Genetic and Immunologic Heterogeneity among Persons Who Control HIV Infection in the Absence of Therapy

Pereyra, Florencia; Addo, Marylyn M.; Kaufmann, Daniel E.; Liu, Yang; Miura, Toshiyuki; Rathod, Almas; Baker, B.M.; Trocha, Alicja; Rosenberg, Rachel; Mackey, Elizabeth W; Ueda, Peggy; Lu, Zhigang; Cohen, Daniel E.; Wrin, Terri; Petropoulos, Christos J.; Rosenberg, Eric S.; Walker, Bruce D.

doi:10.1086/526786

Cited by 468 publications

(573 citation statements)

References 44 publications

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“…Accordingly, a major thrust of current vaccine research focuses on stimulating robust T-cell immunity for defense against infections such as HIV, malaria, tuberculosis, Ebola virus, herpes viruses, and hepatitis C virus (HCV) (1)(2)(3)(4)(5)(6)(7)(8). Inducing effective CD8 T-cell immunity is also an important goal for cancer vaccines (9,10).…”

mentioning

confidence: 99%

Initial viral load determines the magnitude of the human CD8 T cell response to yellow fever vaccination

Akondy

Johnson²,

Nakaya

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

105

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CD8 T cells are a potent tool for eliminating intracellular pathogens and tumor cells. Thus, eliciting robust CD8 T-cell immunity is the basis for many vaccines under development. However, the relationship between antigen load and the magnitude of the CD8 T-cell response is not well-described in a human immune response. Here we address this issue by quantifying viral load and the CD8 T-cell response in a cohort of 80 individuals immunized with the live attenuated yellow fever vaccine (YFV-17D) by sampling peripheral blood at days 0, 1, 2, 3, 5, 7, 9, 11, 14, 30, and 90. When the virus load was below a threshold (peak virus load < 225 genomes per mL, or integrated virus load < 400 genome days per mL), the magnitude of the CD8 T-cell response correlated strongly with the virus load (R 2 ∼ 0.63). As the virus load increased above this threshold, the magnitude of the CD8 T-cell responses saturated. Recent advances in CD8 T-cell-based vaccines have focused on replication-incompetent or single-cycle vectors. However, these approaches deliver relatively limited amounts of antigen after immunization. Our results highlight the requirement that T-cellbased vaccines should deliver sufficient antigen during the initial period of the immune response to elicit a large number of CD8 T cells that may be needed for protection.vaccines | human CD8 T cells | viral load | effector T cells | immune memory C D8 T cells provide a powerful mechanism for elimination of intracellular pathogens and tumor cells. Accordingly, a major thrust of current vaccine research focuses on stimulating robust T-cell immunity for defense against infections such as HIV, malaria, tuberculosis, Ebola virus, herpes viruses, and hepatitis C virus (HCV) (1-8). Inducing effective CD8 T-cell immunity is also an important goal for cancer vaccines (9, 10). However, how antigen load affects the CD8 T-cell response has not been quantified in a detailed manner during a human immune response. In this study we address this question using the human live attenuated yellow fever vaccine (YFV-17D) vaccine.The dynamics of CD8 T-cell responses to intracellular infection have been extensively studied in model systems. Infection typically stimulates a rapid burst of proliferation in antigenspecific CD8 T cells with division occurring as quickly as once in 4-6 h (11). This expansion results in a large population of effector CD8 T cells that aid in clearance of infected cells. Although most (90-95%) of the effector CD8 T cells die, a small fraction differentiate to form long-term memory CD8 T cells (12). Detailed quantitative measurements of the dynamics of virus and the CD8 T-cell response to the YFV-17D vaccine allow us to characterize these basic features of the CD8 T-cell responses in humans. Additionally, tracking the dynamics of both virus and CD8 T cells over time in a large cohort allows us to explore the relationship between amount of antigen and the magnitude of expansion and answer the following questions: Is there a threshold amount of virus required to generate a r...

