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Long-Term Non-Progression and Broad HIV-1-Specific Proliferative T-Cell Responses.

Imami N, Westrop SJ, Grageda N, Herasimtschuk AA - Front Immunol (2013)

Bottom Line: Such an approach would enable long-term co-existence of host and virus in the absence of toxic and costly drugs.Effective immune homeostasis coupled with a balanced response appropriately targeting conserved viral antigens, in a manner that avoids hyperactivation and exhaustion, may prove to be the strongest correlate of durable viral control.The aim will be to induce long-term non-progressor or elite controller status in every infected host, through immune-mediated control of viremia and reduction of viral reservoirs, leading to lower HIV-1 transmission rates.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, Imperial College London London, UK.

ABSTRACT
Complex mechanisms underlying the maintenance of fully functional, proliferative, HIV-1-specific T-cell responses involve processes from early T-cell development through to the final stages of T-cell differentiation and antigen recognition. Virus-specific proliferative CD4 and CD8 T-cell responses, important for the control of infection, are observed in some HIV-1(+) patients during early stages of disease, and are maintained in long-term non-progressing subjects. In the vast majority of HIV-1(+) patients, full immune functionality is lost when proliferative HIV-1-specific T-cell responses undergo a variable progressive decline throughout the course of chronic infection. This appears irreparable despite administration of potent combination antiretroviral therapy, which to date is non-curative, necessitating life-long administration and the development of effective, novel, therapeutic interventions. While a sterilizing cure, involving clearance of virus from the host, remains a primary aim, a "functional cure" may be a more feasible goal with considerable impact on worldwide HIV-1 infection. Such an approach would enable long-term co-existence of host and virus in the absence of toxic and costly drugs. Effective immune homeostasis coupled with a balanced response appropriately targeting conserved viral antigens, in a manner that avoids hyperactivation and exhaustion, may prove to be the strongest correlate of durable viral control. This review describes novel concepts underlying full immune functionality in the context of HIV-1 infection, which may be utilized in future strategies designed to improve upon existing therapy. The aim will be to induce long-term non-progressor or elite controller status in every infected host, through immune-mediated control of viremia and reduction of viral reservoirs, leading to lower HIV-1 transmission rates.

No MeSH data available.


Related in: MedlinePlus

Central importance of HIV-1-specific CD4 T cells in LTNP: summary of the various elements that contribute to, or are essential features of, the LTNP phenotype. Dashed arrows indicate where, in chronic HIV-1 infection, the functional immune response present in LTNP is compromised. Therapeutic intervention is represented in purple ovals. Concomitant administration of immune-based therapies with effective cART may result in reversal of both the CD4 and CD8 T lymphocyte dysfunction commonly observed to persist in treated HIV-1+ progressors. Such immune-based therapeutic strategies in conjunction with novel approaches (including HDAC inhibitors such as SAHA) for treatment of chronic HIV-1 infection may enable the induction of virus-specific CD4 T cells essential for the subsequent “kick-start” and expansion of specific CD8 T cells. This provides a window of opportunity to steer the immune system to the advantage of the patient and achieve LTNP status or functional cure. APC, antigen-presenting cell; cART, combination antiretroviral therapy; CTL, cytotoxic T lymphocyte; GM-CSF, granulocyte macrophage colony stimulating factor; HIV-1 Ag, HIV-1 antigen; HTL, helper T lymphocyte; IL-2, interleukin-2; NK, natural killer; rhGH, recombinant human growth hormone; RTE, recent thymic emigrants; SAHA, suberoylanilide hydroxamic acid.
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Figure 3: Central importance of HIV-1-specific CD4 T cells in LTNP: summary of the various elements that contribute to, or are essential features of, the LTNP phenotype. Dashed arrows indicate where, in chronic HIV-1 infection, the functional immune response present in LTNP is compromised. Therapeutic intervention is represented in purple ovals. Concomitant administration of immune-based therapies with effective cART may result in reversal of both the CD4 and CD8 T lymphocyte dysfunction commonly observed to persist in treated HIV-1+ progressors. Such immune-based therapeutic strategies in conjunction with novel approaches (including HDAC inhibitors such as SAHA) for treatment of chronic HIV-1 infection may enable the induction of virus-specific CD4 T cells essential for the subsequent “kick-start” and expansion of specific CD8 T cells. This provides a window of opportunity to steer the immune system to the advantage of the patient and achieve LTNP status or functional cure. APC, antigen-presenting cell; cART, combination antiretroviral therapy; CTL, cytotoxic T lymphocyte; GM-CSF, granulocyte macrophage colony stimulating factor; HIV-1 Ag, HIV-1 antigen; HTL, helper T lymphocyte; IL-2, interleukin-2; NK, natural killer; rhGH, recombinant human growth hormone; RTE, recent thymic emigrants; SAHA, suberoylanilide hydroxamic acid.

