expansions of antigen-specific CD8+ T lymphocytes bearing specific TCR Vbeta chains were restricted to cells of particular CD45 isoforms. Immunity against CMV comprises a large population of CD8+ T lymphocytes with heterogeneous potential, a spectrum in which CD45 isoform expression may play a central role.

The effects of the immunocompromised state after liver transplantation on the frequency of cytomegalovirus-specific cytotoxic T lymphocytes (CTL) were investigated in 93 patients by using HLA class I tetrameric complexes corresponding to HLA-A*0201, HLA-B*0702, HLA-B*0801, and HLA-B*3501 refolded with peptides from the ppUL83 matrix protein. ppUL83 CTL frequencies were suppressed during the first 6 months after transplantation. Patients with >1 HLA-restricted response detected had high correlation among ppUL83 CD8(+) CTL frequencies restricted by different HLA haplotypes (Spearman's rho=.67; P<.0001). There was an inverse correlation among levels of the calcineurin inhibitor, tacrolimus, and ppUL83 CD8(+) CTL frequencies (r=-.31; P=.005), which is consistent with the presence of a large proportion (70%) of activated (CD38(+)) ppUL83 CD8(+) CTL within the population of HLA class I tetramer-positive cells.

AIDS Research and Human RetrovirusesVol. 17, No. 11 Short CommunicationsEffects of Retroviral Protease Inhibitors on Proteasome Function and Processing of HIV-Derived MHC Class I-Restricted Cytotoxic T Lymphocyte EpitopesAnthony D. Kelleher, Bruce L. BoothJr, Andrew K. Sewell, Annette Oxenius, Vincenzo Cerundolo, Andrew J. McMichael, Rodney E. Phillips, and David A. PriceAnthony D. KelleherSearch for more papers by this author, Bruce L. BoothJrSearch for more papers by this author, Andrew K. SewellSearch for more papers by this author, Annette OxeniusSearch for more papers by this author, Vincenzo CerundoloSearch for more papers by this author, Andrew J. McMichaelSearch for more papers by this author, Rodney E. PhillipsSearch for more papers by this author, and David A. PriceSearch for more papers by this authorPublished Online:5 Jul 2004https://doi.org/10.1089/088922201300343744AboutSectionsPDF/EPUB Permissions & CitationsPermissionsDownload CitationsTrack CitationsAdd to favorites Back To Publication ShareShare onFacebookTwitterLinked InRedditEmail FiguresReferencesRelatedDetailsCited byHIV protease inhibitors and autoimmunity: An odd, but promising ideaAutoimmunity Reviews, Vol. 18, No. 10Transmitted/Founder HIV-1 Subtype C Viruses Show Distinctive Signature Patterns in Vif, Vpr, and Vpu That Are Under Subsequent Immune Pressure During Early Infection Raabya Rossenkhan, Iain J. MacLeod, Zabrina L. Brumme, Craig A. Magaret, Theresa K. Sebunya, Rosemary Musonda, Berhanu A. Gashe, Paul T. Edlefsen, Vlad Novitsky, and M. Essex1 November 2016 | AIDS Research and Human Retroviruses, Vol. 32, No. 10-11Sequence-Specific Alterations of Epitope Production by HIV Protease Inhibitors15 April 2014 | The Journal of Immunology, Vol. 192, No. 8Vector replication and expression of HIV-1 antigens by the HIV/AIDS vaccine candidate MVA-B is not affected by HIV-1 protease inhibitorsVirus Research, Vol. 167, No. 2Restoration of anti-tetanus toxoid responses in patients initiating highly active antiretroviral therapy with or without a boost immunization: an INITIO substudy9 April 2008 | Clinical and Experimental Immunology, Vol. 152, No. 2Antiretroviral therapy-induced lipid alterations: in-vitro, animal and human studiesCurrent Opinion in HIV and AIDS, Vol. 2, No. 4Partial treatment interruption of protease inhibitors augments HIV-specific immune responses in vertically infected pediatric patientsAIDS, Vol. 19, No. 15Antitumour effects of antiretroviral therapyNature Reviews Cancer, Vol. 4, No. 11Dyslipidemia due to retroviral protease inhibitorsNature Medicine, Vol. 8, No. 4Reply to 'Dyslipidemia due to retroviral protease inhibitors'Nature Medicine, Vol. 8, No. 4 Volume 17Issue 11Jul 2001 To cite this article:Anthony D. Kelleher, Bruce L. BoothJr, Andrew K. Sewell, Annette Oxenius, Vincenzo Cerundolo, Andrew J. McMichael, Rodney E. Phillips, and David A. Price.Effects of Retroviral Protease Inhibitors on Proteasome Function and Processing of HIV-Derived MHC Class I-Restricted Cytotoxic T Lymphocyte Epitopes.AIDS Research and Human Retroviruses.Jul 2001.1063-1066.http://doi.org/10.1089/088922201300343744Published in Volume: 17 Issue 11: July 5, 2004PDF download