Subdominant Response Research Articles

Modulating immunodominance hierarchy of immunoglobulin germline-encoded structural motifs targeting the influenza hemagglutinin stem

Antibodies targeting epitopes through germline-encoded motifs can be found in different individuals. While these public antibodies are often beneficial, they also pose hurdles for subdominant antibodies to emerge. Here, we use transgenic mice that reproduce the human IGHV1-69∗01 germline-encoded antibody response to the conserved stem epitope on group 1 hemagglutinin (HA) of influenza A virus to show that this germline-endowed response can be overridden by a subdominant yet cross-group reactive public antibody response. Immunization with a non-cognate group 2 HA stem enriched B cells harboring the IGHD3-9 gene, thereby switching from IGHV1-69- to IGHD3-9-encoded motif-dependent epitope recognition. These IGHD3-9 antibodies bound, neutralized, and conferred cross-group protection in mice against influenza A viruses. A cryoelectron microscopy (cryo-EM) structure of an IGHD3-9 antibody resembled the human broadly neutralizing antibody FI6v3, which uses IGHD3-9. Together, our findings offer insights into vaccine regimens that engage an immunoglobulin repertoire with broader cross-reactivity to influenza A viruses.

Household chaos as a moderator of the link between parents' inhibitory control and parenting quality.

This study considered how mothers' and fathers' inhibitory control, an aspect of executive functioning (EF) that reflects how well an individual can suppress a dominant response to perform a subdominant response, is associated with observations of their parenting quality when children were 7.5 years old. Furthermore, aspects of the daily home environment may strengthen or undermine parents' ability to draw on their inhibitory control and exhibit high-quality parenting. Household chaos, including clutter, confusion, and ambient noise, may impair parents' ability to successfully activate inhibitory control and engage in high-quality parenting. Thus, additional analyses examined whether parents' perceptions of household chaos moderated associations between inhibitory control and parenting. Data came from a sample of approximately 102 families headed by different-sex parents (n = 99 mothers; n = 90 fathers) of 7.5-year-old children who participated in a study of family development. Findings from multilevel models indicated that inhibitory control predicted greater positive-sensitive parenting in contexts of low household chaos. Associations between inhibitory control and parenting quality were not statistically significant in contexts of average or high household chaos. These findings highlight the importance of considering household chaos and inhibitory control as factors associated with parenting quality for fathers and mothers. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Self-regulation in preschool: Are executive function and effortful control overlapping constructs?

The concepts of executive function (EF) and effortful control (EC) are strikingly similar. EF originate from neurocognitive research and are described as an accumulation of cognitive processes that serve the goal-oriented self-regulation (SR) of an individual. EC originates from temperament research and is defined as the efficiency of executive attention, including the ability to inhibit a dominant response, to activate a subdominant response, to proceed in a planned manner and to recognize conflicts or errors. The aim of this article was to examine the association between the constructs of EF and EC at the preschool-age. Eighty-eight children (49 female; M-age=3.93 years, SD=.78) were tested with a computerized battery designed to assess EF at 3-6 years of age (EF Touch). Children's parents completed questionnaires assessing EF impairments (BRIEF-P) and EC (CBQ). Associations between the constructs and their conceptual overlap were analyzed using correlations and confirmatory factor analyses. We found significant correlations between EF and EC measures. A one-factor confirmatory model fitted the data very well and indicated that EF and EC are indeed overlapping and highly similar constructs. Therefore, our results show that measures of EC and EF have substantial overlap in preschoolers and suggest an integrated model of self-regulation.

Abstract P010: Antigen dominance hierarchies shape CD8 T cell phenotypes and immunotherapy response in tumors

