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Nef-specific CD45RA+ CD8+ T cells secreting MIP-1beta but not IFN-gamma are associated with nonprogressive HIV-1 infection.

Dembek CJ, Kutscher S, Heltai S, Allgayer S, Biswas P, Ghezzi S, Vicenzi E, Hoffmann D, Reitmeir P, Tambussi G, Bogner JR, Lusso P, Stellbrink HJ, Santagostino E, Vollbrecht T, Goebel FD, Protzer U, Draenert R, Tinelli M, Poli G, Erfle V, Malnati M, Cosma A - AIDS Res Ther (2010)

Bottom Line: This population was present in 7 out of 11 NP.In addition, we detected Nef-specific CD45RA+ IFN-gammaneg MIP-1beta+ CD8+ T cells in only 1 out of 10 HIV-1 infected individuals with untreated progressive disease.The novel antigen-specific CD45RA+ IFN-gammaneg MIP-1beta+ CD8+ T cell population represents a new candidate marker of long-term natural control of HIV-1 disease progression and a relevant functional T-cell subset in the evaluation of the immune responses induced by candidate HIV-1 vaccines.

View Article: PubMed Central - HTML - PubMed

Affiliation: Institute of Virology, Helmholtz Zentrum München - German Research Center for Environmental Health, 85764 Neuherberg, Germany. claudia.dembek@helmholtz-muenchen.de.

ABSTRACT

Background: Long-term survival of HIV-1 infected individuals is usually achieved by continuous administration of combination antiretroviral therapy (ART). An exception to this scenario is represented by HIV-1 infected nonprogressors (NP) which maintain relatively high circulating CD4+ T cells without clinical symptoms for several years in the absence of ART. Several lines of evidence indicate an important role of the T-cell response in the modulation of HIV-1 infection during the acute and chronic phase of the disease.

Results: We analyzed the functional and the differentiation phenotype of Nef- and Tat-specific CD8+ T cells in a cohort of HIV-1 infected NP in comparison to progressors, ART-treated seropositive individuals and individuals undergoing a single cycle of ART interruption. We observed that a distinctive feature of NP is the presence of Nef-specific CD45RA+ CD8+ T cells secreting MIP-1beta but not IFN-gamma. This population was present in 7 out of 11 NP. CD45RA+ IFN-gammaneg MIP-1beta+ CD8+ T cells were not detected in HIV-1 infected individuals under ART or withdrawing from ART and experiencing a rebounding viral replication. In addition, we detected Nef-specific CD45RA+ IFN-gammaneg MIP-1beta+ CD8+ T cells in only 1 out of 10 HIV-1 infected individuals with untreated progressive disease.

Conclusion: The novel antigen-specific CD45RA+ IFN-gammaneg MIP-1beta+ CD8+ T cell population represents a new candidate marker of long-term natural control of HIV-1 disease progression and a relevant functional T-cell subset in the evaluation of the immune responses induced by candidate HIV-1 vaccines.

No MeSH data available.


Related in: MedlinePlus

Nef-specific CD8+ T-cell responses during TI. (A) Frequency of the total Nef-specific response before and after TI. The median is shown for each group. (B) Quality of the Nef-specific CD8+ T-cell responses before (light gray boxes) and after (dark gray boxes) TI. The graph is divided into the CD45RA+ (left part) and the CD45RAneg (right part) CD8+ T-cell populations. All possible combinations of responses are shown on the X axis. Tukey boxes and whisker plots are shown.
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Figure 4: Nef-specific CD8+ T-cell responses during TI. (A) Frequency of the total Nef-specific response before and after TI. The median is shown for each group. (B) Quality of the Nef-specific CD8+ T-cell responses before (light gray boxes) and after (dark gray boxes) TI. The graph is divided into the CD45RA+ (left part) and the CD45RAneg (right part) CD8+ T-cell populations. All possible combinations of responses are shown on the X axis. Tukey boxes and whisker plots are shown.

Mentions: To investigate further the role of in vivo HIV-1 replication in generating CD45RA+ IFN-γneg IL-2neg MIP-1β+ CD8+ T cells, we analyzed Nef- and Tat-specific CD8+ T-cell responses in a longitudinal set-up. Six ART-treated patients with highly suppressed viremia (ART01, ART02, ART03, ART04, ART05 and ART06) underwent a single cycle of therapy interruption (TI). Viremia became detectable in all patients between day 5 and 21 after TI. ART was resumed between day 27 and 185 when viremia levels reached >100,000 HIV-1 RNA copies/ml. A significant expansion of the Nef-specific CD8+ T-cell responses was observed in all the subjects analyzed (Figure 4A). However, the quality of the CD8+ T-cell response remained unchanged in that CD45RA+ IFN-γneg IL-2neg MIP-1β+ CD8+ T cells remained undetectable even during the boost of the total Nef-specific CD8+ T-cell response that followed the peak of virus replication post TI (Figure 4B). Of note, we observed a decrease of Nef-specific CD8+ T cells expressing multiple effector functions and an increase of Nef-specific CD8+ T cells expressing solely IFN-γ, but these differences were not significant, probably due to the low number of subjects included in the longitudinal analysis. The Tat-specific CD8+ T-cell response was substantially undetectable before and after TI (data not shown).


