The key attributes of CD8+ T cell protective immunity in human immunodeficiency virus (HIV) infection remain unclear. We report that CD8+ T cell responses specific for Gag and, in particular, the immunodominant p24 epitope KK10 correlate with control of HIV-1 replication in human histocompatibility leukocyte antigen (HLA)–B27 patients. To understand further the nature of CD8+ T cell–mediated antiviral efficacy, we performed a comprehensive study of CD8+ T cells specific for the HLA-B27–restricted epitope KK10 in chronic HIV-1 infection based on the use of multiparametric flow cytometry together with molecular clonotypic analysis and viral sequencing. We show that B27-KK10–specific CD8+ T cells are characterized by polyfunctional capabilities, increased clonal turnover, and superior functional avidity. Such attributes are interlinked and constitute the basis for effective control of HIV-1 replication. These data on the features of effective CD8+ T cells in HIV infection may aid in the development of successful T cell vaccines.

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Natural killer (NK) cells are affected by infection with human cytomegalovirus (HCMV) manifested by increased expression of the HLA-E binding activating receptor NKG2C. We here show that HCMV seropositivity was associated with a profound expansion of NKG2C killer cell immunoglobulin-like receptors (KIRs) specific for self-HLA class I molecules, with predominant usage of KIR2DL2/3. KIR engagement dampened NKG2C-mediated activation suggesting that such biased expression of self-specific KIRs may preserve self-tolerance and limit immune-pathology during viral infection. Together, these findings shed new light on how the human NK-cell compartment adjusts to HCMV infection resulting in clonal expansion and differentiation of educated and polyfunctional NK cells. IntroductionNatural killer (NK) cells have the ability to kill targets without prior sensitization and their involvement in antiviral and antitumor immunity is well established [1,2]. Recent studies have demonstrated a high degree of functional heterogeneity in the NK-cell compartment attributable to a vast network of inhibitory or activating receptors that allow these cells to recognize target cells [3,4]. Killer cell immunoglobulin-like receptors (KIR) and CD94/NKG2 heterodimers are two major types of HLA class I binding receptors that regulate NK cell function [5,6]. Both these receptor-families exist in activating and inhibitory forms and contribute to the functional education of human NK cells by interactions with their cognate ligands [7], whereas KIR are expressed in a stochastic manner with a variegated distribution in the NK cell population [8,9], NKG2A is expressed on all CD56bright NK cells and disappears gradually during differentiation of CD56 dim NK cells [10,11]. NKG2C and NKG2A are covalently associated with CD94 [12]. Both NKG2A and NKG2C specifically interact with the non-classical MHC class-Ib molecule HLA-E, which is expressed at low levels on almost all nucleated cells, and presents peptides derived from signal sequences of other HLA class-I molecules [13]. The affinity of their interaction depends on the sequence of the HLA-E-bound nonamers and is higher for NKG2A than for NKG2C [14,15]. In the CD56 dim subset, NKG2C expression largely excludes NKG2A expression [10,16]. Expression of NKG2C is induced by co-culture with HCMV-infected fibroblasts and correlates with HCMV seropositivity in healthy donors [16,17]. Recently, NKG2C 1 NK cells were shown to expand during HIV and hantavirus infections in HCMV-seropositive patients, suggesting that HCMV may prime the NK-cell compartment for specific expansion of the NKG2C 1 subset upon additional viral encounters [18,19]. Two recent papers have demonstrated increased expression of NKG2C on NK cells in patients with chronic HBV and HCV infection [20,21]. Therefore, we choose this clinical setting to perform an in-depth characterization of the NKG2C 1 NK-cell subset. We show that NKG2C 1 CD56 dim NK cells are terminally differentiated, highly polyfunctional and display a clonal expression of inhib...

Human immunodeficiency virus (HIV) enters cells in vitro via CD4 and a coreceptor. Which of 15 known coreceptors are important in vivo is poorly defined but may be inferred from disease-modifying mutations, as for CCR5. Here two single nucleotide polymorphisms are described in Caucasians in CX3CR1, an HIV coreceptor and leukocyte chemotactic/adhesion receptor for the chemokine fractalkine. HIV-infected patients homozygous for CX3CR1-I249 M280, a variant haplotype affecting two amino acids (isoleucine-249 and methionine-280), progressed to AIDS more rapidly than those with other haplotypes. Functional CX3CR1 analysis showed that fractalkine binding is reduced among patients homozygous for this particular haplotype. Thus, CX3CR1-I249 M280 is a recessive genetic risk factor in HIV/AIDS.