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Peripheral Vγ9Vδ2 T Cells Are a Novel Reservoir of Latent HIV Infection.

Soriano-Sarabia N, Archin NM, Bateson R, Dahl NP, Crooks AM, Kuruc JD, Garrido C, Margolis DM - PLoS Pathog. (2015)

Bottom Line: Eradication of HIV infection will require the identification of all cellular reservoirs that harbor latent infection.We found that upregulation of the CD4 receptor may render primary Vδ2 cells target for HIV infection in vitro and we propose that HIV-induced immune activation may allow infection of γδ T cells in vivo.In 14 patients we recovered latent but replication-competent HIV from highly purified Vδ2 cells demonstrating that peripheral Vδ2 T cells are a previously unrecognized reservoir in which latent HIV infection is unexpectedly frequent.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.

ABSTRACT
Eradication of HIV infection will require the identification of all cellular reservoirs that harbor latent infection. Despite low or lack of CD4 receptor expression on Vδ2 T cells, infection of these cells has previously been reported. We found that upregulation of the CD4 receptor may render primary Vδ2 cells target for HIV infection in vitro and we propose that HIV-induced immune activation may allow infection of γδ T cells in vivo. We assessed the presence of latent HIV infection by measurements of DNA and outgrowth assays within Vδ2 cells in 18 aviremic patients on long-standing antiretroviral therapy. In 14 patients we recovered latent but replication-competent HIV from highly purified Vδ2 cells demonstrating that peripheral Vδ2 T cells are a previously unrecognized reservoir in which latent HIV infection is unexpectedly frequent.

No MeSH data available.


Related in: MedlinePlus

Expression of CD4, CCR5 and activation markers on Vδ2 cells.PBMC from HIV-uninfected donors were cultured and treated with IL-2 alone or IPP and IL-2 for six days. The surface expression of CD4, CCR5, and activation markers (HLA-DR, CD38 and CD25) on Vδ2 cells were analyzed by flow cytometry on days 0 and 6. A) Majority of peripheral Vδ2 cells do not express the CD4 receptor but CD4 is significantly upregulated after six days in culture with IL-2 or with IPP and IL-2 (*p<0.01). However, CCR5 is expressed on the surface of Vδ2 cells at baseline without a significant induction after treatments. B) Analysis of activation markers (HLA-DR, CD25 and CD38) showed peak activation after six days of culture with IPP and IL-2 with moderate activation by IL-2 alone (*p<0.05).
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ppat.1005201.g006: Expression of CD4, CCR5 and activation markers on Vδ2 cells.PBMC from HIV-uninfected donors were cultured and treated with IL-2 alone or IPP and IL-2 for six days. The surface expression of CD4, CCR5, and activation markers (HLA-DR, CD38 and CD25) on Vδ2 cells were analyzed by flow cytometry on days 0 and 6. A) Majority of peripheral Vδ2 cells do not express the CD4 receptor but CD4 is significantly upregulated after six days in culture with IL-2 or with IPP and IL-2 (*p<0.01). However, CCR5 is expressed on the surface of Vδ2 cells at baseline without a significant induction after treatments. B) Analysis of activation markers (HLA-DR, CD25 and CD38) showed peak activation after six days of culture with IPP and IL-2 with moderate activation by IL-2 alone (*p<0.05).

Mentions: Isolated Vδ2 cells can be infected in vitro, [17,18] (S2 Fig) despite low or absent surface CD4 receptor expression prior to activation and HIV infection of these cells is inhibited by CD4 blockade [17], (S2 Fig). We further investigated the CD4-dependence of HIV infection in Vδ2 cells. Total PBMC from uninfected donors were activated with IL-2 alone or IPP and IL-2, and surface marker expression was analyzed by flow cytometry (Fig 6A and S3 Fig). As expected, CD4 receptor expression was detected on <0.3% of Vδ2 cells at day 0, but became detectable on up to 25% of cells after six days of culture in the presence of IL-2 alone, or IPP and IL-2. All increases were statistically significant (p <0.01; Fig 6A). Interestingly, treatment with exogenous IL-2 alone induced CD4 expression to similar levels as did IPP and IL-2 (mean 15.3% and 15.9%, respectively). In contrast, none of these conditions significantly increased the surface expression of CCR5 after six days in culture (Fig 6A). In addition, the activation status of Vδ2 cells was also assessed in the same cells by analyzing the expression of the MHC Class II HLA-DR receptor, the IL2 receptor alpha chain CD25, and the activation marker CD38 (Fig 6B). After six days in culture with IL-2 alone or IPP and IL-2 the expression of these markers was significantly increased (p <0.05 in all cases) although treatment with IL-2 alone induced activation in no more than 20% of Vδ2 cells (Fig 6B).


