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Guido Poli

Publications and source records attributed to Guido Poli.

At least 19 recordsLinked to original sources
PubMed2006

Postgenomic up-regulation of CCL3L1 expression in HTLV-2-infected persons curtails HIV-1 replication.

Leukocytes of persons coinfected with HTLV-2 and HIV-1 secrete chemokines that prevent CCR5-dependent (R5) HIV-1 infection of CD4+ T cells and macrophages, with HTLV-2-induced MIP-1alpha as dominant HIV-1 inhibitory molecule. Two nonallelic genes code for CCL3 and CCL3L1 isoforms of MIP-1alpha, and the population-specific copy number of CCL3L1 exerts a profound effect on HIV-1 susceptibility and disease progression. Here, we demonstrate that CCL3L1 is secreted spontaneously by leukocytes of HTLV-2-infected persons and superinduced when cells of HTLV-2/HIV-1 multiply exposed-uninfected seronegative (MEU) persons were stimulated with HIV-1 Env peptides. The CCL3L1 median copy number in MEU, HTLV-2/HIV-1-coinfected long-term nonprogressors (LTNPs) and HIV-1-monoinfected LTNPs were 1, 2, and 3, respectively. An increased CCL3L1/CCL3 mRNA ratio versus PHA-activated healthy leukocytes was observed in both HIV-1-monoinfected LTNPs and in HTLV-2/HIV-1(MEU) subjects. An additional potential correlate of HTLV-2 infection was a rapid and persistent leukocyte secretion of GM-CSF and IFN-gamma, 2 cytokines endowed with CCR5 down-regulation capacity. This study confirms a crucial protective role of CCL3L1 from both HIV infection and disease progression, highlighting a previously not described functional up-regulation of this chemokine variant in both HIV-positive and -negative persons infected with HTLV-2.

Adult↗
PubMed2006

Monocyte-derived macrophages and myeloid cell lines as targets of HIV-1 replication and persistence.

HIV infection of mononuclear phagocytes (MP), mostly as tissue macrophages, is a dominant feature in the pathogenesis of HIV disease and its progression to AIDS. Although the general mechanism of infection is not dissimilar to that of CD4+ T lymphocytes occurring via interaction of the viral envelope with CD4 and a chemokine receptor (usually CCR5), other features are peculiar to MP infection. Among others, the long-term persistence of productive infection, sustained by the absence of substantial cell death, and the capacity of the virions to bud and accumulate in intracellular multivesicular bodies (MVB), has conferred to MP the role of "Trojan horses" perpetuating the chronic state of infection. Because the investigation of tissue macrophages is often very difficult for both ethical and practical reasons of accessibility, most studies of in vitro infection rely upon monocyte-derived macrophages (MDM), a methodology hampered by inter-patient variability and lack of uniformity of experimental protocols. A number of cell lines, mostly Mono Mac, THP-1, U937, HL-60, and their derivative chronically infected counterparts (such as U1 and OM-10.1 cell lines) have complemented the MDM system of infection providing useful information on the features of HIV replication in MP. This article describes and compares the most salient features of these different cellular models of MP infection by HIV.

Cell Line↗
PubMed2006

Nef alleles from human immunodeficiency virus type 1-infected long-term-nonprogressor hemophiliacs with or without late disease progression are defective in enhancing virus replication and CD4 down-regulation.

Infection with human immunodeficiency virus (HIV)-encoding defective nef variants may contribute to a relatively benign course of disease in a minority of long-term nonprogressors (LTNP). We have examined the functions of nef alleles from six individuals belonging to the same cohort of hemophiliacs infected with HIV-1 prior to 1985 and classified as LTNP in 1995. Three out of six individuals have progressed to HIV disease (late progressors [LP]), whereas the three remainders have maintained their LTNP status at least up to 2003. The nef alleles were obtained from both plasma virus and peripheral blood mononuclear cells of all six individuals in 1995 and 1998. The proportion of sequences containing mutations not yielding Nef expression significantly diminished in 1998 versus that in 1995. Several previously defined functional regions of intact nef alleles were highly conserved. However, the major variant obtained in 1998 from plasma RNA of five out of six individuals significantly reduced HIV infectivity/replication and impaired Nef-mediated CD4 but not major histocompatibility complex class I antigen down-modulation from the cell surface. Thus, functional alterations of the nef gene are present in both LP and LTNP, suggesting that Nef defectiveness in vitro is not necessarily associated with the long-term maintenance of LTNP status. Of interest is the fact that isolates from three out of three LP showed a dual CCR5/CXCR4 coreceptor use (R5X4), in contrast to those from LTNP, which were exclusively R5. Thus, in vivo evolution of gp120 Env to CXCR4 use appears to be associated with HIV disease progression in individuals infected with nef-defective viruses.

