HIV p17 enhances lymphocyte proliferation and HIV-1 replication after binding to a human serum factor

Francesco, Maria Antonia De; Caruso, Arnaldo; Fallacara, Francesca; Ad, Canaris; Dima, Francesco; Poiesi, Claudio; Licenziati, Stefano; Corulli, M.; Martinelli, F.; Fiorentini, Simona; Turano, A

doi:10.1097/00002030-199803000-00001

Cited by 26 publications

(31 citation statements)

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“…Consequently, we have focused our efforts on studies of p17 and Env persistence in GCs of LNs. These findings may be relevant to lymphopathogenesis involving GC formation and B cell activation, because both these viral structural protein and glycoproteins interact with mononuclear cells and induce and͞or enhance a number of cytokines and chemokines that are critical in activation, recruitment, and cell proliferation (23)(24)(25).…”

Section: Discussionmentioning

confidence: 99%

“…It is well established that B cell stimulation and prolonged immune deficiency are main risk factors for non-Hodgkin's lymphoma (NHL) in people with AIDS (10). Given that at least the viral structural glycoproteins HIV-1gp120͞gp41 and the matrix protein HIV-1p17 possess a capacity to actively interact with cells of the immune system (23)(24)(25), the long-term presence in GCs of LNs points to the fact that at least one risk factor for NHL was not eliminated by antiretroviral therapy. Earlier observations showed that the serum-soluble CD23 level correlates with the subsequent development of AIDS-related NHL (55,56), and colocalization of CD23 expression in FDCs bounding the HIV-1 antigen-antibody complexes in GCs of LNs was also demonstrated (32 …”

Section: Discussionmentioning

confidence: 99%

“…Earlier in vitro studies explored interactions of mononuclear cells from peripheral blood with native or recombinant HIV-1 structural proteins and glycoproteins, with the matrix protein HIV-1p17 (23,24), and particularly with the HIV-1Env (gp120͞160) (25). These extensive studies of B and T cell interactions with HIV-1Env and HIV-1p17 showed a broad spectrum of changes in cell surface markers, cytokine production, B cell maturation, and increased T cell proliferation and HIV-1 replication in the virus-infected T cell cultures (23)(24)(25).…”

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confidence: 99%

“…These extensive studies of B and T cell interactions with HIV-1Env and HIV-1p17 showed a broad spectrum of changes in cell surface markers, cytokine production, B cell maturation, and increased T cell proliferation and HIV-1 replication in the virus-infected T cell cultures (23)(24)(25). However, the significance of these studies has been in question because of the absence of clear-cut in vivo evidence demonstrating persistence of HIV-1 structural proteins and glycoproteins accessible to mononuclear cells.…”

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confidence: 99%

“…These studies did not address the persistence of other HIV-1 structural proteins and glycoproteins in HIV-1 infected patients under long-term antiretroviral therapy. Taking into consideration earlier in vitro studies on the capacity of HIV-1p17 and -1Env to induce a broad spectrum of changes in mononuclear cells (23)(24)(25), it was important to establish the long-term persistence of these viral structural protein and glycoproteins in patients under HAART. In this paper, we provide evidence demonstrating the long-term persistence of HIV-1p17, -p24, and -gp120͞gp41 in GCs of LNs in seven HIV-1-infected patients under HAART.…”

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confidence: 99%

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Persistence of HIV-1 structural proteins and glycoproteins in lymph nodes of patients under highly active antiretroviral therapy

Popovič

Tenner-Rácz

Pelser

et al. 2005

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

152

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Here we report a long-term persistence of HIV-1 structural proteins and glycoproteins in germinal centers (GCs) of lymph nodes (LNs) in the absence of detectable virus replication in patients under highly active antiretroviral therapy (HAART). The persistence of viral structural proteins and glycoproteins in GCs was accompanied by specific antibody responses to HIV-1. Seven patients during the chronic phase of HIV-1 infection were analyzed for the presence of the capsid protein (HIV-1p24), matrix protein (HIV-1p17), and envelope glycoproteins (HIV-1gp120͞gp41), as well as for viral RNA (vRNA) in biopsy specimens from LNs obtained before initiation of therapy and during HAART that lasted from 5 to 13 months. In parallel, these patients were also monitored for viremia and specific anti-HIV-1 antibody responses to structural proteins and glycoproteins both before and during treatment. Before-therapy viral levels, as determined by RT-PCR, ranged from 3 ؋ 10 3 to 6.3 ؋ 10 5 copies of vRNA per ml, whereas during treatment, vRNA was under detectable levels (<25 copies per ml). The pattern of vRNA detection in peripheral blood was concordant with in situ hybridization results of LN specimens. Before treatment, vRNA associated with follicular dendritic cells (FDCs) was readily detected in GCs of LNs of the patients, whereas during therapy, vRNA was consistently absent in the GCs of LN biopsies of treated patients. In contrast to vRNA hybridization results, viral structural proteins and glycoproteins, evaluated by immunohistochemical staining, were present and persisted in the GC light zone of LNs in abundant amounts not only before initiation of therapy but also during HAART, when no vRNA was detected in GCs. Consistent with immunohistochemical findings, specific antibody responses to HIV1p17, -p24, and -gp120͞gp41, as evaluated by ELISA and virus neutralization, persisted in patients under therapy for up to 13 months of follow-up. The implications of these findings are discussed in relation to HIV-1 persistence in infected individuals and the potential role of chronic antigenic stimulation by the deposited structural proteins in GCs for AIDS-associated B cell malignancies.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Persistence of HIV-1 structural proteins and glycoproteins in lymph nodes of patients under highly active antiretroviral therapy

