Suppression of HIV replication in vitro by CD8+ T-cells from HIV-infected and HIV-seronegative individuals

Tsuchie, Hideaki; Ma, Detorio; Mm, Hossain; Tesfamariam, N; Trickett, Annette; Pr, Lam-Po-Tang; Yamada, Osamu; Ishiguro, Hiroshi; Jm, Dwyer; Kurimura, Takashi

doi:10.1258/0956462971920145

Cited by 4 publications

(4 citation statements)

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“…These data suggest that the gene-modified CD8 T cells can control HIV replication and spread when mixed with infected primary CD4 T cells (Figure 3B), presumably by targeting and killing specifically the infected cells in culture. The levels of p24 suppression could not be explained by any non-specific cytolytic (Grimm et al, 1982) or non-cytolytic suppressive effect (Rosok et al, 1997; Tsuchie et al, 1997) caused by CD8/dTc, because no similar effect was seen with CD8/Tc (Figure 3B, middle).…”

Section: Resultsmentioning

confidence: 94%

Anti-HIV designer T cells progressively eradicate a latently infected cell line by sequentially inducing HIV reactivation then killing the newly gp120-positive cells

et al. 2013

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The current antiretroviral therapy (ART) can effectively reduce plasma HIV loads to undetectable levels, but cannot eliminate latently infected resting memory CD4 T cells that persist for the lifetime of infected patients. Therefore, designing new therapeutic approaches to eliminate these latently infected cells or the cells that produce HIV upon reactivation from latency is a priority in the ART era in order to progress to a cure of HIV. Here, we show that “designer” T cells expressing chimeric antigen receptor (CAR), CD4-CD28-CD3ζ, can target and kill HIV Env-expressing cells. Further, they secrete effector cytokines upon contact with HIV Env+ target cells that can reactivate latent HIV in a cell line model, thereby exposing those cells to recognition and killing by anti-HIV CAR+ T cells. Taken to the limit, this process could form the basis for an eventual functional or sterilizing cure for HIV in patients.

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Section: Resultsmentioning

confidence: 94%

Anti-HIV designer T cells progressively eradicate a latently infected cell line by sequentially inducing HIV reactivation then killing the newly gp120-positive cells

et al. 2013

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“…CD8 + T cells play a crucial role especially early on the course of HIV infection [60], [67], [68], [69], [70], [71], [72], [73] and the main mechanism that these cells exert their cytotoxic function is through production and release of killing molecules (perforin, granzymes, granulysin). As rapid expression of perforin is considered as a novel correlate of control of HIV replication [23], this novel finding that blocking Tim-3 pathway leads to an increase in perforin release and direct cytotoxicity in particular, further indicates that the Tim-3 pathway might be a potential therapeutic target for the rescue of dysfunctional CD8 + T cells resulting in the better suppression of HIV infection.…”

Section: Discussionmentioning

confidence: 99%

Tim-3 Negatively Regulates Cytotoxicity in Exhausted CD8+ T Cells in HIV Infection

et al. 2012

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Cytotoxic CD8 + T cells (CTLs) contain virus infections through the release of granules containing both perforin and granzymes. T cell ‘exhaustion’ is a hallmark of chronic persistent viral infections including HIV. The inhibitory regulatory molecule, T cell Immunoglobulin and Mucin domain containing 3 (Tim-3) is induced on HIV-specific T cells in chronic progressive infection. These Tim-3 expressing T cells are dysfunctional in terms of their capacities to proliferate or to produce cytokines. In this study, we evaluated the effect of Tim-3 expression on the cytotoxic capabilities of CD8 + T cells in the context of HIV infection. We investigated the cytotoxic capacity of Tim-3 expressing T cells by examining 1) the ability of Tim-3 + CD8 + T cells to make perforin and 2) the direct ability of Tim-3 + CD8 + T cells to kill autologous HIV infected CD4 + target cells. Surprisingly, Tim-3 + CD8 + T cells maintain higher levels of perforin, which was mainly in a granule-associated (stored) conformation, as well as express high levels of T-bet. However, these cells were also defective in their ability to degranulate. Blocking the Tim-3 signalling pathway enhanced the cytotoxic capabilities of HIV specific CD8 + T cells from chronic progressors by increasing; a) their degranulation capacity, b) their ability to release perforin, c) their ability to target activated granzyme B to HIV antigen expressing CD4 + T cells and d) their ability to suppress HIV infection of CD4 + T cells. In this latter effect, blocking the Tim-3 pathway enhances the cytotoxcity of CD8 + T cells from chronic progressors to the level very close to that of T cells from viral controllers. Thus, the Tim-3 receptor, in addition to acting as a terminator for cytokine producing and proliferative functions of CTLs, can also down-regulate the CD8 + T cell cytotoxic function through inhibition of degranulation and perforin and granzyme secretion.