Alleles↗
PubMed2006

Long-lasting CCR5 internalization by antibodies in a subset of long-term nonprogressors: a possible protective effect against disease progression.

Exposure to HIV-1 does not necessarily result in infection and progression toward disease, thus suggesting that the control of viral infection may be achieved. Antibodies to CCR5 have been detected in HIV-exposed but uninfected subjects (ESNs); thus, these antibodies could be involved in HIV protection. To assess whether anti-CCR5 antibodies may also contribute to slow HIV disease progression, we searched for anti-CCR5 antibodies in 497 subjects, including 85 long-term nonprogressors (LTNPs), 70 progressors, 135 HIV(+) patients treated with highly active antiretroviral therapy (HAART), and 207 seronegative donors. We found anti-CCR5 antibodies in a fraction of the LTNPs(23.5%) but not in the other populations studied (P < .001). These antibodies recognized a conformational epitope within the first extramembrane loop of CCR5, and they induced a stable and long-lasting downregulation of CCR5 on the surface of T lymphocytes, which inhibited HIV entry. In addition, CD4(+) lymphocytes from LTNPs having anti-CCR5 antibodies are resistance to R5 strains of HIV-1. Follow-up studies showed that the loss of anti-CCR5 antibodies occurred in some subjects, and this loss was significantly associated with a progression toward disease, whereas subjects who retained anti-CCR5 Abs maintained their LTNP status. Induction of anti-CCR5 Abs could be relevant to vaccine design and therapeutics.

AIDS Vaccines↗
PubMed2006

Pertussis toxin B-oligomer suppresses IL-6 induced HIV-1 and chemokine expression in chronically infected U1 cells via inhibition of activator protein 1.

Pertussis toxin B-oligomer (PTX-B) inhibits HIV replication in T lymphocytes and monocyte-derived macrophages by interfering with multiple steps of the HIV life cycle. PTX-B prevents CCR5-dependent (R5) virus entry in a noncompetitive manner, and it also exerts suppressive effects on both R5- and CXCR4-dependent HIV expression at a less-characterized postentry level. We demonstrate in this study that PTX-B profoundly inhibits HIV expression in chronically infected promonocytic U1 cells stimulated with several cytokines and, particularly, the IL-6-mediated effect, a cytokine that triggers viral production in these cells independently of NF-kappaB activation. From U1 cells we have subcloned a cell line, named U1-CR1, with increased responsiveness to IL-6. In these cells, PTX-B neither down-regulated the IL-6R nor prevented IL-6 induced signaling in terms of STAT3 phosphorylation and DNA binding. In contrast, PTX-B inhibited AP-1 binding to target DNA and modified its composition with a proportional increases in FosB, Fra2, and ATF2. PTX-B inhibited IL-6-induced HIV-1 long-terminal repeat-driven transcription from A, C, E, and F viral subtypes, which contain functional AP-1 binding sites, but failed to inhibit transcription from subtypes B and D LTR devoid of these sites. In addition, PTX-B inhibited the secretion of IL-6-induced, AP-1-dependent genes, including urokinase-type plasminogen activator, CXCL8/IL-8, and CCL2/monocyte chemotactic protein-1. Thus, PTX-B suppression of IL-6 induced expression of HIV and cellular genes in chronically infected promonocytic cells is strongly correlated to inhibition of AP-1.

Base Sequence↗
PubMed2006

Differential dynamics of Epstein-Barr virus in individuals infected with human immunodeficiency virus-1 receiving intermittent interleukin-2 and antiretroviral therapy.