Peripheral Vγ9Vδ2 T Cells Are a Novel Reservoir of Latent HIV Infection.

Soriano-Sarabia N, Archin NM, Bateson R, Dahl NP, Crooks AM, Kuruc JD, Garrido C, Margolis DM - PLoS Pathog. (2015)

Expression of CD4, CCR5 and activation markers on Vδ2 cells.PBMC from HIV-uninfected donors were cultured and treated with IL-2 alone or IPP and IL-2 for six days. The surface expression of CD4, CCR5, and activation markers (HLA-DR, CD38 and CD25) on Vδ2 cells were analyzed by flow cytometry on days 0 and 6. A) Majority of peripheral Vδ2 cells do not express the CD4 receptor but CD4 is significantly upregulated after six days in culture with IL-2 or with IPP and IL-2 (*p<0.01). However, CCR5 is expressed on the surface of Vδ2 cells at baseline without a significant induction after treatments. B) Analysis of activation markers (HLA-DR, CD25 and CD38) showed peak activation after six days of culture with IPP and IL-2 with moderate activation by IL-2 alone (*p<0.05).
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4608739&req=5

ppat.1005201.g006: Expression of CD4, CCR5 and activation markers on Vδ2 cells.PBMC from HIV-uninfected donors were cultured and treated with IL-2 alone or IPP and IL-2 for six days. The surface expression of CD4, CCR5, and activation markers (HLA-DR, CD38 and CD25) on Vδ2 cells were analyzed by flow cytometry on days 0 and 6. A) Majority of peripheral Vδ2 cells do not express the CD4 receptor but CD4 is significantly upregulated after six days in culture with IL-2 or with IPP and IL-2 (*p<0.01). However, CCR5 is expressed on the surface of Vδ2 cells at baseline without a significant induction after treatments. B) Analysis of activation markers (HLA-DR, CD25 and CD38) showed peak activation after six days of culture with IPP and IL-2 with moderate activation by IL-2 alone (*p<0.05).
Mentions: Isolated Vδ2 cells can be infected in vitro, [17,18] (S2 Fig) despite low or absent surface CD4 receptor expression prior to activation and HIV infection of these cells is inhibited by CD4 blockade [17], (S2 Fig). We further investigated the CD4-dependence of HIV infection in Vδ2 cells. Total PBMC from uninfected donors were activated with IL-2 alone or IPP and IL-2, and surface marker expression was analyzed by flow cytometry (Fig 6A and S3 Fig). As expected, CD4 receptor expression was detected on <0.3% of Vδ2 cells at day 0, but became detectable on up to 25% of cells after six days of culture in the presence of IL-2 alone, or IPP and IL-2. All increases were statistically significant (p <0.01; Fig 6A). Interestingly, treatment with exogenous IL-2 alone induced CD4 expression to similar levels as did IPP and IL-2 (mean 15.3% and 15.9%, respectively). In contrast, none of these conditions significantly increased the surface expression of CCR5 after six days in culture (Fig 6A). In addition, the activation status of Vδ2 cells was also assessed in the same cells by analyzing the expression of the MHC Class II HLA-DR receptor, the IL2 receptor alpha chain CD25, and the activation marker CD38 (Fig 6B). After six days in culture with IL-2 alone or IPP and IL-2 the expression of these markers was significantly increased (p <0.05 in all cases) although treatment with IL-2 alone induced activation in no more than 20% of Vδ2 cells (Fig 6B).

Bottom Line: Eradication of HIV infection will require the identification of all cellular reservoirs that harbor latent infection.We found that upregulation of the CD4 receptor may render primary Vδ2 cells target for HIV infection in vitro and we propose that HIV-induced immune activation may allow infection of γδ T cells in vivo.In 14 patients we recovered latent but replication-competent HIV from highly purified Vδ2 cells demonstrating that peripheral Vδ2 T cells are a previously unrecognized reservoir in which latent HIV infection is unexpectedly frequent.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.

ABSTRACT
Eradication of HIV infection will require the identification of all cellular reservoirs that harbor latent infection. Despite low or lack of CD4 receptor expression on Vδ2 T cells, infection of these cells has previously been reported. We found that upregulation of the CD4 receptor may render primary Vδ2 cells target for HIV infection in vitro and we propose that HIV-induced immune activation may allow infection of γδ T cells in vivo. We assessed the presence of latent HIV infection by measurements of DNA and outgrowth assays within Vδ2 cells in 18 aviremic patients on long-standing antiretroviral therapy. In 14 patients we recovered latent but replication-competent HIV from highly purified Vδ2 cells demonstrating that peripheral Vδ2 T cells are a previously unrecognized reservoir in which latent HIV infection is unexpectedly frequent.

No MeSH data available.


Related in: MedlinePlus