Gag-Specific CD8+ T Lymphocytes Recognize Infected Cells before AIDS-Virus Integration and Viral Protein Expression

Sacha, Jonah B.; Chung, Chungwon; Rakasz, Eva G.; Spencer, Sean P.; Jonas, Anna K.; Bean, Alexander T.; Lee, Wonhee; Burwitz, Benjamin J.; Stephany, Jason J.; Loffredo, John T.; Allison, David B.; Adnan, Sama; Hoji, Akihiko; Wilson, Nancy A.; Friedrich, Thomas C.; Lifson, Jeffrey D.; Yang, Otto O.; Watkins, David I.

doi:10.4049/jimmunol.178.5.2746

Cited by 237 publications

(239 citation statements)

References 41 publications

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“…CD4 ϩ T cells were isolated and cultured as previously described (47). For presentation assays, CD4 ϩ T cells were activated with either Con A (10 g/mL) or irradiated, peptide-pulsed BLCL up to 72 h before infection.…”

mentioning

confidence: 99%

Gag- and Nef-specific CD4⁺T cells recognize and inhibit SIV replication in infected macrophages early after infection

Sacha¹,

Giraldo-Vela²,

Buechler³

et al. 2009

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

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The precise immunological role played by CD4 ؉ T cells in retroviral infections is poorly defined. Here, we describe a new function of these cells, the elimination of retrovirus-infected macrophages. After experimental CD8 ؉ cell depletion, elite controlling macaques with set-point viral loads <500 viral RNA copies/mL mounted robust Gagand Nef-specific CD4 ؉ T cell responses during reestablishment of control with >54% of all virus-specific CD4 ؉ T cells targeting these 2 proteins. Ex vivo, these simian immunodeficiency virus (SIV)-specific CD4 ؉ T cells neither recognized nor suppressed viral replication in SIV-infected CD4 ؉ T cells. In contrast, they recognized SIV-infected macrophages as early as 2 h postinfection because of presentation of epitopes derived from virion-associated Gag and Nef proteins. Furthermore, virus-specific CD4 ؉ T cells displayed direct effector function and eliminated SIV-infected macrophages. These results suggest that retrovirus-specific CD4 ؉ T cells may contribute directly to elite control by inhibiting viral replication in macrophages.antigen processing and presentation ͉ HIV

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mentioning

confidence: 99%

Gag- and Nef-specific CD4⁺T cells recognize and inhibit SIV replication in infected macrophages early after infection

Sacha¹,

Giraldo-Vela²,

Buechler³

et al. 2009

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

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“…This enhanced capacity to suppress HIV infection is linked to a higher frequency of further differentiated cells in association with a discordant CD38 low HLA-DR high phenotype [67]. HIV-specific CD8þ T cell responses in HICs preferentially target epitopes in Gag, and Gag-specific responses account for most of their capacity to suppress HIV infection [125], which may be due to faster recognition of infected cells [126].…”

Section: (B) Adaptive Cellular Responses (I) Cd8þ T Cell Responsesmentioning

confidence: 99%

Immune responses during spontaneous control of HIV and AIDS: what is the hope for a cure?

Sáez‐Cirión

Jacquelin

Barré‐Sinoussi

et al. 2014

Phil. Trans. R. Soc. B

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International audienceHIV research has made rapid progress and led to remarkable achievements in recent decades, the most important of which are combination antiretroviral therapies (cART). However, in the absence of a vaccine, the pandemic continues, and additional strategies are needed. The 'towards an HIV cure' initiative aims to eradicate HIV or at least bring about a lasting remission of infection during which the host can control viral replication in the absence of cART. Cases of spontaneous and treatment-induced control of infection offer substantial hope. Here, we describe the scientific knowledge that is lacking, and the priorities that have been established for research into a cure. We discuss in detail the immunological lessons that can be learned by studying natural human and animal models of protection and spontaneous control of viraemia or of disease progression. In particular, we describe the insights we have gained into the immune mechanisms of virus control, the impact of early virus-host interactions and why chronic inflammation, a hallmark of HIV infection, is an obstacle to a cure. Finally, we enumerate current interventions aimed towards improving the host immune response

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“…Data from models of simian immunodeficiency virus (SIV) infection indicate that Gag epitopes are uniquely presented earlier than any other viral protein, suggesting that early recognition of Gag epitopes by SIV-specific CD8 + T cells may lead to rapid clearance of infected CD4 + T cells. 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.…”

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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Gag-Specific CD8+ T Lymphocytes Recognize Infected Cells before AIDS-Virus Integration and Viral Protein Expression

Cited by 237 publications

References 41 publications

Gag- and Nef-specific CD4⁺T cells recognize and inhibit SIV replication in infected macrophages early after infection

Gag- and Nef-specific CD4⁺T cells recognize and inhibit SIV replication in infected macrophages early after infection

Immune responses during spontaneous control of HIV and AIDS: what is the hope for a cure?

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

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Gag-Specific CD8+ T Lymphocytes Recognize Infected Cells before AIDS-Virus Integration and Viral Protein Expression

Cited by 237 publications

References 41 publications

Gag- and Nef-specific CD4+T cells recognize and inhibit SIV replication in infected macrophages early after infection

Gag- and Nef-specific CD4+T cells recognize and inhibit SIV replication in infected macrophages early after infection

Immune responses during spontaneous control of HIV and AIDS: what is the hope for a cure?

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

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Product

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Gag- and Nef-specific CD4⁺T cells recognize and inhibit SIV replication in infected macrophages early after infection

Gag- and Nef-specific CD4⁺T cells recognize and inhibit SIV replication in infected macrophages early after infection