Initial HIV-1 Antigen-Specific CD8
            <sup>+</sup>
            T Cells in Acute HIV-1 Infection Inhibit Transmitted/Founder Virus Replication

Freel, Stephanie A.; Picking, R A; Ferrari, Guido; Ding, Haitao; Ochsenbauer, Christina; Kappes, John C.; Kirchherr, Jennifer; Soderberg, Kelly A.; Weinhold, Kent J.; Cunningham, Coleen K.; Denny, Thomas N.; Crump, John A.; Cohen, Myron S.; McMichael, Andrew J.; Haynes, Barton F.; Tomaras, Georgia D.

doi:10.1128/jvi.00437-12

Cited by 55 publications

(75 citation statements)

References 60 publications

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“…This is in line with results obtained for EC and chronic subjects with broad anti-Gag responses (16,35) and could provide an additional mechanistic explanation for the pivotal role of Gag-specific cells in delayed disease progression. Although Freel et al (41) found that Nefspecific cells could mediate VIA to the same extent as Gag-specific cells in acutely infected subjects, no association between these activities and clinical parameters was studied by these authors, as it is the case of the present work. Also, it is important to denote that both studies differ in definition of the specificity of VIA-mediating cells, which may account for the different results obtained.…”

Section: Discussioncontrasting

confidence: 52%

“…4). To our knowledge, there exists only one very recent report studying VIA in acute HIV infection (41). In that work, Freel and collaborators also demonstrate (i) that VIA magnitude correlates with the percentage of HIV-specific CD8 ϩ T cells expressing CD107A, MIP-1␤, and IFN-␥ and with the secretion of MIP-1␣, MIP-1␤, IFN-␥, IP-10, and IL-1␣ after cell stimulation with peptide antigens and (ii) that early escape from CD8 ϩ T-cell-mediated VIA occurs during PHI.…”

Section: Discussionmentioning

confidence: 99%

“…These findings are of particular importance, since these molecules are produced by CD8 ϩ T cells upon stimulation and the percentage of cells expressing IL-2 and MIP-1␤ either alone or in combination with other functions were previ- ously associated with virus control (6,17,18,20,40). Moreover, soluble MIP-1␤ was also reported to mediate viral inhibition in vitro (41). The fact that there exists an association between important soluble antiviral mediators such as IL-2 and MIP-1␤ and Gag immunodominance is in line with the evidence indicating that early relative Gag immunodominance is somehow related to the generation of a robust, efficient, and multifaceted antiviral immune response, thus reinforcing the notion that it is one key determinant of protective immunity contributing to slower disease progression.…”

Section: Cd8mentioning

confidence: 99%

See 2 more Smart Citations

Early Gag Immunodominance of the HIV-Specific T-Cell Response during Acute/Early Infection Is Associated with Higher CD8 ⁺ T-Cell Antiviral Activity and Correlates with Preservation of the CD4 ⁺ T-Cell Compartment

Turk

Ghiglione

Falivene

et al. 2013

J Virol

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The important role of the CD8؉ T-cell response on HIV control is well established. Moreover, the acute phase of infection represents a proper scenario to delineate the antiviral cellular functions that best correlate with control. Here, multiple functional aspects (specificity, ex vivo viral inhibitory activity [VIA] and polyfunctionality) of the HIV-specific CD8 ؉ T-cell subset arising early after infection, and their association with disease progression markers, were examined. Blood samples from 44 subjects recruited within 6 months from infection (primary HIV infection [PHI] group), 16 chronically infected subjects, 11 elite controllers (EC), and 10 healthy donors were obtained. Results indicated that, although Nef dominated the anti-HIV response during acute/early infection, a higher proportion of early anti-Gag T cells correlated with delayed progression. Polyfunctional HIV-specific CD8 ؉ T cells were detected at early time points but did not associate with virus control. Conversely, higher CD4 ؉ T-cell set points were observed in PHI subjects with higher HIV-specific CD8 ؉ T-cell VIA at baseline. Importantly, VIA levels correlated with the magnitude of the anti-Gag cellular response. The advantage of Gag-specific cells may result from their enhanced ability to mediate lysis of infected cells (evidenced by a higher capacity to degranulate and to mediate VIA) and to simultaneously produce IFN-␥. Finally, Gag immunodominance was associated with elevated plasma levels of interleukin 2 (IL-2) and macrophage inflammatory protein 1␤ (MIP-1␤). All together, this study underscores the importance of CD8 ؉ T-cell specificity in the improved control of disease progression, which was related to the capacity of Gag-specific cells to mediate both lytic and nonlytic antiviral mechanisms at early time points postinfection. Human immunodeficiency virus (HIV) still represents a major public health concern. Although the instauration of highly active antiretroviral treatment (HAART) had a tremendous impact on the epidemic dynamics, the development of an effective prophylactic vaccine is still a main objective in the HIV-related research field. As HIV is highly diverse among different isolates, evolves continuously under selective pressure, infects immune cells, and encodes proteins with the capacity to modulate immune cell functions, it imposes definite challenges that should be overcome in the race of getting a successful vaccine. However, the description of (i) infected subjects able to control HIV replication over long periods of time to very low levels without therapy (known as long-term nonprogressors [LTNP] and elite controllers [EC]); (ii) uninfected subjects who, despite being highly exposed to the virus, remain seronegative (exposed seronegatives [ESN]); and (iii) the results from the Thai vaccine trial RV-144, which showed 30% efficacy (1), suggests that the objective is reachable. In this line, much of the research work conducted over the past few years was aimed to define the immune correlates of protection, i.e....