Abstract CD8 T cell responses against different tumor neoantigens occur simultaneously, yet it is unclear whether they interact to potentiate or antagonize the overall anti-tumor response. In a genetically engineered mouse model of lung adenocarcinoma, we find that antigen dominance hierarchies are established in tumors wherein the antigen that most stably binds MHC dominates the CD8 T cell response. This negatively impacts the response to subdominant antigens, suppressing T cell expansion, differentiation and effector function; a phenotype that is reversed when the dominant antigen is removed. Intriguingly, the subdominant response is also enriched for a TCF1+ progenitor cell phenotype that has been correlated with response to immune checkpoint blockade (ICB) therapy. However, we find that the subdominant response does not preferentially benefit from ICB due to predominance of a dysfunctional subset of TCF1+ cells marked by CCR6 expression and differentiation to a Tc17 phenotype. CCR6+ TCF1+ cells are also found broadly across human cancers and do not correlate with patient response to ICB. This subset appears to be derived from poor T cell receptor stimulation, due to competition of T cells for good interactions with antigen presenting cells. Vaccination eliminates CCR6+ TCF1+ cells and disrupts the antigen dominance hierarchy, preferentially expanding the subdominant CD8 T cell response in tumors. Overall enrichment of TCF1+ cells is maintained amongst the subdominant response post-vaccination and current studies are exploring whether this promotes more durable tumor control or better response to ICB. These findings provide strong rationale for evaluating the relative response to high versus low pMHC stability antigens in clinical trials of pooled neoantigen vaccines, where low stability, subdominant antigens may contribute more to tumor control than previously realized. Citation Format: Megan L. Burger, Amanda M. Cruz, Grace E. Crossland, Giorgio Gaglia, Cecily C. Ritch, Sarah E. Blatt, Arjun Bhutkar, Sara Z. Tavana, Sandro Santagata, Tyler Jacks. Antigen dominance hierarchies shape CD8 T cell phenotypes and immunotherapy response in tumors [abstract]. In: Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy; 2021 Oct 5-6. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(1 Suppl):Abstract nr P010.

Antigen dominance hierarchies shape TCF1+ progenitor CD8 T cell phenotypes in tumors

CD8 Tcell responses against different tumor neoantigens occur simultaneously, yet little is known about the interplay between responses and its impact on Tcell function and tumor control. In mouse lung adenocarcinoma, we found that immunodominance is established in tumors, wherein CD8 Tcell expansion is predominantly driven by the antigen that most stably binds MHC. Tcells responding to subdominant antigens were enriched for a TCF1+ progenitor phenotype correlated with response to immune checkpoint blockade (ICB) therapy. However, the subdominant Tcell response did not preferentially benefit from ICB due to a dysfunctional subset of TCF1+ cells marked by CCR6 and Tc17 differentiation. Analysis of human samples and sequencing datasets revealed that CCR6+ TCF1+ cells exist across human cancers and are not correlated with ICB response. Vaccination eliminated CCR6+ TCF1+ cells and dramatically improved the subdominant response, highlighting a strategy to optimally engage concurrent neoantigen responses against tumors.

Antigen Dominance Hierarchies Shape TCF1+ Progenitor CD8 T Cell Phenotypes in Tumors

CD8 T cell responses against different tumor neoantigens occur simultaneously, yet little is known about their interplay and its impact on T cell function and tumor control. In mouse lung adenocarcinoma, we find that immunodominance is established in tumors, wherein CD8 T cell expansion is predominantly driven by the antigen that most stably binds MHC. T cells responding to subdominant antigens are enriched for a TCF1+ progenitor phenotype that has been correlated with response to immune checkpoint blockade (ICB) therapy. However, the subdominant T cell response does not preferentially benefit from ICB due to a dysfunctional subset of TCF1+ progenitor cells marked by CCR6 and Tc17 differentiation. Analysis of human samples and sequencing datasets indicates CCR6+ TCF1+ cells exist across human cancers and correlate with poor ICB response. Vaccination eliminates CCR6+ TCF1+ cells and dramatically expands the subdominant response, highlighting a strategy to optimally engage concurrent neoantigen responses against tumors.

Predicting child effortful control: An integrative analysis of child physiological, familial, and community factors.

Effortful control (EC) is a regulatory capacity that refers to children's ability to inhibit a dominant response to perform a subdominant response. Although attempts have been made to identify early predictors of children's EC, the confluence and interaction of child-, familial-, and community factors has not been pursued adequately. This study investigated how predictors from different aspects of children's rearing environment interacted to predict later EC. In a sample of 88 primiparous women with elevated depressive symptomotology and low household income, we examined how children's own psychobiology (baseline cortisol), familial relationship (mother-child attachment), and community resources (social support) at 17months independently and jointly predicted EC at age 5. Our results showed that, controlling for maternal depressive symptomotology and household income, predictors from child-, familial-, and community-aspect function integratively, rather than independently, in predicting later EC. Specifically, within the context of a secure attachment relationship, baseline cortisol positively predicts later EC only for children of mothers who reported low social support. Whereas within the context of an insecure attachment relationship, baseline cortisol negatively predicts later EC, regardless of the perceived social support levels. Our results highlighted the importance of taking into consideration predictors from multiple aspects for intervention designs.

