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The enduring tale of T cells in HIV immunopathogenesis.

Vajpayee M, Negi N, Kurapati S - Indian J. Med. Res. (2013)

Bottom Line: It has been shown that HIV has multipronged effects especially on the adaptive immunity, with CD4+ T cells being the worst affected T cell populations.Apart from causing phenotypic changes, HIV has adverse effects on the functional aspect of the immune system, with evidences implicating it in the loss of the capacity of T cells to secrete various antiviral cytokines and chemokines.However, there continues to be many aspects of the immunopathogenesis of HIV that are still unknown and thus require further research to convert the malaise of HIV into a manageable epidemic.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology, All India Institute of Medical Sciences, New Delhi, India.

ABSTRACT
HIV continues to be a major health problem worldwide even today. Owing to the intricate nature of its interactions with the immune system, HIV has remained an enigma that cleverly utilizes the host machinery to survive. Its ability to evade the host immune system, at both levels, innate and adaptive, allows the pathogen to replicate and transmit from one host to another. It has been shown that HIV has multipronged effects especially on the adaptive immunity, with CD4+ T cells being the worst affected T cell populations. Various analyses have revealed that the exposure to HIV results in clonal expansion and excessive activation of the immune system. Also, an abnormal process of differentiation has been observed suggestive of an alteration and blocks in the maturation of various T cell subsets. Additionally, HIV has shown to accelerate immunosenescence and exhaustion of the overtly activated T cells. Apart from causing phenotypic changes, HIV has adverse effects on the functional aspect of the immune system, with evidences implicating it in the loss of the capacity of T cells to secrete various antiviral cytokines and chemokines. However, there continues to be many aspects of the immunopathogenesis of HIV that are still unknown and thus require further research to convert the malaise of HIV into a manageable epidemic.

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Related in: MedlinePlus

Hypothetical model of gastrointestinal tract (A) Normal Healthy state and (B) chronic HIV infection. (A) In a normal healthy state, the epithelial and M cells lining the mucosal barrier of the gastrointestinal tract forms an effective barrier against invading pathogens. The lamina propria contains loose clusters of T cells, macrophages, plasmacytoid dendritirc cells (pDCs) and follicles. (B) During chronic HIV infection, the mucosal barrier lining the gastrointestinal tract becomes leaky facilitating translocation of microbial products. This results in increased infiltration of inflammatory cells into the lamina propria leading to more proinflammatory cytokine production. Lipopolysaccharide has been reported to activate IFN-α and Indoleamine 2, 3 dioxygenase (IDO) production by (pDCs) promoting immune activation and a shift in the balance from Th17 to Treg population by unknown mechanisms.
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Figure 1: Hypothetical model of gastrointestinal tract (A) Normal Healthy state and (B) chronic HIV infection. (A) In a normal healthy state, the epithelial and M cells lining the mucosal barrier of the gastrointestinal tract forms an effective barrier against invading pathogens. The lamina propria contains loose clusters of T cells, macrophages, plasmacytoid dendritirc cells (pDCs) and follicles. (B) During chronic HIV infection, the mucosal barrier lining the gastrointestinal tract becomes leaky facilitating translocation of microbial products. This results in increased infiltration of inflammatory cells into the lamina propria leading to more proinflammatory cytokine production. Lipopolysaccharide has been reported to activate IFN-α and Indoleamine 2, 3 dioxygenase (IDO) production by (pDCs) promoting immune activation and a shift in the balance from Th17 to Treg population by unknown mechanisms.

Mentions: (iii) Microbial translocation: The human gut has vast surface area that allows it to absorb nutrients and water without infiltration of the gut flora and thereby restricts the translocation of microbial products. Contrary to this notion, the presences of histological abnormalities and lymphocytes in the gut associated lymphoid tissue (GALT) of chronically HIV infected individuals have been reported745 highlighting a possible association between mucosal immunity and HIV disease progression. Since then, substantial data have been gathered and different theories have been proposed as the underlying mechanisms. Some researchers endorse the most apparent mechanism of virus mediated toxicity in enterocytes46. This could be due to the inhibitory role of Tat, an HIV protein, on uptake of glucose by enterocytes. Also, gp120 has shown to increase the concentration of calcium in enterocytes leading to ionic imbalance47. Thus, these changes affect the integrity of the mucosa lining of the gastrointestinal tract leading to mobilization of microbial products such as LPS, sCD14 and EndoCAb. To prove this hypothesis, Brenchley et al48 showed that LPS, a common component of bacterial cell wall was increased in plasma of chronically infected HIV individuals and SIV-infected macaques and correlated with immune activation. Supporting evidence was provided by measurement of soluble CD14 (sCD14) in HIV infected individuals and significantly higher levels of plasma CD14 were found in the acute and chronic HIV infected individuals as compared to the HIV seronegative individuals49. Apart from this, they also reported that LPS levels strongly correlated with plasma IFN-α level which led to their hypothesis that certain factors in the intestinal flora could also induce IFN-α production. Thus, they concluded that the microbial products translocated across a leaky gut, may result in systemic hyperactivation of the innate immune system and may further impair the adaptive immune responses4 (Figure). Other microbial products such as flagellin, bacterial 16sDNA and peptidoglycans have also been shown to translocate across the mucosal barrier. These microbial products through their interaction with Toll-like receptors (TLRs) activate the innate immune system. Boasso and Shearer39 proved this hypothesis through their work on murine models and reported that in mice lacking the IFN-α receptor showed milder physiological and functional alterations in their lymphoid organs on treatment with CpG oligodeoxynucleotides (ODN) as compared to those with IFN-γ receptor. Therefore, they propounded the theory that the administration of CpG ODN activates pDC through TLR9 and results in alterations50 which were similar to those seen in HIV infection39.


