Differential Neutralization of Human Immunodeficiency Virus (HIV) Replication in Autologous CD4 T Cells by HIV-Specific Cytotoxic T Lymphocytes

Chen, Huabiao; Piechocka-Trocha, Alicja; Miura, Toshiyuki; Brockman, Mark A.; Jülg, Boris; Baker, B.M.; Rothchild, Alissa C.; Block, Brian L.; Schneidewind, Arne; Koibuchi, Tomohiko; Pereyra, Florencia; Allen, Todd M.; Walker, Bruce D.

doi:10.1128/jvi.02073-08

Cited by 82 publications

(98 citation statements)

References 40 publications

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“…An ex vivo viral inhibition assay was carried out to determine the ability of CD8 ϩ T cells to suppress virus replication by measuring the amount of HIV p24 antigen as previously described (36,37). Log inhibition values were calculated by subtracting log 10 p24 values of the infected CD4 ϩ T cells cocultured with CD8 ϩ T cells from log 10 p24 values of the infected CD4 ϩ T cells without CD8 ϩ T cells at day 7.…”

Section: Methodsmentioning

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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Section: Methodsmentioning

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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“…Inhibition of viral replication was assessed in a previously established assay system [21,22]. Primary CD4+ T cells were generated from freshly isolated PBMC by the addition of CD3:CD8 bi-specific monoclonal antibody [27,28] or by positive selection with anti-CD4 antibody-coated beads [29].…”

Section: Viral Inhibition Assaymentioning

confidence: 99%

“…The CTL response in this subject is characteristic of a dominant immune response targeting the KK10 epitope (KRWIILGLNK, residues 263-272) in p24 Gag (Figure 1a). We first assessed the antiviral function of KK10-specific CD8+ T cells in this subject by comparison of antiviral efficacy of bulk CD8+ T cells and KK10-tetramer-depleted CD8+ T cells to inhibit virus replication using our well-established virus inhibition assay [22]. We evaluated the production of p24 antigen in virally infected autologous CD4+ T cells in the presence of ex vivo isolated bulk CD8+ T cells or KK10-tetramer-depleted CD8+ T cells.…”

Section: B*27-kk10-specific Ctls Contribute To the Control Of Virus Rmentioning

confidence: 99%

“…We have developed a robust in vitro viral inhibition assay that allows identification of CTLs that control HIV-1 replication in autologous CD4 T cells [22]. This approach incorporates numerous steps that influence virus replication in vivo, including viral entry, antigen processing, epitope presentation, epitope recognition by CD8 T cells, infected cell lysis, and subsequent spread of infection to uninfected cells.…”

Section: Introductionmentioning

confidence: 99%

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Differential Potency and Breadth of the Same Epitope-Specific CTLs to Inhibit HIV-1 Replication based on TCR Usage

Tu¹,

Zhou²,

Li³

et al. 2017

J AIDS Clin Res

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“…19 Recent data further indicate that Gag-specific CD8 + T cell responses may be more effective at neutralizing virus than Env-specific CD8 + T cells. 20 Additionally, immune escape mutations in CD8 + T cell epitopes in Gag can decrease viral fitness. 21,22 We found no association of Env-specific T cell responses with outcome, even though these responses are more dominant in CD8 + T cells than Gag-specific responses in the first year of life.…”

Section: Nqoko Et Almentioning

confidence: 99%

HIV-Specific Gag Responses in Early Infancy Correlate with Clinical Outcome and Inversely with Viral Load

Nqoko

Day

Mansoor

et al. 2011

AIDS Research and Human Retroviruses

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Many HIV-infected infants progress to AIDS during the first year of life when antiretroviral therapy (ART) is not given. The immune determinants of progression to AIDS are not known. We hypothesized that distinct HIVspecific T cell responses correlate with viral load and survival over the first year of life. Whole blood of infants at 3, 6, 9, and 12 months of age was incubated with HIV antigens Gag and Env. The frequency of specific T cells producing interferon (IFN)-c was then measured by flow cytometry. Viral load and CD4% in HIV + infants were determined at each time point. ART was not available for this population at the time of sample collection. Those infants who survived to 12 months of age (n = 12) had lower viral loads and higher Gag-specific CD8 + T cell responses at 3 months, compared with infants who died (n = 8). Furthermore, the frequency of Gag-specific CD4 + T cells correlated inversely with viral load at 3 and 6 months of age. Together these data indicate that the early presence of quantitatively higher Gag-specific T cell responses in HIV-infected infants is associated with lower viral loads and decreased mortality in the first year of life. Our data support the design of a vaccine that preferentially elicits Gag responses, which may result in lower levels of viremia and possibly improve outcome.

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Differential Neutralization of Human Immunodeficiency Virus (HIV) Replication in Autologous CD4 T Cells by HIV-Specific Cytotoxic T Lymphocytes

Abstract: Defining the antiviral efficacy of CD8 T cells is important for immunogen design

Cited by 82 publications

References 40 publications

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

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

Differential Potency and Breadth of the Same Epitope-Specific CTLs to Inhibit HIV-1 Replication based on TCR Usage

HIV-Specific Gag Responses in Early Infancy Correlate with Clinical Outcome and Inversely with Viral Load

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Differential Neutralization of Human Immunodeficiency Virus (HIV) Replication in Autologous CD4 T Cells by HIV-Specific Cytotoxic T Lymphocytes

Abstract: Defining the antiviral efficacy of CD8 T cells is important for immunogen design

Cited by 82 publications

References 40 publications

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

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

Differential Potency and Breadth of the Same Epitope-Specific CTLs to Inhibit HIV-1 Replication based on TCR Usage

HIV-Specific Gag Responses in Early Infancy Correlate with Clinical Outcome and Inversely with Viral Load

Contact Info

Product

Resources

About

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

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