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mentioning

confidence: 99%

Initial viral load determines the magnitude of the human CD8 T cell response to yellow fever vaccination

Akondy

Johnson²,

Nakaya

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

105

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“…For example, approximately 60% of Caucasian elite controllers express HLA-B*27 and/or HLA-B*57, and approximately 60% of South African elite controllers express HLA-B*57/58:01 and/or HLA-B*81:01 (28)(29)(30). In these cases of viremic control in the absence of protective HLA molecules, it is unclear whether immunological or other mechanisms of viral control are involved.…”

mentioning

confidence: 99%

CD8 ⁺ T Cell Breadth and Ex Vivo Virus Inhibition Capacity Distinguish between Viremic Controllers with and without Protective HLA Class I Alleles

Koofhethile

Ndhlovu

Thobakgale-Tshabalala

et al. 2016

J Virol

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The mechanisms of viral control and loss of viral control in chronically infected individuals with or without protective HLA class I alleles are not fully understood. We therefore characterized longitudinally the immunological and virological features that may explain divergence in disease outcome in 70 HIV-1 C-clade-infected antiretroviral therapy (ART)-naive South African adults, 35 of whom possessed protective HLA class I alleles. We demonstrate that, over 5 years of longitudinal study, 35% of individuals with protective HLA class I alleles lost viral control compared to none of the individuals without protective HLA class I alleles (P ‫؍‬ 0.06). Sustained HIV-1 control in patients with protective HLA class I alleles was characteristically related to the breadth of HIV-1 CD8 ؉ T cell responses against Gag and enhanced ability of CD8 ؉ T cells to suppress viral replication ex vivo. In some cases, loss of virological control was associated with reduction in the total breadth of CD8 ؉ T cell responses in the absence of differences in HIV-1-specific CD8 ؉ T cell polyfunctionality or proliferation. In contrast, viremic controllers without protective HLA class I alleles possessed reduced breadth of HIV-1-specific CD8 ؉ T cell responses characterized by reduced ability to suppress viral replication ex vivo. These data suggest that the control of HIV-1 in individuals with protective HLA class I alleles may be driven by broad CD8 ؉ T cell responses with potent viral inhibitory capacity while control among individuals without protective HLA class I alleles may be more durable and mediated by CD8 ؉ T cell-independent mechanisms. H IV remains a global problem, and sub-Saharan Africa continues to bear the brunt of the epidemic, accounting for 67% of the infected people worldwide (1). Understanding the mechanisms of natural viral control in HIV infection is crucial for the identification of correlates of immune protection and for the design of an effective HIV vaccine. Previous studies have linked HIV control to a number of immunological factors, particularly HIVspecific CD8 ϩ cytotoxic T lymphocytes (CTLs), which have been demonstrated to play an important role (2-5). However, virusspecific CD8 ϩ T cell immune responses are not equally effective in HIV control, as the majority of infected individuals progress to disease despite the presence of these cells. HIV is able to evade immune responses by developing mutations that mediate escape from CTL recognition (6-12). In addition, the expression of certain HLA class I molecules by HIV-infected patients, such as HLA-B*27, HLA-B*57, HLA-B*58:01, HLA-B*81:01, and HLA-A*74: 01, is associated with better clinical disease outcomes in some population settings (3,(13)(14)(15)(16)(17)(18). HLA class I proteins present viral peptides on the surface of antigen-presenting cells to CTLs, and a major mechanism by which these protective alleles slow HIV disease progression is believed to be through CTL activity (18).