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“…Allogeneic stimulation of polyclonal CD8 + T cells from HIV-seronegative individuals as well as PHA stimulation can also produce an antiviral soluble factor, such as CAF ( 176 – 179 ). This finding supports observations that CAF is an innate immune factor that responds to cell activating signals (section III.F).…”

Section: (Iv) Further Characteristics Of Cnarmentioning

confidence: 99%

“…Factors that induce and enhance CNAR/CAF include the following: HIV replication ( 2 ) HLA concordance ( 33 ) Conserved retroviral motifs Activation: CD3 or PHA stimulation of CD8 + T cells IL-2 ( 121 , 160 , 161 ) CD40/CD40L-stimulated DCs ( 168 , 169 ) CD28 costimulation ( 121 ) Early ART treatment ( 31 , 162 , 175 ) IL-15 ( 153 , 173 ) IL-21 ( 110 ) Allogeneic mixed lymphocyte reaction ( 176 – 179 , 342 ) LFA-1 agonist antibody ( 180 ) Thymosin α1 ( 181 ) TLR7/8 agonists ( 182 ) Potential vaccine ( 64 ) …”

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confidence: 99%

The CD8⁺T Cell Noncytotoxic Antiviral Responses

Morvan

Teque

Locher³

et al. 2021

Microbiol Mol Biol Rev

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SUMMARY The CD8+ T cell noncytotoxic antiviral response (CNAR) was discovered during studies of asymptomatic HIV-infected subjects more than 30 years ago. In contrast to CD8+ T cell cytotoxic lymphocyte (CTL) activity, CNAR suppresses HIV replication without target cell killing. This activity has characteristics of innate immunity: it acts on all retroviruses and thus is neither epitope specific nor HLA restricted. The HIV-associated CNAR does not affect other virus families. It is mediated, at least in part, by a CD8+ T cell antiviral factor (CAF) that blocks HIV transcription. A variety of assays used to measure CNAR/CAF and the effects on other retrovirus infections are described. Notably, CD8+ T cell noncytotoxic antiviral responses have now been observed with other virus families but are mediated by different cytokines. Characterizing the protein structure of CAF has been challenging despite many biologic, immunologic, and molecular studies. It represents a low-abundance protein that may be identified by future next-generation sequencing approaches. Since CNAR/CAF is a natural noncytotoxic activity, it could provide promising strategies for HIV/AIDS therapy, cure, and prevention.

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Suppression of HIV replication in vitro by CD8+ T-cells from HIV-infected and HIV-seronegative individuals

Cited by 4 publications

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Anti-HIV designer T cells progressively eradicate a latently infected cell line by sequentially inducing HIV reactivation then killing the newly gp120-positive cells

Anti-HIV designer T cells progressively eradicate a latently infected cell line by sequentially inducing HIV reactivation then killing the newly gp120-positive cells

Tim-3 Negatively Regulates Cytotoxicity in Exhausted CD8+ T Cells in HIV Infection

The CD8⁺T Cell Noncytotoxic Antiviral Responses

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Suppression of HIV replication in vitro by CD8+ T-cells from HIV-infected and HIV-seronegative individuals

Cited by 4 publications

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Anti-HIV designer T cells progressively eradicate a latently infected cell line by sequentially inducing HIV reactivation then killing the newly gp120-positive cells

Anti-HIV designer T cells progressively eradicate a latently infected cell line by sequentially inducing HIV reactivation then killing the newly gp120-positive cells

Tim-3 Negatively Regulates Cytotoxicity in Exhausted CD8+ T Cells in HIV Infection

The CD8+T Cell Noncytotoxic Antiviral Responses

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The CD8⁺T Cell Noncytotoxic Antiviral Responses