HIV-associated immune dysfunction and viral infection: role in the pathogenesis of AIDS-related lymphoma

Epeldegui, Marta; Vendrame, Elena; Martı́nez-Maza, Otoniel

doi:10.1007/s12026-010-8168-8

Cited by 81 publications

(85 citation statements)

References 94 publications

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“…HIV-NHLs derived from either germinal or postgerminal center B lymphocytes are often characterized by clinical aggressiveness and display a predilection for extranodal sites (3)(4)(5). To date, the usual reason for the increase of HIV-NHL is said to be an HIV-1-driven immune dysfunction (6). The onset of HIV-NHL is often preceded by an overproduction of B-cell stimulatory cytokines, which further sustains B-cell activation and possibly drives the generation of activation-induced DNA modification errors and oncogenic translocations, conferring the transformed phenotype to B cells (7).…”

Section: B-cell Clonogenicitymentioning

confidence: 99%

Role of HIV-1 matrix protein p17 variants in lymphoma pathogenesis

Dolcetti

Giagulli

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

102

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Although in decline after successful anti-HIV therapy, B-cell lymphomas are still elevated in HIV-1-seropositive (HIV+) persons, and the mechanisms are obscure. The HIV-1 matrix protein p17 persists in germinal centers long after HIV-1 drug suppression, and some p17 variants (vp17s) activate Akt signaling and promote growth of transformed B cells. Here we show that vp17s derived from four of five non-Hodgkin lymphoma (NHL) tissues from HIV+ subjects display potent B-cell growth-promoting activity. They are characterized by amino acid insertions at position 117-118 (Ala-Ala) or 125-126 (Gly-Asn or Gly-Gln-Ala-Asn-Gln-Asn) among some other mutations throughout the sequence. Identical dominant vp17s are found in both tumor and plasma. Three of seven plasma samples from an independent set of NHL cases manifested multiple Ala insertions at position 117-118, and one with the Ala-Ala profile also promoted B-cell growth and activated Akt signaling. Ultradeep pyrosequencing showed that vp17s with C-terminal insertions are more frequently detected in plasma of HIV+ subjects with than without NHL. Insertion of Ala-Ala at position 117-118 into reference p17 (refp17) was sufficient to confer B-cell growth-promoting activity. In contrast, refp17 bearing the Gly-Asn insertion at position 125-126 did not, suggesting that mutations not restricted to the C terminus can also account for this activity. Biophysical analysis revealed that the Ala-Ala insertion mutant is destabilized compared with refp17, whereas the Gly-Asn form is stabilized. This finding provides an avenue for further exploration of structure function relationships and new treatment strategies in combating HIV-1-related NHL.non-Hodgkin lymphoma | HIV-1 matrix protein p17 | AIDS | p17 variants | B-cell clonogenicity

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Section: B-cell Clonogenicitymentioning

confidence: 99%

Role of HIV-1 matrix protein p17 variants in lymphoma pathogenesis

Dolcetti

Giagulli

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

102

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“…40 This environment with dysregulated cytokine/chemokine release and B-cell hyperstimulation 41 along with the presence of concomitant infection (eg, Epstein-Barr virus, human herpesvirus type 8, cytomegalovirus) may promote a permissive environment for HIV-1-induced B-cell expansion and impaired immune surveillance, culminating in lympho-proliferative disorders. 42 Up until now, the molecular mechanisms responsible for B-cell transformation associated with ARLs have not been elucidated. However, in this respect it is worth noting that recent data have highlighted a role for p17 variants in promoting B-cell growth and malignant transformation in vitro.…”

Section: Discussionmentioning

confidence: 99%

HIV-1 Matrix Protein p17 Promotes Lymphangiogenesis and Activates the Endothelin-1/Endothelin B Receptor Axis

Caccuri

Rueckert

Giagulli

et al. 2014

ATVB

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Objective— AIDS-related lymphomas are high grade and aggressively metastatic with poor prognosis. Lymphangiogenesis is essential in supporting proliferation and survival of lymphoma, as well as tumor dissemination. Data suggest that aberrant lymphangiogenesis relies on action of HIV-1 proteins rather than on a direct effect of the virus itself. HIV-1 matrix protein p17 was found to accumulate and persist in lymph nodes of patients even under highly active antiretroviral therapy. Because p17 was recently found to exert a potent proangiogenic activity by interacting with chemokine (C-X-C motif) receptors 1 and 2, we tested the prolymphangiogenic activity of the viral protein. Approach and Results— Human primary lymph node–derived lymphatic endothelial cells were used to perform capillary-like structure formation, wound healing, spheroids, and Western blot assays after stimulation with or without p17. Here, we show that p17 promotes lymphangiogenesis by binding to chemokine (C-X-C motif) receptor-1 and chemokine (C-X-C motif) receptor-2 expressed on lymph node–derived lymphatic endothelial cells and activating the Akt/extracellular signal–regulated kinase signaling pathway. In particular, it was found to induce capillary-like structure formation, sprout formation from spheroids, and increase lymph node–derived lymphatic endothelial cells motility. The p17 lymphangiogenic activity was, in part, sustained by activation of the endothelin-1/endothelin receptor B axis. A Matrigel plug assay showed that p17 was able to promote the outgrowth of lymphatic vessels in vivo, demonstrating that p17 directly regulates lymphatic vessel formation. Conclusions— Our results suggest that p17 may generate a prolymphangiogenic microenvironment and plays a role in predisposing the lymph node to lymphoma growth and metastasis. This finding offers new opportunities to identify treatment strategies in combating AIDS-related lymphomas.

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“…Moreover, during HIV infection, altered immune responses including chronic B cell activation has been reported [39]. It has been suggested that combination of highly regulated latent infection of EBV in B cell and chronic reactivation of replication in lymphoid tissue and mucosal surfaces may 7 lead to many patterns of virus-host interaction, which may reveal important strategies of EBV mediated immune evasion [85].…”

Section: B Cell Response During Viral Infectionmentioning

confidence: 99%

Immune Regulation and Evasion of Mammalian Host Cell Immunity During Viral Infection

et al. 2013

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The mammalian host immune system has wide array of defence mechanisms against viral infections. Depending on host immunity and the extent of viral persistence, either the host immune cells might clear/restrict the viral load and disease progression or the virus might evade host immunity by down regulating host immune effector response(s). Viral antigen processing and presentation in the host cells through major histocompatibility complex (MHC) elicit subsequent anti-viral effector T cell response(s). However, modulation of such response(s) might generate one of the important viral immune evasion strategies. Viral peptides are mostly generated by proteolytic cleavage in the cytosol of the infected host cells. CD8 ? T lymphocytes play critical role in the detection of viral infection by recognizing these peptides displayed at the plasma membrane by MHC-I molecules. The present review summarises the current knowledge on the regulation of mammalian host innate and adaptive immune components, which are operative in defence mechanisms against viral infections and the variety of strategies that viruses have evolved to escape host cell immunity. The understanding of viral immune evasion strategies is important for designing anti-viral immunotherapies.

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HIV-associated immune dysfunction and viral infection: role in the pathogenesis of AIDS-related lymphoma

Cited by 81 publications

References 94 publications

Role of HIV-1 matrix protein p17 variants in lymphoma pathogenesis

Role of HIV-1 matrix protein p17 variants in lymphoma pathogenesis

HIV-1 Matrix Protein p17 Promotes Lymphangiogenesis and Activates the Endothelin-1/Endothelin B Receptor Axis

Immune Regulation and Evasion of Mammalian Host Cell Immunity During Viral Infection

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