Mentions: The primary aim of our current and future work is to determine whether the proliferative IL-2-secreting HIV-1-specific T cells in HIV-1+ patients exhibiting successful suppressive control over viral replication are influenced by viral fitness. We have recently described the criteria important to define cohorts internationally (Guergnon et al., 2012; Mandalia et al., 2012), along with standardized methodology for measurement of the efficacy of T-cell responses and characterization of the immune correlates of the non-progressive phenotype (Gotch et al., 2005). Further to the derivation of the salient mechanisms of suppressive anti-HIV-1 immune responses observed in LTNP, the introduction of validated assays which can be used to describe immunological phenomena in chronically infected HIV-1+ patients undergoing immunotherapy, are necessary to enable meaningful comparisons with responses observed in LTNP (Figure 1). We also emphasize the importance of comprehensive analyses assessing T cells directed against diverse HIV-1 proteins in order to determine the entire quantity (breadth and magnitude), and also the quality (proliferative capacity, polyfunctionality and subset phenotype) of virus-specific immune responses, enabling us to boost T-cell responses to novel epitopes. Creating gold standard LTNP status remains the ultimate aim where proliferation competent HIV-1-specific T-cell responses are induced, and maintained, with the ability to purge viral reservoirs, eradicate infection, and achieve either functional or sterilizing cure, as illustrated in Figure 3. Hence, sustaining such responses form the rationale for novel immunotherapeutic intervention in the context of cART.


Long-Term Non-Progression and Broad HIV-1-Specific Proliferative T-Cell Responses.

Imami N, Westrop SJ, Grageda N, Herasimtschuk AA - Front Immunol (2013)

Central importance of HIV-1-specific CD4 T cells in LTNP: summary of the various elements that contribute to, or are essential features of, the LTNP phenotype. Dashed arrows indicate where, in chronic HIV-1 infection, the functional immune response present in LTNP is compromised. Therapeutic intervention is represented in purple ovals. Concomitant administration of immune-based therapies with effective cART may result in reversal of both the CD4 and CD8 T lymphocyte dysfunction commonly observed to persist in treated HIV-1+ progressors. Such immune-based therapeutic strategies in conjunction with novel approaches (including HDAC inhibitors such as SAHA) for treatment of chronic HIV-1 infection may enable the induction of virus-specific CD4 T cells essential for the subsequent “kick-start” and expansion of specific CD8 T cells. This provides a window of opportunity to steer the immune system to the advantage of the patient and achieve LTNP status or functional cure. APC, antigen-presenting cell; cART, combination antiretroviral therapy; CTL, cytotoxic T lymphocyte; GM-CSF, granulocyte macrophage colony stimulating factor; HIV-1 Ag, HIV-1 antigen; HTL, helper T lymphocyte; IL-2, interleukin-2; NK, natural killer; rhGH, recombinant human growth hormone; RTE, recent thymic emigrants; SAHA, suberoylanilide hydroxamic acid.
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Related In: Results  -  Collection

