Human leukocyte antigen (HLA) B*27 and B*57 are associated with protection against HIV-1 disease progression, yet most persons expressing these alleles are unable to control HIV-1. Here we show that HLA-B*27-restricted CD8+ T cells in controllers and progressors differ in their ability to inhibit virus replication through targeting of the immunodominant Gag epitope. This is associated with distinct TCR clonotypes, characterized by superior control of HIV-1 replication in vitro, greater cross-reactivity against epitope variants, and enhanced perforin delivery. Clonotype-specific differences in antiviral efficacy were also observed for an immunodominant HLA-B*57 restricted response in controllers and progressors. Thus, the efficacy of protective alleles is modulated by specific TCR clonotypes selected in natural infection, providing a functional explanation for divergent HIV-1 outcomes.

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A subset of HLA-B*35 alleles, B*35-Px, are strongly associated with accelerated HIV-1 disease progression for reasons that are not understood. Interestingly, the alternative set of B*35 subtypes, B*35-PY, have no detectable impact on HIV-1 disease outcomes, even though they can present identical HIV-1 epitopes as B*35-Px molecules. Thus, the differential impact of these alleles on HIV-1 disease progression may be unrelated to interactions with HIV-1–specific CD8+ T cells. Here, we show that the B*35-Px molecule B*3503 binds with greater affinity to immunoglobulin-like transcript 4 (ILT4), an inhibitory MHC class I receptor expressed on dendritic cells, than does the B*35-PY molecule B*3501, even though these two B*35 molecules differ by only one amino acid and present identical HIV-1 epitopes. The preferential recognition of B*3503 by ILT4 was associated with significantly stronger dendritic cell dysfunction in in vitro functional assays. Moreover, HIV-1–infected carriers of B*3503 had poor dendritic cell functional properties in ex vivo assessments when compared with carriers of the B*3501 allele. Differential interactions between HLA class I allele subtypes and immunoregulatory MHC class I receptors on dendritic cells thus provide a novel perspective for the understanding of MHC class I associations with HIV-1 disease progression and for the manipulation of host immunity against HIV-1.

Elite controllers maintain undetectable levels of HIV-1 replication in the absence of antiretroviral therapy, but the correlates of immune protection in this patient population are ill defined. Here, we demonstrate that in comparison to patients with progressive HIV-1 infection or healthy persons not infected with HIV-1, elite controllers have circulating myeloid dendritic cells with significantly increased antigen-presenting properties, while their ability to secrete proinflammatory cytokines is substantially diminished. This unique functional profile is associated with a distinct surface expression pattern of immunomodulatory leukocyte-immunoglobulin-like receptors (LILR) and a strong and selective upregulation of LILRB1 and LILRB3. Blockade of these two receptors by monoclonal antibodies or short interfering RNA (siRNA) abrogated the specific antigenpresenting properties of dendritic cells, implying an important regulatory role of these molecules. These data reveal previously unrecognized innate components of immune protection against HIV-1 in elite controllers and offer novel perspectives for the manipulation of host immunity for the prevention and treatment of HIV-1 infection.

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...