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“…However, genetics cannot entirely account for viremic control because it was found that 67% of long-term nonprogressors possess enriched HLA B57 and other protective HLA alleles, whereas the same alleles were also found in 37% of HIV-1 progressors (13,14). The purpose of the present study is to further explore a possible relationship between the expression of TOE1 and HIV-1 replication and to define whether TOE1 may function in an innate immune, CAF-like manner.…”

Section: Significancementioning

confidence: 92%

TOE1 is an inhibitor of HIV-1 replication with cell-penetrating capability

Sperandio

Barat

Cabrita

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Target of Egr1 (TOE1) is a nuclear protein localized primarily in nucleoli and Cajal bodies that was identified as a downstream target of the immediate early gene Egr1. TOE1 displays a functional deadenylation domain and has been shown to participate in spliceosome assembly. We report here that TOE1 can function as an inhibitor of HIV-1 replication and show evidence that supports a direct interaction of TOE1 with the viral specific transactivator response element as part of the inhibitory mechanism. In addition, we show that TOE1 can be secreted by activated CD8 + T lymphocytes and can be cleaved by the serine protease granzyme B, one of the main components of cytotoxic granules. Both full-length and cleaved TOE1 can spontaneously cross the plasma membrane and penetrate cells in culture, retaining HIV-1 inhibitory activity. Antiviral potency of TOE1 and its cell-penetrating capability have been identified to lie within a 35-amino-acid region containing the nuclear localization sequence.W e previously reported the cloning of a gene encoding the Target Of Egr1 (TOE1) protein as a target for the immediate early transcription factor Egr1 using ChIP-based methodology and its partial characterization as an inhibitor of cell growth (1). Mechanistically, TOE1 overexpression correlates with up-regulation of the cyclin-dependent kinase inhibitor p21 and produces an accumulation of cells in the G2/M phase of the cell cycle. Subsequently, we found that TOE1 is able to bind to the C-terminal tetramerization domain of the p53 tumor suppressor protein and enhances its transcriptional activity, further underscoring the potential importance of a role for TOE1 in the cellular growth inhibition through cell cycle modulation (2).A previous report from another group studying RNA turnover and investigating human homologs for the yeast Ccr4p and Caf1p/ Pop2p found that TOE1 possesses RNA deadenylase catalytic activity in vitro (3). Interestingly, only transfection of TOE1 with a deletion in its nuclear localization signal, restricting cytoplasmic localization of TOE1, displayed deadenylase activity in cultured cells.Although heterokaryon experiments using HeLa and NIH 3T3 cells detected nucleocytoplasmic shuttling, it remains uncertain whether retention of TOE1 in the cytoplasm occurs to permit effective deadenylation of RNA substrates. An additional report from another group studying Cajal body structure and function identified a role for TOE1 in Cajal body formation, as well as in RNA splicing, although its precise role in RNA splicing is yet to be determined (4). Together, the combination of the published work points to the involvement of TOE1 in the regulation of multiple cellular functions including those involving growth regulation and RNA metabolism.With regard to human disease pathology, clues for a biological role for TOE1 were revealed in a study by investigators in search for the identity of an endogenous noncytotoxic proteinaceous factor secreted from CD8 + T lymphocytes able to control the replication of HIV-1 in infected...

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Genetic and Immunologic Heterogeneity among Persons Who Control HIV Infection in the Absence of Therapy

Cited by 468 publications

References 44 publications

Initial viral load determines the magnitude of the human CD8 T cell response to yellow fever vaccination

Initial viral load determines the magnitude of the human CD8 T cell response to yellow fever vaccination

CD8 ⁺ T Cell Breadth and Ex Vivo Virus Inhibition Capacity Distinguish between Viremic Controllers with and without Protective HLA Class I Alleles

TOE1 is an inhibitor of HIV-1 replication with cell-penetrating capability

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Genetic and Immunologic Heterogeneity among Persons Who Control HIV Infection in the Absence of Therapy

Cited by 468 publications

References 44 publications

Initial viral load determines the magnitude of the human CD8 T cell response to yellow fever vaccination

Initial viral load determines the magnitude of the human CD8 T cell response to yellow fever vaccination

CD8 + T Cell Breadth and Ex Vivo Virus Inhibition Capacity Distinguish between Viremic Controllers with and without Protective HLA Class I Alleles

TOE1 is an inhibitor of HIV-1 replication with cell-penetrating capability

Contact Info

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Resources

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CD8 ⁺ T Cell Breadth and Ex Vivo Virus Inhibition Capacity Distinguish between Viremic Controllers with and without Protective HLA Class I Alleles