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Section: Discussioncontrasting

confidence: 52%

Section: Discussionmentioning

confidence: 99%

Section: Cd8mentioning

confidence: 99%

See 1 more Smart Citation

Early Gag Immunodominance of the HIV-Specific T-Cell Response during Acute/Early Infection Is Associated with Higher CD8 ⁺ T-Cell Antiviral Activity and Correlates with Preservation of the CD4 ⁺ T-Cell Compartment

Turk

Ghiglione

Falivene

et al. 2013

J Virol

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“…Of interest, several recent studies have highlighted the importance of the virus inhibition assays which is a new assay measuring CD8 + T-cell mediated inhibition of virus replication in vitro [35][36][37][38]. This assay may be relevant as it directly reflects the ability of virus-specific CD8 + T cells to limit HIV spreading and does thus integrate several components of the immune response such as the effector function and the recognition of distinct virus isolates.…”

Section: Discussionmentioning

confidence: 99%

NYVAC immunization induces polyfunctional HIV‐specific T‐cell responses in chronically‐infected, ART‐treated HIV patients

et al. 2012

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We report the results of the Theravac-01 phase I trial, which was conducted to evaluate the safety and immunogenicity of a poxvirus-based vector, NYVAC, expressing Gag, Pol, Nef, and Env from an HIV clade B isolate. NYVAC-B vaccine was injected intramuscularly into ten HIV-infected patients successfully treated with antiretroviral therapy, twice on day 0 and again at week 4. Safety and immunogenicity were monitored for 48 weeks. HIV-specific T-cell responses following immunization were quantitatively analyzed using an IFN-γ ELISPOT assay and qualitatively characterized for their functional profile (including multiple cytokines secretion plus cytotoxic and proliferation capacity) by polychromatic flow cytometry. Our results indicate that the NYVAC-B vaccine is safe and highly immunogenic, as indicated by increased HIV-specific T-cell responses in virtually all vaccinees. Interestingly, both an expansion of preexisting T-cell responses, and the appearance of newly detected HIV-specific CD4 + and CD8 + T-cell responses were observed. Furthermore, immunization mostly induced an increase in Gag-specific T-cell responses. In conclusion, NYVAC-B immunization induces broad, vigorous, and polyfunctional HIV-specific T-cell responses, suggesting that poxvirus-based vaccine regimens may be instrumental in the therapeutic HIV vaccine field. Eur. J. Immunol. 2012. 42: 3038-3048 Clinical immunology 3039 IntroductionThe development of antiviral therapy has dramatically changed the course and the prognosis of HIV infection. More than 30 antiviral drugs available offer many therapeutic options for the patients and some of these drugs used in combination are able to induce long-term suppression of virus replication as indicated by the persistence of levels of viremia below the limit of detection of highly sensitive PCR assays [1]. The antiviral therapy-mediated suppression of virus replication has resulted in dramatic reduction of morbidity and mortality, and HIV infection has shifted from being a life threatening to a chronic viral disease [2]. In this regard, recent studies have estimated a life expectancy of 25-30 years for subjects with HIV infection [3,4]. Despite the long-term suppression of virus replication and the normalization of a series of immunological parameters, which are not limited to the CD4 + T-cell counts but also to the recovery of a series of antigen-specific (including HIV) immunological functions, the interruption of antiviral therapy is almost invariably associated to virus rebound [1,5]. These observations indicated that the long-term suppression of virus replication does not result in the generation of an effective HIV-specific immune response [6].For these reasons, a number of immunological interventions have been investigated in the past and are currently being investigated to stimulate HIV-specific immune responses that may efficiently control HIV replication also in the absence of antiviral therapy. Among these interventions, particular attention has been given to the development of therapeutic v...