The enduring tale of T cells in HIV immunopathogenesis.

Vajpayee M, Negi N, Kurapati S - Indian J. Med. Res. (2013)

Hypothetical model of gastrointestinal tract (A) Normal Healthy state and (B) chronic HIV infection. (A) In a normal healthy state, the epithelial and M cells lining the mucosal barrier of the gastrointestinal tract forms an effective barrier against invading pathogens. The lamina propria contains loose clusters of T cells, macrophages, plasmacytoid dendritirc cells (pDCs) and follicles. (B) During chronic HIV infection, the mucosal barrier lining the gastrointestinal tract becomes leaky facilitating translocation of microbial products. This results in increased infiltration of inflammatory cells into the lamina propria leading to more proinflammatory cytokine production. Lipopolysaccharide has been reported to activate IFN-α and Indoleamine 2, 3 dioxygenase (IDO) production by (pDCs) promoting immune activation and a shift in the balance from Th17 to Treg population by unknown mechanisms.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3928699&req=5

Figure 1: Hypothetical model of gastrointestinal tract (A) Normal Healthy state and (B) chronic HIV infection. (A) In a normal healthy state, the epithelial and M cells lining the mucosal barrier of the gastrointestinal tract forms an effective barrier against invading pathogens. The lamina propria contains loose clusters of T cells, macrophages, plasmacytoid dendritirc cells (pDCs) and follicles. (B) During chronic HIV infection, the mucosal barrier lining the gastrointestinal tract becomes leaky facilitating translocation of microbial products. This results in increased infiltration of inflammatory cells into the lamina propria leading to more proinflammatory cytokine production. Lipopolysaccharide has been reported to activate IFN-α and Indoleamine 2, 3 dioxygenase (IDO) production by (pDCs) promoting immune activation and a shift in the balance from Th17 to Treg population by unknown mechanisms.
Mentions: (iii) Microbial translocation: The human gut has vast surface area that allows it to absorb nutrients and water without infiltration of the gut flora and thereby restricts the translocation of microbial products. Contrary to this notion, the presences of histological abnormalities and lymphocytes in the gut associated lymphoid tissue (GALT) of chronically HIV infected individuals have been reported745 highlighting a possible association between mucosal immunity and HIV disease progression. Since then, substantial data have been gathered and different theories have been proposed as the underlying mechanisms. Some researchers endorse the most apparent mechanism of virus mediated toxicity in enterocytes46. This could be due to the inhibitory role of Tat, an HIV protein, on uptake of glucose by enterocytes. Also, gp120 has shown to increase the concentration of calcium in enterocytes leading to ionic imbalance47. Thus, these changes affect the integrity of the mucosa lining of the gastrointestinal tract leading to mobilization of microbial products such as LPS, sCD14 and EndoCAb. To prove this hypothesis, Brenchley et al48 showed that LPS, a common component of bacterial cell wall was increased in plasma of chronically infected HIV individuals and SIV-infected macaques and correlated with immune activation. Supporting evidence was provided by measurement of soluble CD14 (sCD14) in HIV infected individuals and significantly higher levels of plasma CD14 were found in the acute and chronic HIV infected individuals as compared to the HIV seronegative individuals49. Apart from this, they also reported that LPS levels strongly correlated with plasma IFN-α level which led to their hypothesis that certain factors in the intestinal flora could also induce IFN-α production. Thus, they concluded that the microbial products translocated across a leaky gut, may result in systemic hyperactivation of the innate immune system and may further impair the adaptive immune responses4 (Figure). Other microbial products such as flagellin, bacterial 16sDNA and peptidoglycans have also been shown to translocate across the mucosal barrier. These microbial products through their interaction with Toll-like receptors (TLRs) activate the innate immune system. Boasso and Shearer39 proved this hypothesis through their work on murine models and reported that in mice lacking the IFN-α receptor showed milder physiological and functional alterations in their lymphoid organs on treatment with CpG oligodeoxynucleotides (ODN) as compared to those with IFN-γ receptor. Therefore, they propounded the theory that the administration of CpG ODN activates pDC through TLR9 and results in alterations50 which were similar to those seen in HIV infection39.

Bottom Line: It has been shown that HIV has multipronged effects especially on the adaptive immunity, with CD4+ T cells being the worst affected T cell populations.Apart from causing phenotypic changes, HIV has adverse effects on the functional aspect of the immune system, with evidences implicating it in the loss of the capacity of T cells to secrete various antiviral cytokines and chemokines.However, there continues to be many aspects of the immunopathogenesis of HIV that are still unknown and thus require further research to convert the malaise of HIV into a manageable epidemic.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology, All India Institute of Medical Sciences, New Delhi, India.

ABSTRACT
HIV continues to be a major health problem worldwide even today. Owing to the intricate nature of its interactions with the immune system, HIV has remained an enigma that cleverly utilizes the host machinery to survive. Its ability to evade the host immune system, at both levels, innate and adaptive, allows the pathogen to replicate and transmit from one host to another. It has been shown that HIV has multipronged effects especially on the adaptive immunity, with CD4+ T cells being the worst affected T cell populations. Various analyses have revealed that the exposure to HIV results in clonal expansion and excessive activation of the immune system. Also, an abnormal process of differentiation has been observed suggestive of an alteration and blocks in the maturation of various T cell subsets. Additionally, HIV has shown to accelerate immunosenescence and exhaustion of the overtly activated T cells. Apart from causing phenotypic changes, HIV has adverse effects on the functional aspect of the immune system, with evidences implicating it in the loss of the capacity of T cells to secrete various antiviral cytokines and chemokines. However, there continues to be many aspects of the immunopathogenesis of HIV that are still unknown and thus require further research to convert the malaise of HIV into a manageable epidemic.

Show MeSH
Related in: MedlinePlus