Abstract PR11: Antigen dominance hierarchies shape tumor T-cell phenotypes and immunotherapy responses

Abstract In order to drive a productive T-cell response to checkpoint immunotherapy, tumors must be sufficiently antigenic. However, antigens vary in their degree of immunogenicity and consequently drive T-cell responses of different magnitudes and quality. In a genetically engineered mouse model of lung adenocarcinoma expressing model T-cell antigens, we find that antigen dominance hierarchies are established in tumors, where the T-cell response is largely focused on a dominant epitope as observed in viral infections. Interestingly, while T cells responding to a subdominant antigen are fewer in number, we find that they are less exhausted and express more markers of memory cells. T cells responding to the dominant antigen rapidly contract, while those responding to the subdominant antigen persist better over time. Despite their seemingly greater functional potential, T cells responding to the subdominant antigen fail to respond significantly to checkpoint immunotherapy in the context of this dominance hierarchy. Remarkably, removal of the dominant antigen unleashes the subdominant response and these cells expand to fill the effector niche previously occupied by the dominant response. Current experiments are testing the ability of vaccination to “break dominance” and improve the contribution of the subdominant response to tumor control. These findings could have great relevance to the design of personalized cancer vaccines, where targeting subdominant antigens over dominant antigens may lead to surprising therapeutic benefit. This abstract is also being presented as Poster B36. Citation Format: Megan L. Burger, Grace E. Crossland, Jason M. Schenkel, David A. Canner, Tyler Jacks. Antigen dominance hierarchies shape tumor T-cell phenotypes and immunotherapy responses [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr PR11.

A natural polymorphism of EsxH in Mycobacterium tuberculosis disrupts the immunodominant CD8 T cell response.

Abstract Mycobacterium tuberculosis (Mtb), the cause of tuberculosis (TB), is an intracellular bacterium that evades antibacterial immunity. As control of Mtb requires T cell immunity, most vaccine strategies focus on eliciting protective T cells. How Mtb benefits from promoting T cell activation or evading T cell recognition is not certain. Here, we took advantage of a naturally occurring Mtb polymorphism to address this question in mouse model. EsxH elicits an immunodominant CD8 T cell response. At the peak of immunity against Mtb in C57BL/6 mice, 30–50% of CD8 T cells are specific for EsxH4–11. Clinical Isolate 667 (CI667) is an Mtb strain containing a polymorphism in EsxH that has a single amino acid change of WT EsxH4–11 epitope from IMYNYPAM into IMYNYPTM (A10T). We hypothesized that this naturally occurring polymorphism would alter the hierarchy of CD8 T cell responses elicited by Mtb. Following Erdman (WT) Mtb infection of C57BL/6 mice, CD8 T cells respond to three distinct epitopes, including the reported immunodominant EsxH4–11 epitope. In contrast, there was no response to any of EsxH epitopes after CI667 infection. Instead, the subdominant response to the 32C antigen became dominant. In BALB/c mice, CI667 stimulated a reduced but detectable CD8 response to EsxH20–28; the CD4 response to EsxH74–88 was similar to WT Mtb infection. These results show that naturally occurring polymorphisms can have drastic effects on T cell immunity. We hypothesize that EsxH acts as a decoy antigen, and distracts the CD8 response from focusing on antigens that are presented by infected macrophages and protective. We are in the process of testing this hypothesis by developing isogenic Mtb strains that express EsxHErdman or EsxHCI667.

The Emergence of Effortful Control in Young Boys With Fragile X Syndrome.

Effortful control, or the ability to suppress a dominant response to perform a subdominant response, is an early-emerging temperament trait that is linked with positive social-emotional development. Fragile X syndrome (FXS) is a single-gene disorder characterized by hallmark regulatory impairments, suggesting diminished effortful control. This study compared the development of effortful control in preschool boys with FXS ( n = 97) and typical development ( n = 32). Unlike their typical peers, the boys with FXS did not exhibit growth in effortful control over time, which could not be accounted for by adaptive impairments, FMR1 molecular measures, or autism symptoms. These results contribute to our understanding of the childhood phenotype of FXS that may be linked to the poor social-emotional outcomes seen in this group.

