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HIV disease progression correlates with the generation of dysfunctional naive CD8(low) T cells.

ABSTRACT: HIV infection can result in depletion of total CD4(+) T cells and naive CD8(+) T cells, and in the generation of dysfunctional effector CD8(+) T cells. In this study, we show that naive CD8(+) T cells in subjects with progressive HIV disease express low levels of CD8? and CD8? chains. Such naive CD8(low) T cells display broad signaling defects across the T-cell receptor complex, and their appearance correlates with generalized up-regulation of major histocompatibility complex class I (MHC-I) antigens on peripheral blood mononuclear cells (PBMCs). To explore a causal link between increased MHC-I up-regulation and the generation of naive CD8(low) T cells, we used the humanized SCID-hu Thy/Liv mouse model to show that HIV infection of the thymus and interferon ? (IFN?) treatment alone result in MHC-I up-regulation and in the generation of dysfunctional CD3(high)CD8(+)CD4(-) single-positive 8 (SP8) thymocytes with low expression of CD8. We suggest that dysfunctional naive CD8(low) T cells are generated as a result of IFN?-mediated up-regulation of MHC-I on stromal cells in the thymus and antigen-presenting cells in the periphery, and that dysfunction in this naive compartment contributes to the immunodeficiency of HIV disease. This study is registered at www.clinicaltrials.gov as NCT00187512.

SUBMITTER: Favre D

PROVIDER: S-EPMC3062328 | biostudies-literature | 2011 Feb

REPOSITORIES: biostudies-literature

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HIV disease progression correlates with the generation of dysfunctional naive CD8(low) T cells.

Favre David D Stoddart Cheryl A CA Emu Brinda B Hoh Rebecca R Martin Jeffrey N JN Hecht Frederick M FM Deeks Steven G SG McCune Joseph M JM

Blood 20110103 7

HIV infection can result in depletion of total CD4(+) T cells and naive CD8(+) T cells, and in the generation of dysfunctional effector CD8(+) T cells. In this study, we show that naive CD8(+) T cells in subjects with progressive HIV disease express low levels of CD8α and CD8β chains. Such naive CD8(low) T cells display broad signaling defects across the T-cell receptor complex, and their appearance correlates with generalized up-regulation of major histocompatibility complex class I (MHC-I) ant ...[more]

PMID: 21200021

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Project description:Genetic and immunologic analyses of epidemiologically-linked HIV transmission enable insights into the impact of immune responses on clinical outcomes. Human vaccine trials and animal studies of HIV-1 infection have suggested immune correlates of protection; however, their role in natural infection in terms of protection from disease progression is mostly unknown. Four HIV-1+ Cameroonian individuals, three of them epidemiologically-linked in a polygamous heterosexual relationship and one incidence-matched case, were studied over 15 years for heterologous and cross-neutralizing antibody responses, antibody binding, IgA/IgG levels, antibody-dependent cellular cytotoxicity (ADCC) against cells expressing wild-type or CD4-bound Env, viral evolution, Env epitopes, and host factors including HLA-I alleles. Despite viral infection with related strains, the members of the transmission cluster experienced contrasting clinical outcomes including cases of rapid progression and long-term non-progression in the absence of strongly protective HLA-I or CCR5Δ32 alleles. Slower progression and higher CD4/CD8 ratios were associated with enhanced IgG antibody binding to native Env and stronger V1V2 antibody binding responses in the presence of viruses with residue K169 in V2. ADCC against cells expressing Env in the CD4-bound conformation in combination with low Env-specific IgA/IgG ratios correlated with better clinical outcome. This data set highlights for the first time that V1V2-directed antibody responses and ADCC against cells expressing open, CD4-exposed Env, in the presence of low plasma IgA/IgG ratios, can correlate with clinical outcome in natural infection. These parameters are comparable to the major correlates of protection, identified post-hoc in the RV144 vaccine trial; thus, they may also modulate the rate of clinical progression once infected. The findings illustrate the potential of immune correlate analysis in natural infection to guide vaccine development.

Project description:UnlabelledChronic HIV infection results in a loss of HIV-specific CD8(+) T cell effector function, termed "exhaustion," which is mediated, in part, by the membrane coinhibitory receptor T cell immunoglobulin mucin domain-3 (Tim-3). Like many other receptors, a soluble form of this protein has been described in human blood plasma. However, soluble Tim-3 (sTim-3) is poorly characterized, and its role in HIV disease is unknown. Here, we show that Tim-3 is shed from the surface of responding CD8(+) T cells by the matrix metalloproteinase ADAM10, producing a soluble form of the coinhibitory receptor. Despite previous reports in the mouse model, no alternatively spliced, soluble form of Tim-3 was observed in humans. Shed sTim-3 was found in human plasma and was significantly elevated during early and chronic untreated HIV infection, but it was not found differentially modulated in highly active antiretroviral therapy (HAART)-treated HIV-infected subjects or in elite controllers compared to HIV-uninfected subjects. Plasma sTim-3 levels were positively correlated with HIV load and negatively correlated with CD4 counts. Thus, plasma sTim-3 shedding correlated with HIV disease progression. Despite these correlations, we found that shedding Tim-3 did not improve the function of CD8(+) T cells in terms of gamma interferon production or prevent their apoptosis through galectin-9. Further characterization studies of sTim-3 function are needed to understand the contribution of sTim-3 in HIV disease pathogenesis, with implications for novel therapeutic interventions.ImportanceDespite the overall success of HAART in slowing the progression to AIDS in HIV-infected subjects, chronic immune activation and T cell exhaustion contribute to the eventual deterioration of the immune system. Understanding these processes will aid in the development of interventions and therapeutics to be used in combination with HAART to slow or reverse this deterioration. Here, we show that a soluble form of T cell exhaustion associated coinhibitory molecule 3, sTim-3, is shed from the surface of T cells. Furthermore, sTim-3 is elevated in the plasma of treatment-naive subjects with acute or chronic HIV infection and is associated with markers of disease progression. This is the first study to characterize sTim-3 in human plasma, its source, and mechanism of production. While it is still unclear whether sTim-3 contributes to HIV pathogenesis, sTim-3 may represent a new correlate of HIV disease progression.