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Show All Figures
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Figure 3: Central importance of HIV-1-specific CD4 T cells in LTNP: summary of the various elements that contribute to, or are essential features of, the LTNP phenotype. Dashed arrows indicate where, in chronic HIV-1 infection, the functional immune response present in LTNP is compromised. Therapeutic intervention is represented in purple ovals. Concomitant administration of immune-based therapies with effective cART may result in reversal of both the CD4 and CD8 T lymphocyte dysfunction commonly observed to persist in treated HIV-1+ progressors. Such immune-based therapeutic strategies in conjunction with novel approaches (including HDAC inhibitors such as SAHA) for treatment of chronic HIV-1 infection may enable the induction of virus-specific CD4 T cells essential for the subsequent “kick-start” and expansion of specific CD8 T cells. This provides a window of opportunity to steer the immune system to the advantage of the patient and achieve LTNP status or functional cure. APC, antigen-presenting cell; cART, combination antiretroviral therapy; CTL, cytotoxic T lymphocyte; GM-CSF, granulocyte macrophage colony stimulating factor; HIV-1 Ag, HIV-1 antigen; HTL, helper T lymphocyte; IL-2, interleukin-2; NK, natural killer; rhGH, recombinant human growth hormone; RTE, recent thymic emigrants; SAHA, suberoylanilide hydroxamic acid.
Mentions: The primary aim of our current and future work is to determine whether the proliferative IL-2-secreting HIV-1-specific T cells in HIV-1+ patients exhibiting successful suppressive control over viral replication are influenced by viral fitness. We have recently described the criteria important to define cohorts internationally (Guergnon et al., 2012; Mandalia et al., 2012), along with standardized methodology for measurement of the efficacy of T-cell responses and characterization of the immune correlates of the non-progressive phenotype (Gotch et al., 2005). Further to the derivation of the salient mechanisms of suppressive anti-HIV-1 immune responses observed in LTNP, the introduction of validated assays which can be used to describe immunological phenomena in chronically infected HIV-1+ patients undergoing immunotherapy, are necessary to enable meaningful comparisons with responses observed in LTNP (Figure 1). We also emphasize the importance of comprehensive analyses assessing T cells directed against diverse HIV-1 proteins in order to determine the entire quantity (breadth and magnitude), and also the quality (proliferative capacity, polyfunctionality and subset phenotype) of virus-specific immune responses, enabling us to boost T-cell responses to novel epitopes. Creating gold standard LTNP status remains the ultimate aim where proliferation competent HIV-1-specific T-cell responses are induced, and maintained, with the ability to purge viral reservoirs, eradicate infection, and achieve either functional or sterilizing cure, as illustrated in Figure 3. Hence, sustaining such responses form the rationale for novel immunotherapeutic intervention in the context of cART.

Bottom Line: Such an approach would enable long-term co-existence of host and virus in the absence of toxic and costly drugs.Effective immune homeostasis coupled with a balanced response appropriately targeting conserved viral antigens, in a manner that avoids hyperactivation and exhaustion, may prove to be the strongest correlate of durable viral control.The aim will be to induce long-term non-progressor or elite controller status in every infected host, through immune-mediated control of viremia and reduction of viral reservoirs, leading to lower HIV-1 transmission rates.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, Imperial College London London, UK.

ABSTRACT
Complex mechanisms underlying the maintenance of fully functional, proliferative, HIV-1-specific T-cell responses involve processes from early T-cell development through to the final stages of T-cell differentiation and antigen recognition. Virus-specific proliferative CD4 and CD8 T-cell responses, important for the control of infection, are observed in some HIV-1(+) patients during early stages of disease, and are maintained in long-term non-progressing subjects. In the vast majority of HIV-1(+) patients, full immune functionality is lost when proliferative HIV-1-specific T-cell responses undergo a variable progressive decline throughout the course of chronic infection. This appears irreparable despite administration of potent combination antiretroviral therapy, which to date is non-curative, necessitating life-long administration and the development of effective, novel, therapeutic interventions. While a sterilizing cure, involving clearance of virus from the host, remains a primary aim, a "functional cure" may be a more feasible goal with considerable impact on worldwide HIV-1 infection. Such an approach would enable long-term co-existence of host and virus in the absence of toxic and costly drugs. Effective immune homeostasis coupled with a balanced response appropriately targeting conserved viral antigens, in a manner that avoids hyperactivation and exhaustion, may prove to be the strongest correlate of durable viral control. This review describes novel concepts underlying full immune functionality in the context of HIV-1 infection, which may be utilized in future strategies designed to improve upon existing therapy. The aim will be to induce long-term non-progressor or elite controller status in every infected host, through immune-mediated control of viremia and reduction of viral reservoirs, leading to lower HIV-1 transmission rates.

No MeSH data available.


Related in: MedlinePlus