The reaction of firstborn children to a sibling before the birth: the role of the time at which they are told about the mother’s pregnancy and their effortful control

Objectives: The reaction of firstborns to the impending arrival of a sibling has received little attention from family psychologists. The present study examined whether firstborns’ positive feelings about their sibling before the birth were related to the time at which they were told about the mother’s pregnancy and their effortful control, which was defined as the self-regulatory ability to inhibit a dominant response to perform a subdominant response. The goal of this research was to provide preliminary evidence in the social context of the two-child policy in China.Methods: The sample included 52 Chinese parents and their firstborns when mothers were in their third trimester of pregnancy with their second child. Data were obtained by means of observation and parent-reported questionnaires.Results: Firstborn children who were told earlier in their mothers’ pregnancy were more likely to have positive feelings about their sibling before the birth. In addition, firstborns’ effortful control was positively associated with positive feelings about a sibling before the birth. Last, firstborns’ effortful control moderated the association between the time at which they were told and positive feelings about the sibling before the birth. Specifically, only when firstborns had low levels of effortful control, being told later about the pregnancy, was related to lower levels of positive feelings about the sibling.Conclusions: Findings enhanced our understanding of how parents’ preparation and firstborns’ individual characteristics may have a role on firstborns’ positive adjustment before the birth of a sibling.

High effortful control is associated with reduced emotional expressiveness in young children

The current study tested the claim that trait effortful control (EC), the ability to suppress a dominant response to perform a subdominant response, is associated with children’s emotion expression. Participants were 206 community children between the ages of 3 and 7years. Children completed a battery of 10 laboratory tasks to assess temperamental differences in EC, as well as positive and negative emotionality. We report on bivariate associations between laboratory-assessed and parent-reported EC and laboratory-assessed emotions of different valences and intensity levels. Children coded as high in lab-assessed EC exhibited fewer total emotional expressions (positive and negative emotions), and engaged in lower intensity expressions than children lower in EC. Parent-reported EC measures were weakly associated with laboratory measures of emotion.

Subdominant H60 antigen-specific CD8 T-cell response precedes dominant H4 antigen-specific response during the initial phase of allogenic skin graft rejection.

In allogeneic transplantation, including the B6 anti-BALB.B settings, H60 and H4 are two representative dominant minor histocompatibility antigens that induce strong CD8 T-cell responses. With different distribution patterns, H60 expression is restricted to hematopoietic cells, whereas H4 is ubiquitously expressed. H60-specific CD8 T-cell response has been known to be dominant in most cases of B6 anti-BALB.B allo-responses, except in the case of skin transplantation. To understand the mechanism underlying the subdominance of H60 during allogeneic skin transplantation, we investigated the dynamics of the H60-specific CD8 T cells in B6 mice transplanted with allogeneic BALB.B tail skin. Unexpectedly, longitudinal bioluminescence imaging and flow cytometric analyses revealed that H60-specific CD8 T cells were not always subdominant to H4-specific cells but instead showed a brief dominance before the H4 response became predominant. H60-specific CD8 T cells could expand in the draining lymph node and migrate to the BALB.B allografts, indicating their active participation in the anti-BALB.B allo-response. Enhancing the frequencies of H60-reactive CD8 T cells prior to skin transplantation reversed the immune hierarchy between H60 and H4. Additionally, H60 became predominant when antigen presentation was limited to the direct pathway. However, when antigen presentation was restricted to the indirect pathway, the expansion of H60-specific CD8 T cells was limited, whereas H4-specific CD8 T cells expanded significantly, suggesting that the temporary immunodominance and eventual subdominance of H60 could be due to their reliance on the direct antigen presentation pathway. These results enhance our understanding of the immunodominance phenomenon following allogeneic tissue transplantation.

Exploring dimensionality of effortful control using hot and cool tasks in a sample of preschool children

Effortful control (EC) is an important developmental construct associated with academic performance, socioemotional growth, and psychopathology. EC, defined as the ability to inhibit or delay a prepotent response typically in favor of a subdominant response, undergoes rapid development during children’s preschool years. Research involving EC in preschool children can be aided by ensuring that the measured model of EC matches the latent structure of EC. Extant research indicates that EC may be multidimensional, consisting of hot (affectively salient) and cool (affectively neutral) dimensions. However, there are several untested assumptions regarding the defining features of hot EC. Confirmatory factor analysis was used in a sample of 281 preschool children (Mage=55.92months, SD=4.16; 46.6% male and 53.4% female) to compare a multidimensional model composed of hot and cool EC factors with a unidimensional model. Hot tasks were created by adding affective salience to cool tasks so that hot and cool tasks varied only by this aspect of the tasks. Tasks measuring EC were best described by a single factor and not distinct hot and cool factors, indicating that affective salience alone does not differentiate between hot and cool EC. EC shared gender-invariant associations with academic skills and externalizing behavior problems.