Project description:UnlabelledDuring the chronic phase of HIV-1 infection, polyfunctional CD8+ T cell responses, which are characterized by a high frequency of cells able to secrete multiple cytokines simultaneously, are associated with lower virus loads and slower disease progression. This relationship may arise for different reasons. Polyfunctional responses may simply be stronger. Alternatively, it could be that the increased functional diversity in polyfunctional responses leads to lower virus loads and slower disease progression. Lastly, polyfunctional responses could contain more CD8+ T cells that mediate a specific key function that is primarily responsible for viral control. Disentangling the influences of overall strength, functional diversity, and specific function on viral control and disease progression is very relevant for the rational design of vaccines and immunotherapy using cellular immune responses. We developed a mathematical model to study how polyfunctional CD8+ T cell responses mediating lytic and nonlytic effector functions affect the CD4+ T cell count and plasma viral load. We based our model on in vitro data on the efficacy of gamma interferon (IFN-?) and macrophage inflammatory protein 1? (MIP-1?)/RANTES against HIV. We find that the strength of the response is a good predictor of disease progression, while functional diversity has only a minor influence. In addition, our model predicts for realistic levels of cytotoxicity that immune responses dominated by nonlytic effector functions most positively influence disease outcome.ImportanceIt is an open question in HIV research why polyfunctional CD8+ T cell responses are associated with better viral control, while individual functional correlates of protection have not been identified so far. Identifying the role of CD8+ T cells in HIV-1 infection has important implications for the potential development of effective T cell-based vaccines. Our analysis provides new ways to think about a causative role of CD8+ T cells by studying different hypotheses regarding why polyfunctional CD8+ T cells might be more advantageous. We identify measurements that have to be obtained in order to evaluate the role of CD8+ T cells in HIV-1 infection. In addition, our method shows how individual cell functionality data can be used in population-based virus dynamics models.

Project description:BACKGROUND:In human immunodeficiency virus (HIV) infection, 10-15% of individuals exhibit a rapid decline in CD4+ T cells and become rapid progressors (RPs). Overall, understanding the factors affecting rapid disease progression in early HIV infection (EHI) can aid in treatment initiation. Recent studies show that eIF3s, classic scaffold proteins during the translation initiation process, can directly promote or inhibit the translation of mRNA, therefore participating in the regulation of cell function. However, to our knowledge, it has not been addressed whether eIF3s are involved in the diverse prognosis of HIV infection. METHODS:Expression of eIF3s in primary cells from early or chronic HIV-infected patients was detected by real-time PCR. To investigate the potential mechanisms of eIF3d in the regulation of CD8+ T cell function, complete transcriptomes of eIF3d-inhibited Jurkat T cells were sequenced by RNA sequencing (RNA-Seq). Additionally, to examine the effect of eIF3d on CD8+ T cell function, eIF3d expression was inhibited alone or in combination with SOCS-7 knockdown by siRNA in isolated CD8+ T cells. CD8+ T cell proliferation, IFN-r secretion and apoptosis were detected by flow cytometry. Moreover, the effect of eIF3d on HIV replication was evaluated in Jurkat cells, peripheral blood mononuclear cells (PBMCs) and CD4+ T cells with eIF3d knockdown using a pNL4-3 pseudotyped virus. RESULTS:At approximately 100 days of infection, only eIF3d was markedly decreased in RPs compared with chronic progressors (CPs). Expression of eIF3d correlated significantly with disease progression in EHI. Based on in vitro analyses, reduced eIF3d expression led to decreased proliferation and IFN-γ secretion and increased apoptosis in CD8+ T cells. Inhibited expression of eIF3d caused enhanced expression of SOCS-7, and inhibiting SOCS-7 expression by siRNA rescued the attenuated CD8+ T cell function caused by eIF3d. Finally, when eIF3d was inhibited in Jurkat cells, PBMCs and CD4+ T cells, pNL4-3-VSV-G virus replication was enhanced. CONCLUSIONS:The current data highlight the importance of eIF3d in HIV infection by inhibiting CD8+ T cell function and promoting viral replication. Our study provides potential targets for improved immune intervention.

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HIV disease progression correlates with the generation of dysfunctional naive CD8(low) T cells.

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HIV disease progression correlates with the generation of dysfunctional naive CD8(low) T cells.

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