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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

Human thymus and thymic function in HIV-1+ long-term non-progressors and chronic progressors. (A) Histological section of a healthy human thymus. SR, subcapsular region; C, cortex; CMJ, cortico-medullary junction; M, medulla. (B) TREC levels in PBMC of HIV controllers (HIC; “True LTNP”) compared to age-matched HIV-1+ chronic progressors (CP). Histogram plots show median values with standard deviations. Data from Imami et al. (2001), Pido-Lopez et al. (2003), and Westrop et al. (2009b).
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Figure 2: Human thymus and thymic function in HIV-1+ long-term non-progressors and chronic progressors. (A) Histological section of a healthy human thymus. SR, subcapsular region; C, cortex; CMJ, cortico-medullary junction; M, medulla. (B) TREC levels in PBMC of HIV controllers (HIC; “True LTNP”) compared to age-matched HIV-1+ chronic progressors (CP). Histogram plots show median values with standard deviations. Data from Imami et al. (2001), Pido-Lopez et al. (2003), and Westrop et al. (2009b).

Mentions: The thymus (Figure 2A), the site where hematopoietic stem cells from the bone marrow differentiate into T cells before circulating and surveilling the periphery, is damaged by HIV-1 infection, resulting in reduced output of T cells into the periphery (Douek et al., 1998; Dion et al., 2004). HIV-1 expressing cells have been shown to be present in both the perivascular space and the true epithelial thymus of HIV-1+ chronically infected individuals, with evidence of thymic epithelial cell death and calcification (Haynes et al., 1999, 2000). Infection of thymic epithelial cells may result in presentation of HIV-1 epitopes as “self” to developing thymocytes, and subsequent deletion of “self-reactive” HIV-1-specific clonotypes leading to absence of these cells from the periphery. In LTNP, and other patients exhibiting stable CD4 T-cell counts throughout HIV-1 infection, the thymic epithelium, as with peripheral CD4+ T cells, may be resistant to HIV-1 infection (Chen et al., 2011). This offers an explanation for the observed preservation of thymic function, high output of naïve signal joint TCR excision circle-positive (sjTREC+) T cells, and proliferation competent HIV-1-specific T cells (Figure 2B) (Imami et al., 2001; Pido-Lopez et al., 2001; Westrop et al., 2009b). Degeneration of the thymus is characterized by replacement of the thymic tissue with adipocytes, and such age-related thymic involution has been shown to be accelerated in progressive HIV-1 infection (Douek et al., 1998; Zhang et al., 1999). Accordingly, generation of naïve CD4+ and CD8+ T cells in untreated HIV-1+ individuals has been shown, by sjTREC analysis, to be significantly lower in peripheral blood and lymph nodes than in age-matched uninfected controls (Douek et al., 1998; Pido-Lopez et al., 2003). This observed thymic atrophy, the high rate of T-cell turnover and the increased number of T cells in the lymphoid tissues induced by HIV-1 during chronic infection, indicates a significant role for the thymus in T-cell homeostasis during HIV-1 infection (Ho Tsong Fang et al., 2008; Bandera et al., 2010; Sasson et al., 2012).


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

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

Human thymus and thymic function in HIV-1+ long-term non-progressors and chronic progressors. (A) Histological section of a healthy human thymus. SR, subcapsular region; C, cortex; CMJ, cortico-medullary junction; M, medulla. (B) TREC levels in PBMC of HIV controllers (HIC; “True LTNP”) compared to age-matched HIV-1+ chronic progressors (CP). Histogram plots show median values with standard deviations. Data from Imami et al. (2001), Pido-Lopez et al. (2003), and Westrop et al. (2009b).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3585435&req=5

Figure 2: Human thymus and thymic function in HIV-1+ long-term non-progressors and chronic progressors. (A) Histological section of a healthy human thymus. SR, subcapsular region; C, cortex; CMJ, cortico-medullary junction; M, medulla. (B) TREC levels in PBMC of HIV controllers (HIC; “True LTNP”) compared to age-matched HIV-1+ chronic progressors (CP). Histogram plots show median values with standard deviations. Data from Imami et al. (2001), Pido-Lopez et al. (2003), and Westrop et al. (2009b).
Mentions: The thymus (Figure 2A), the site where hematopoietic stem cells from the bone marrow differentiate into T cells before circulating and surveilling the periphery, is damaged by HIV-1 infection, resulting in reduced output of T cells into the periphery (Douek et al., 1998; Dion et al., 2004). HIV-1 expressing cells have been shown to be present in both the perivascular space and the true epithelial thymus of HIV-1+ chronically infected individuals, with evidence of thymic epithelial cell death and calcification (Haynes et al., 1999, 2000). Infection of thymic epithelial cells may result in presentation of HIV-1 epitopes as “self” to developing thymocytes, and subsequent deletion of “self-reactive” HIV-1-specific clonotypes leading to absence of these cells from the periphery. In LTNP, and other patients exhibiting stable CD4 T-cell counts throughout HIV-1 infection, the thymic epithelium, as with peripheral CD4+ T cells, may be resistant to HIV-1 infection (Chen et al., 2011). This offers an explanation for the observed preservation of thymic function, high output of naïve signal joint TCR excision circle-positive (sjTREC+) T cells, and proliferation competent HIV-1-specific T cells (Figure 2B) (Imami et al., 2001; Pido-Lopez et al., 2001; Westrop et al., 2009b). Degeneration of the thymus is characterized by replacement of the thymic tissue with adipocytes, and such age-related thymic involution has been shown to be accelerated in progressive HIV-1 infection (Douek et al., 1998; Zhang et al., 1999). Accordingly, generation of naïve CD4+ and CD8+ T cells in untreated HIV-1+ individuals has been shown, by sjTREC analysis, to be significantly lower in peripheral blood and lymph nodes than in age-matched uninfected controls (Douek et al., 1998; Pido-Lopez et al., 2003). This observed thymic atrophy, the high rate of T-cell turnover and the increased number of T cells in the lymphoid tissues induced by HIV-1 during chronic infection, indicates a significant role for the thymus in T-cell homeostasis during HIV-1 infection (Ho Tsong Fang et al., 2008; Bandera et al., 2010; Sasson et al., 2012).

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