Nef-specific CD45RA+ CD8+ T cells secreting MIP-1beta but not IFN-gamma are associated with nonprogressive HIV-1 infection.

Dembek CJ, Kutscher S, Heltai S, Allgayer S, Biswas P, Ghezzi S, Vicenzi E, Hoffmann D, Reitmeir P, Tambussi G, Bogner JR, Lusso P, Stellbrink HJ, Santagostino E, Vollbrecht T, Goebel FD, Protzer U, Draenert R, Tinelli M, Poli G, Erfle V, Malnati M, Cosma A - AIDS Res Ther (2010)

Nef-specific CD8+ T-cell responses during TI. (A) Frequency of the total Nef-specific response before and after TI. The median is shown for each group. (B) Quality of the Nef-specific CD8+ T-cell responses before (light gray boxes) and after (dark gray boxes) TI. The graph is divided into the CD45RA+ (left part) and the CD45RAneg (right part) CD8+ T-cell populations. All possible combinations of responses are shown on the X axis. Tukey boxes and whisker plots are shown.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2909146&req=5

Figure 4: Nef-specific CD8+ T-cell responses during TI. (A) Frequency of the total Nef-specific response before and after TI. The median is shown for each group. (B) Quality of the Nef-specific CD8+ T-cell responses before (light gray boxes) and after (dark gray boxes) TI. The graph is divided into the CD45RA+ (left part) and the CD45RAneg (right part) CD8+ T-cell populations. All possible combinations of responses are shown on the X axis. Tukey boxes and whisker plots are shown.
Mentions: To investigate further the role of in vivo HIV-1 replication in generating CD45RA+ IFN-γneg IL-2neg MIP-1β+ CD8+ T cells, we analyzed Nef- and Tat-specific CD8+ T-cell responses in a longitudinal set-up. Six ART-treated patients with highly suppressed viremia (ART01, ART02, ART03, ART04, ART05 and ART06) underwent a single cycle of therapy interruption (TI). Viremia became detectable in all patients between day 5 and 21 after TI. ART was resumed between day 27 and 185 when viremia levels reached >100,000 HIV-1 RNA copies/ml. A significant expansion of the Nef-specific CD8+ T-cell responses was observed in all the subjects analyzed (Figure 4A). However, the quality of the CD8+ T-cell response remained unchanged in that CD45RA+ IFN-γneg IL-2neg MIP-1β+ CD8+ T cells remained undetectable even during the boost of the total Nef-specific CD8+ T-cell response that followed the peak of virus replication post TI (Figure 4B). Of note, we observed a decrease of Nef-specific CD8+ T cells expressing multiple effector functions and an increase of Nef-specific CD8+ T cells expressing solely IFN-γ, but these differences were not significant, probably due to the low number of subjects included in the longitudinal analysis. The Tat-specific CD8+ T-cell response was substantially undetectable before and after TI (data not shown).

Bottom Line: This population was present in 7 out of 11 NP.In addition, we detected Nef-specific CD45RA+ IFN-gammaneg MIP-1beta+ CD8+ T cells in only 1 out of 10 HIV-1 infected individuals with untreated progressive disease.The novel antigen-specific CD45RA+ IFN-gammaneg MIP-1beta+ CD8+ T cell population represents a new candidate marker of long-term natural control of HIV-1 disease progression and a relevant functional T-cell subset in the evaluation of the immune responses induced by candidate HIV-1 vaccines.

View Article: PubMed Central - HTML - PubMed

Affiliation: Institute of Virology, Helmholtz Zentrum München - German Research Center for Environmental Health, 85764 Neuherberg, Germany. claudia.dembek@helmholtz-muenchen.de.

ABSTRACT

Background: Long-term survival of HIV-1 infected individuals is usually achieved by continuous administration of combination antiretroviral therapy (ART). An exception to this scenario is represented by HIV-1 infected nonprogressors (NP) which maintain relatively high circulating CD4+ T cells without clinical symptoms for several years in the absence of ART. Several lines of evidence indicate an important role of the T-cell response in the modulation of HIV-1 infection during the acute and chronic phase of the disease.

Results: We analyzed the functional and the differentiation phenotype of Nef- and Tat-specific CD8+ T cells in a cohort of HIV-1 infected NP in comparison to progressors, ART-treated seropositive individuals and individuals undergoing a single cycle of ART interruption. We observed that a distinctive feature of NP is the presence of Nef-specific CD45RA+ CD8+ T cells secreting MIP-1beta but not IFN-gamma. This population was present in 7 out of 11 NP. CD45RA+ IFN-gammaneg MIP-1beta+ CD8+ T cells were not detected in HIV-1 infected individuals under ART or withdrawing from ART and experiencing a rebounding viral replication. In addition, we detected Nef-specific CD45RA+ IFN-gammaneg MIP-1beta+ CD8+ T cells in only 1 out of 10 HIV-1 infected individuals with untreated progressive disease.

Conclusion: The novel antigen-specific CD45RA+ IFN-gammaneg MIP-1beta+ CD8+ T cell population represents a new candidate marker of long-term natural control of HIV-1 disease progression and a relevant functional T-cell subset in the evaluation of the immune responses induced by candidate HIV-1 vaccines.

No MeSH data available.


Related in: MedlinePlus