Effortful Control in “Hot” and “Cool” Tasks Differentially Predicts Children’s Behavior Problems and Academic Performance

Effortful control (EC), the capacity to deliberately suppress a dominant response and perform a subdominant response, rapidly developing in toddler and preschool age, has been shown to be a robust predictor of children's adjustment. Not settled, however, is whether a view of EC as a heterogeneous rather than unidimensional construct may offer advantages in the context of predicting diverse developmental outcomes. This study focused on the potential distinction between "hot" EC function (delay-of-gratification tasks that called for suppressing an emotionally charged response) and more abstract "cool" EC functions (motor inhibition tasks, suppressing-initiating response or Go-No Go tasks, and effortful attention or Stroop-like tasks). Children (N = 100) were observed performing EC tasks at 38 and 52 months. Mothers, fathers, and teachers rated children's behavior problems and academic performance at 67, 80, and 100 months, and children participated in a clinical interview at 100 months. Structural Equation Modeling (SEM) analyses with latent variables produced consistent findings across all informants: Children's scores in "hot" EC tasks, presumably engaging emotion regulation skills, predicted behavior problems but not academic performance, whereas their scores in "cool" EC tasks, specifically those engaging effortful attention, predicted academic performance but not behavior problems. The models of EC as a heterogeneous construct offered some advantages over the unidimensional models. Methodological and clinical implications of the findings are discussed.

Chemotherapy broadens the range of tumor antigens seen by cytotoxic CD8(+) T cells in vivo.

Cytotoxic chemotherapies may expose the immune system to high levels of tumor antigens and expand the CD8(+) T-cell response to include weak or subdominant antigens. Here, we evaluated the in vivo CTL response to tumor antigens using a murine mesothelioma tumor cell line transfected with a neotumor antigen, ovalbumin, that contains a known hierarchy of epitopes for MHC class I molecules. We show that as tumors progress, effector CTLs are generated in vivo that focus on the dominant epitope SIINFEKL, although a weak response was seen to one (KVVRFDKL) subdominant epitope. These CTLs did not prevent tumor growth. Cisplatin treatment slowed tumor growth, slightly improved in vivo SIINFEKL presentation to T cells and reduced SIINFEKL-CTL activity. However, the CTL response to KVVRFDKL was amplified, and a response to another subdominant epitope, NAIVFKGL, was revealed. Similarly, gemcitabine cured most mice, slightly enhanced SIINFEKL presentation, reduced SIINFEKL-CTL activity yet drove a significant CTL response to NAIVFKGL, but not KVVRFDKL. These NAIVFKGL-specific CTLs secreted IFNγ and proliferated in response to in vitro NAIVFKGL stimulation. IL-2 treatment during chemotherapy refocused the response to SIINFEKL and simultaneously degraded the cisplatin-driven subdominant CTL response. These data show that chemotherapy reveals weaker tumor antigens to the immune system, a response that could be rationally targeted. Furthermore, while integrating IL-2 into the chemotherapy regimen interfered with the hierarchy of the response, IL-2 or other strategies that support CTL activity could be considered upon completion of chemotherapy.

Decline of influenza-specific CD8+ T cell repertoire in healthy geriatric donors

BackgroundWhile influenza vaccination results in protective antibodies against primary infections, clearance of infection is primarily mediated through CD8+ T cells. Studying the CD8+ T cell response to influenza epitopes is crucial in understanding the disease associated morbidity and mortality especially in at risk populations such as the elderly. We compared the CD8+ T cell response to immunodominant and subdominant influenza epitopes in HLA-A2+ control, adult donors, aged 21-42, and in geriatric donors, aged 65 and older.ResultsWe used a novel artificial Antigen Presenting Cell (aAPC) based stimulation assay to reveal responses that could not be detected by enzyme-linked immunosorbent spot (ELISpot). 14 younger control donors and 12 geriatric donors were enrolled in this study. The mean number of influenza-specific subdominant epitopes per control donor detected by ELISpot was only 1.4 while the mean detected by aAPC assay was 3.3 (p = 0.0096). Using the aAPC assay, 92% of the control donors responded to at least one subdominant epitopes, while 71% of control donors responded to more than one subdominant influenza-specific response. 66% of geriatric donors lacked a subdominant influenza-specific response and 33% of geriatric donors responded to only 1 subdominant epitope. The difference in subdominant response between age groups is statistically significant (p = 0.0003).ConclusionGeriatric donors lacked the broad, multi-specific response to subdominant epitopes seen in the control donors. Thus, we conclude that aging leads to a decrease in the subdominant influenza-specific CTL responses which may contribute to the increased morbidity and mortality in older individuals.

