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Viral mutational escape can reduce or abrogate recognition by the T cell receptor (TCR) of virus-specific CD8+ T cells. However, very little is known about the impact of cytotoxic T lymphocyte (CTL) epitope mutations on interactions between peptide–major histocompatibility complex (MHC) class I complexes and MHC class I receptors expressed on other cell types. Here, we analyzed a variant of the immunodominant human leukocyte antigen (HLA)-B2705–restricted HIV-1 Gag KK10 epitope (KRWIILGLNK) with an L to M amino acid substitution at position 6 (L6M), which arises as a CTL escape variant after primary infection but is sufficiently immunogenic to elicit a secondary, de novo HIV-1–specific CD8+ T cell response with an alternative TCR repertoire in chronic infection. In addition to altering recognition by HIV-1–specific CD8+ T cells, the HLA-B2705–KK10 L6M complex also exhibits substantially increased binding to the immunoglobulin-like transcript (ILT) receptor 4, an inhibitory MHC class I–specific receptor expressed on myelomonocytic cells. Binding of the B2705–KK10 L6M complex to ILT4 leads to a tolerogenic phenotype of myelomonocytic cells with lower surface expression of dendritic cell (DC) maturation markers and co-stimulatory molecules. These data suggest a link between CTL-driven mutational escape, altered recognition by innate MHC class I receptors on myelomonocytic cells, and functional impairment of DCs, and thus provide important new insight into biological consequences of viral sequence diversification.

Human immunodeficiency virus type 1 (HIV-1)-specific CD8؉ T cells in early infection are associated with the dramatic decline of peak viremia, whereas their antiviral activity in chronic infection is less apparent. The functional properties accounting for the antiviral activity of HIV-1-specific CD8 ؉ T cells during early infection are unclear. Using cytokine secretion and tetramer decay assays, we demonstrated in intraindividual comparisons that the functional avidity of HIV-1-specific CD8 ؉ T cells was consistently higher in early infection than in chronic infection in the presence of high-level viral replication. This change of HIV-1-specific CD8 ؉ T-cell avidity between early and chronic infections was linked to a substantial switch in the clonotypic composition of epitope-specific CD8 ؉ T cells, resulting from the preferential loss of high-avidity CD8 ؉ T-cell clones. In contrast, the maintenance of the initially recruited clonotypic pattern of HIV-1-specific CD8 ؉ T cells was associated with low-level set point HIV-1 viremia. These data suggest that high-avidity HIV-1-specific CD8 ؉ T-cell clones are recruited during early infection but are subsequently lost in the presence of persistent high-level viral replication.

The relative contributions of HLA alleles and T-cell receptors (TCRs) to the prevention of mutational viral escape are unclear. Here, we examined human immunodeficiency virus type 1 (HIV-1)-specific CD8 ؉ T-cell responses restricted by two closely related HLA class I alleles, B*5701 and B*5703, that differ by two amino acids but are both associated with a dominant response to the same HIV-1 Gag epitope KF11 (KAFSPEVIP MF). When this epitope is presented by HLA-B*5701, it induces a TCR repertoire that is highly conserved among individuals, cross-recognizes viral epitope variants, and is rarely associated with mutational escape. In contrast, KF11 presented by HLA-B*5703 induces an entirely different, more heterogeneous TCR ␤-chain repertoire that fails to recognize specific KF11 escape variants which frequently arise in clade C-infected HLA-B*5703 ؉ individuals. These data show the influence of HLA allele subtypes on TCR selection and indicate that extensive TCR diversity is not a prerequisite to prevention of allowable viral mutations. Sequence mutations resulting in loss of recognition by CD8ϩ

Antiviral Abs, for example those produced in response to influenza virus infection, are critical for virus neutralization and defense against secondary infection. While the half-life of Abs is short, Ab titers can last a lifetime due to a subset of the Ab-secreting cells (ASCs) that is long lived. However, the mechanisms governing ASC longevity are poorly understood. Here, we have identified a critical role for extrinsic cytokine signals in the survival of respiratory tract ASCs in a mouse model of influenza infection. Irradiation of mice at various time points after influenza virus infection markedly diminished numbers of lung ASCs, suggesting that they are short-lived and require extrinsic factors in order to persist. Neutralization of the TNF superfamily cytokines B lymphocyte stimulator (BLyS; also known as BAFF) and a proliferation-inducing ligand (APRIL) reduced numbers of antiviral ASCs in the lungs and bone marrow, whereas ASCs in the spleen and lung-draining lymph node were surprisingly unaffected. Mice deficient in transmembrane activator and calcium-modulator and cyclophilin ligand interactor (TACI), a receptor for BLyS and APRIL, mounted an initial antiviral B cell response similar to that generated in WT mice but failed to sustain protective Ab titers in the airways and serum, leading to increased susceptibility to secondary viral challenge. These studies highlight the importance of TACI signaling for the maintenance of ASCs and protection against influenza virus infection.

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Exhaustion of virus-specific T cells may play an important role in the pathophysiology of chronic viral infections. Here, we analyzed telomere length and telomerase activity in HIV-1-specific CD8 ؉ T cells from progressors or controllers to determine underlying molecular pathways of T-cell exhaustion and senescence. Telomere lengths of HIV-1-specific CD8 ؉ T cells from progressors were significantly shorter compared with autologous cytomegalovirus (CMV)/Epstein-Barr virus (EBV)-specific CD8 ؉ T cells or bulk CD8 ؉ T cells, while telomere lengths from controllers significantly exceeded those of autologous bulk CD8 ؉ T cells and reached a similar level as HIV-1-specific CD8 ؉ T cells collected during primary HIV-1 infection. Telomere length stabilization in controllers corresponded to high levels of constitutive telomerase activity, which was associated with preservation of cytotoxic and proliferative properties. Conversely, limited constitutive telomerase activity was observed in HIV-1-specific CD8 ؉ T cells from progressors, although an increase in both telomere length and telomerase activity was IntroductionSpontaneous control of HIV-1 viremia is achieved in a small proportion of infected individuals called HIV controllers. The relative overrepresentation of specific MHC class I alleles such as HLA-B57 and HLA-B27 in this specific patient population 1,2 suggests that low-level viremia in these persons is at least partially mediated by HIV-1-specific CD8 ϩ T cells. However, progressive viremia in advanced stages of infection typically occurs in the presence of strong, broadly diversified, and polyclonal HIV-1-specific CD8 ϩ T-cell populations [3][4][5] with preserved recognition of the autologous virus 6 and a similar immunodominance pattern as described in controllers. 7,8 This paradoxic finding has recently been related to a defective functional profile of HIV-1-specific CD8 ϩ T cells in chronic progressive infection, which have preserved IFN-␥ secretion, but lack ex vivo antigen-specific proliferative activities. In contrast, HIV-1-specific CD8 ϩ T cells collected from HIV-1 controllers were found to have strong ex vivo proliferative activities, which was associated with increased perforin expression and superior cytotoxic properties. 3 Although cellular exhaustion and accelerated immune senescence has been repeatedly suggested as key mechanisms in HIV immunopathogenesis, 9-13 aging of HIV-1-specific T cells as well as regulatory molecular processes governing their senescence have never been analyzed. Moreover, how alterations in immune senescence are involved in the development of HIV-1-specific T-cell dysfunction in progressive HIV-1 infection or in the maintenance of polyfunctional HIV-1-specific T cells in HIV controllers is currently unknown. In addition, it is currently unclear whether progressive senescence of HIV-1-specific T cells is an irreversible process, or whether aging of these cells can actively be manipulated for immunotherapeutic purposes.In the present study, we conducted a detailed analys...