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“…It has been reported that the initial antigen-specific CTL response to T/F viruses contributes to the control of acute viremia in infected individuals (46,47). How T/F viruses interact with MDDCs and induce antigen presentation is not fully characterized.…”

Section: Discussionmentioning

confidence: 99%

SAMHD1 Limits HIV-1 Antigen Presentation by Monocyte-Derived Dendritic Cells

Ayinde

Bruel

Cardinaud

et al. 2015

J Virol

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Monocyte-derived dendritic cells (MDDC) stimulate CD8؉ cytotoxic T lymphocytes (CTL) by presenting endogenous and exogenous viral peptides via major histocompatibility complex class I (MHC-I) molecules. MDDC are poorly susceptible to HIV-1, in part due to the presence of SAMHD1, a cellular enzyme that depletes intracellular deoxynucleoside triphosphates (dNTPs) and degrades viral RNA. Vpx, an HIV-2/SIVsm protein absent from HIV-1, antagonizes SAMHD1 by inducing its degradation. The impact of SAMHD1 on the adaptive cellular immune response remains poorly characterized. Here, we asked whether SAMHD1 modulates MHC-I-restricted HIV-1 antigen presentation. Untreated MDDC or MDDC pretreated with Vpx were exposed to HIV-1, and antigen presentation was examined by monitoring the activation of an HIV-1 Gag-specific CTL clone. SAMHD1 depletion strongly enhanced productive infection of MDDC as well as endogenous HIV-1 antigen presentation. Time-lapse microscopy analysis demonstrated that in the absence of SAMHD1, the CTL rapidly killed infected MDDC. We also report that various transmitted/founder (T/F) HIV-1 strains poorly infected MDDC and, as a consequence, did not stimulate CTL. Vesicular stomatitis virus glycoprotein (VSV-G) pseudotyping of T/F alleviated a block in viral entry and induced antigen presentation only in the absence of SAMHD1. Furthermore, by using another CTL clone that mostly recognizes incoming HIV-1 antigens, we demonstrate that SAMHD1 does not influence exogenous viral antigen presentation. Altogether, our results demonstrate that the antiviral activity of SAMHD1 impacts antigen presentation by DC, highlighting the link that exists between restriction factors and adaptive immune responses. IMPORTANCEUpon viral infection, DC may present antigens derived from incoming viral material in the absence of productive infection of DC or from newly synthesized viral proteins. In the case of HIV, productive infection of DC is blocked at an early postentry step. This is due to the presence of SAMHD1, a cellular enzyme that depletes intracellular levels of dNTPs and inhibits viral reverse transcription. We show that the depletion of SAMHD1 in DCs strongly stimulates the presentation of viral antigens derived from newly produced viral proteins, leading to the activation of HIV-1-specific cytotoxic T lymphocytes (CTL). We further show in real time that the enhanced activation of CTL leads to killing of infected DCs. Our results indicate that the antiviral activity of SAMHD1 not only impacts HIV replication but also impacts antigen presentation by DC. They highlight the link that exists between restriction factors and adaptive immune responses.

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Initial HIV-1 Antigen-Specific CD8 ⁺ T Cells in Acute HIV-1 Infection Inhibit Transmitted/Founder Virus Replication

Cited by 55 publications

References 60 publications

Early Gag Immunodominance of the HIV-Specific T-Cell Response during Acute/Early Infection Is Associated with Higher CD8 ⁺ T-Cell Antiviral Activity and Correlates with Preservation of the CD4 ⁺ T-Cell Compartment

Early Gag Immunodominance of the HIV-Specific T-Cell Response during Acute/Early Infection Is Associated with Higher CD8 ⁺ T-Cell Antiviral Activity and Correlates with Preservation of the CD4 ⁺ T-Cell Compartment

NYVAC immunization induces polyfunctional HIV‐specific T‐cell responses in chronically‐infected, ART‐treated HIV patients

SAMHD1 Limits HIV-1 Antigen Presentation by Monocyte-Derived Dendritic Cells

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Initial HIV-1 Antigen-Specific CD8 + T Cells in Acute HIV-1 Infection Inhibit Transmitted/Founder Virus Replication

Cited by 55 publications

References 60 publications

Early Gag Immunodominance of the HIV-Specific T-Cell Response during Acute/Early Infection Is Associated with Higher CD8 + T-Cell Antiviral Activity and Correlates with Preservation of the CD4 + T-Cell Compartment

Early Gag Immunodominance of the HIV-Specific T-Cell Response during Acute/Early Infection Is Associated with Higher CD8 + T-Cell Antiviral Activity and Correlates with Preservation of the CD4 + T-Cell Compartment

NYVAC immunization induces polyfunctional HIV‐specific T‐cell responses in chronically‐infected, ART‐treated HIV patients

SAMHD1 Limits HIV-1 Antigen Presentation by Monocyte-Derived Dendritic Cells

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Product

Resources

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Initial HIV-1 Antigen-Specific CD8 ⁺ T Cells in Acute HIV-1 Infection Inhibit Transmitted/Founder Virus Replication

Early Gag Immunodominance of the HIV-Specific T-Cell Response during Acute/Early Infection Is Associated with Higher CD8 ⁺ T-Cell Antiviral Activity and Correlates with Preservation of the CD4 ⁺ T-Cell Compartment

Early Gag Immunodominance of the HIV-Specific T-Cell Response during Acute/Early Infection Is Associated with Higher CD8 ⁺ T-Cell Antiviral Activity and Correlates with Preservation of the CD4 ⁺ T-Cell Compartment