Popovič

Tenner-Rácz

Pelser

et al. 2005

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

152

125

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Preclinical studies on immunogenicity of the HIV‐1 p17‐based synthetic peptide AT20‐KLH

et al. 2004

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Several studies have suggested that HIV-1 p17 matrix protein may play an important role in AIDS pathogenesis, since anti-p17 antibodies represent a serological marker of disease progression during HIV-1 infection both in adults and children. Moreover, it has been recently reported that the viral protein is capable of significantly increasing the proliferation of preactivated T lymphocytes and the release of proinflammatory cytokines. Recombinant HIV-1 p17 also has induced an increased rate of HIV-1 replication in vitro. All p17 biological activities are exerted after its binding to a specific cellular receptor expressed on activated T lymphocytes. The functional p17 epitope involved in receptor binding was found to be located at the NH(2)-terminal region of the viral protein. Immunization of C57BL/6 mice with a 20 amino acid synthetic peptide representative of the HIV-1 p17 functional region (AT20) coupled to the carrier protein keyhole limpet hemocyanin (KLH) and given in Freund's incomplete adjuvant, resulted in the development of p17-neutralizing antibodies capable of blocking p17/p17 receptor interaction, and consequently, all biological activities of the viral protein. Moreover, it was possible to skew the humoral response induced by priming mice with AT20-KLH toward cell-mediated immune responses, boosting animals with p17. Our findings may provide a new strategy to develop a synthetic AIDS vaccine based on a potentially effective and safe subunit vaccine against the HIV-1 cytokine-like matrix protein p17. Preclinical immunogenicity data for AT20-KLH provide the basis for evaluation of the peptide-based vaccine, alone and in combination with p17 or p17 DNA vaccines, in Phase I clinical trials.

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Differential expression of constitutive and inducible proteasome subunits in human monocyte‐derived DC differentiated in the presence of IFN‐α or IL‐4

et al. 2009

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Several studies strongly suggest that DC differentiated in vitro in the presence of type I IFN acquire more potent immune stimulatory properties, compared with DC differentiated in vitro with IL-4. However, little is known about the molecular mechanisms underlying this phenomenon. To address this question, we compared the Ag-processing machinery (APM) profile in human DC grown in the presence of IFN-a ( IFN DC) or IL-4 ( IL-4 DC). Using a panel of APM component-specific mAb in Western blot experiments, we found that IFN DC preferentially express inducible proteasome subunits (LMP2, LMP7, and MECL1) both at immature and mature stages. In contrast, immature IL-4 DC co-express both constitutive (b1, b2, and b5) and inducible subunits, as shown by Western blotting analysis. In addition, immature IFN DC express higher levels of TAP1, TAP2, calnexin, calreticulin, tapasin, and HLA class I molecules than IL-4 DC. The different proteasome profiles of IFN DC and IL-4 DC were associated with a greater ability of IFN DC to present an immunodominant epitope that requires LMP7 expression for its processing. In general, these data show the impact of cytokines on APM component expression and hence the Ag-processing ability of DC.Key words: Antibodies . Antigen processing . Cytokines . Human DC Introduction DC play a key role as APC in the initiation of specific immune responses [1,2]. In recent years, attention has been focused on the possibility that tissue microenvironment could markedly influence the phenotype and functional characteristics of DC, thus shaping the immunological effector mechanisms from the first steps of the immune response. For this reason, understanding the effect on DC maturation exerted by cytokines, known to be released in the peripheral tissue, is a crucial issue in immunology. Changes associated with DC maturation include upregulation of MHC and co-stimulatory molecule expression, and a progressive change in Ag-processing machinery (APM) component expression [3][4][5]. The proteasome is a central element of APM; it 56may be expressed in two forms, constitutive and inducible (also called immunoproteasome), endowed with different protein cleavage specificities [6,7]. The constitutive proteasome is a four-ring structure; the outer rings contain seven non-catalytic a-type subunits, whereas the inner rings contain seven b-type subunits, three of which are catalytic (delta/b1, Z/b2, and X/b5). The immunoproteasome contains alternative forms of the catalytic subunits (LMP2, MECL1, and LMP7), that replace the corresponding constitutive homologs b1, b2, and b5 [8][9][10].Differences in the protein cleavage patterns between the constitutive proteasome and the immunoproteasome have been demonstrated, and the spectrum of antigenic peptides produced by a cell may eventually vary under different physiological and pathological stimuli [11]. Most importantly, it has been found that a number of antigenic peptides, mainly derived from selfproteins, are not processed efficiently by the immunoproteasome [7,12]; they in...

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HIV p17 enhances lymphocyte proliferation and HIV-1 replication after binding to a human serum factor

Abstract: Characterization of the human factor(s) and identification of the interacting p17 epitope(s) will improve our understanding of the mechanisms used by HIV to efficiently replicate in our organisms.

Cited by 26 publications

References 31 publications

Persistence of HIV-1 structural proteins and glycoproteins in lymph nodes of patients under highly active antiretroviral therapy

Persistence of HIV-1 structural proteins and glycoproteins in lymph nodes of patients under highly active antiretroviral therapy

Preclinical studies on immunogenicity of the HIV‐1 p17‐based synthetic peptide AT20‐KLH

Differential expression of constitutive and inducible proteasome subunits in human monocyte‐derived DC differentiated in the presence of IFN‐α or IL‐4

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