T Cell Receptor Clonotype Influences Epitope Hierarchy in the CD8+ T Cell Response to Respiratory Syncytial Virus Infection

CD8+ T cell responses are important for recognizing and resolving viral infections. To better understand the selection and hierarchy of virus-specific T cell responses, we compared the T cell receptor (TCR) clonotype in parent and hybrid strains of respiratory syncytial virus-infected mice. K(d)M2(82-90) (SYIGSINNI) in BALB/c and D(b)M(187-195) (NAITNAKII) in C57Bl/6 are both dominant epitopes in parent strains but assume a distinct hierarchy, with K(d)M2(82-90) dominant to D(b)M(187-195) in hybrid CB6F1/J mice. The dominant K(d)M2(82-90) response is relatively public and is restricted primarily to the highly prevalent Vβ13.2 in BALB/c and hybrid mice, whereas D(b)M(187-195) responses in C57BL/6 mice are relatively private and involve multiple Vβ subtypes, some of which are lost in hybrids. A significant frequency of TCR CDR3 sequences in the D(b)M(187-195) response have a distinct "(D/E)WG" motif formed by a limited number of recombination strategies. Modeling of the dominant epitope suggested a flat, featureless structure, but D(b)M(187-195) showed a distinctive structure formed by Lys(7). The data suggest that common recombination events in prevalent Vβ genes may provide a numerical advantage in the T cell response and that distinct epitope structures may impose more limited options for successful TCR selection. Defining how epitope structure is interpreted to inform T cell function will improve the design of future gene-based vaccines.

Examining the dimensionality of effortful control in preschool children and its relation to academic and socioemotional indicators.

Effortful control (EC) is an important developmental construct, associated with socioemotional growth, academic performance, and psychopathology. EC is defined as the ability to execute goal-directed behavior to inhibit or delay a prepotent response in favor of a subdominant response. Extant research indicates that EC may be multidimensional. Confirmatory factor analysis with a sample of 234 preschoolers was used to determine if tasks designed to measure EC were best described by hot (affectively salient) and cool (affectively neutral) dimensions or by a single factor. Analyses revealed that EC is best described by a single factor, even when variance associated with children's language skills was removed. This EC factor was strongly related to measures of academic performance and significantly less related to measures of socioemotional development.

Efficacious early antiviral activity of HIV Gag- and Pol-specific HLA-B 2705-restricted CD8+ T cells.

The association between HLA-B 2705 and the immune control of human immunodeficiency virus type 1 (HIV-1) has previously been linked to the targeting of the HLA-B 2705-restricted Gag epitope KRWIILGLNK (KK10) by CD8(+) T cells. In order to better define the mechanisms of the HLA-B 2705 immune control of HIV, we first characterized the CD8(+) T-cell responses of nine highly active antiretroviral therapy (HAART)-naïve B 2705-positive subjects. Unexpectedly, we observed a strong response to an HLA-B 2705-restricted Pol epitope, KRKGGIGGY (KY9), in 8/9 subjects. The magnitude of the KY9 response was only marginally lower than that of the KK10-specific response (median, 695 versus 867 spot-forming cells [SFC]/million peripheral blood mononuclear cells [PBMCs]; not significant [NS]), and viral escape mutants were observed in both KY9 and KK10, resulting from selection pressure driven by the respective CD8(+) T-cell response. By comparing inhibitions of viral replication by CD8(+) T cells specific for the Gag KK10, Pol KY9, and Vpr VL9 HLA-B 2705-restricted epitopes, we observed a consistent hierarchy of antiviral efficacy (Gag KK10 > Pol KY9 > Vpr VL9). This hierarchy was associated with early recognition of HIV-1-infected cells, within 6 h of infection, by KK10- and KY9-specific CD8(+) T cells but not until 18 h postinfection by VL9-specific CD8(+) T cells. There was no association between antiviral efficacy and proliferative capacity, cytotoxicity, polyfunctionality, or T-cell receptor (TCR) avidity. These data are consistent with previous studies indicating an important role for the B 2705-Gag KK10 response in the control of HIV but also suggest a previously unrecognized role played by the subdominant Pol-specific KY9 response in HLA-B 2705-mediated control of HIV and that the recognition of HIV-infected cells by CD8(+) T cells early in the viral life cycle may be important for viral containment in HIV-infected individuals.