Interleukin-2 (IL-2) increases circulating CD4(+) lymphocytes in patients infected with human immunodeficiency virus-1. We studied Epstein-Barr virus (EBV) dynamics in 40 patients treated with antiretroviral therapy (ART) plus different IL-2 regimens. EBV-DNA tended to increase in both peripheral blood cells and plasma after continous infusion followed by intermittent subcutaneous high-dose IL-2, while EBV-DNA decreased in cells (p=0.0078) and disappeared in plasma after intermittent subcutaneous low-dose IL-2. Over 12 months, the dynamics of EBV differed between the two groups both in cells (p=0.0184) and plasma (p=0.0114). Thus, as a function of dose, IL-2 therapy may significantly affect the dynamics of EBV infection.

Anti-Retroviral Agents↗
PubMed2005

Preparing for phase II/III HIV vaccine trials in Africa.

Before performing phase II/III clinical trials in Africa, preliminary studies, including assessment and building up of clinical and laboratory infrastructures, estimates of human immunodeficiency virus incidence, investigation of the background immune response, and evaluation of the cross-clade immune response, need to be done. Plans and ongoing work in the context of the AIDS Vaccine Integrated Project and some preliminary data are presented.

AIDS Vaccines↗
PubMed2005

Pertussis toxin B-oligomer dissociates T cell activation and HIV replication in CD4 T cells released from infected lymphoid tissue.

OBJECTIVE: To investigate, in human lymphoid tissue infected with HIV-1 ex vivo, the immunostimulatory and HIV inhibitory properties of pertussis toxin B oligomer (PTX-B) and of the genetically modified non-toxic PT-9K/129G. METHODS: Human tonsils from uninfected donors were infected ex vivo with R5 or X4 HIV-1 in the presence or absence of PTX-B. Virus replication was evaluated in culture supernatants; cells emigrated from tissue blocks were immunostained for lymphocytic and activation markers. HIV DNA and cell proliferation were evaluated with real-time PCR and [H]thymidine incorporation, respectively. RESULTS: Both PTX-B and PT-9K/129G inhibited HIV-1 replication. These compounds activated and stimulated the proliferation of emigrated cells, most of which were CD4 T lymphocytes. Cells emigrated from infected tissues did not produce detectable virus in unstimulated or in PTX-B- or PT-9K/129G-stimulated cultures whereas robust virus production was triggered by phytohemagglutinin (PHA) or interleukin-2 (IL-2). Analysis of HIV DNA content indicated that infected cells were present among emigrated cells and that their number greatly increased following IL-2 stimulation, whereas it remained constant in the presence of PTX-B or PT-9K/129G. CONCLUSIONS: PTX-B and PT-9K/129G inhibit both R5 and X4 HIV-1 replication in human lymphoid tissue ex vivo. In contrast to PHA and IL-2, they promote the proliferation of CD4 T lymphocytes emigrated from tissue, including HIV-infected cells, without triggering virus replication. Therefore, these emigrated CD4 T cells represent a novel model of a latent inducible HIV reservoir. Thus, PTX-B and the clinically approved PT-9K/129G are potential antiretroviral agents endowed with immunostimulatory capacity.

CD4-Positive T-Lymphocytes↗
PubMed2005

Pertussis toxin B-oligomer inhibits HIV infection and replication in hu-PBL-SCID mice.

Bordetella pertussis toxin B-oligomer (PTX-B) has been shown to inhibit HIV infection and replication in vitro. The potential anti-viral effect of PTX-B was tested here in an in vivo surrogate model of HIV infection, i.e. SCID mice reconstituted with human peripheral blood leukocytes (PBL) (hu-PBL-SCID) and infected with a CCR5-dependent (R5) HIV-1 strain. SCID mice inoculated intra-peritoneal (i.p.) with PTX-B and then infected with the R5 strain SF-162 were sacrificed 7 days later and analyzed for human PBL (hu-PBL) lymphoid tissue reconstitution, infection of hu-PBL, plasma viremia and viral rescue from ex vivo-cultivated i.p. hu-PBL. Unlike mice treated with 500 ng per animal of PTX-B showing no evidence of viral inhibition, daily administration of PTX-B (50 ng per mouse) strongly inhibited virus infection and replication, as determined by undetectable viremia, absence of infected hu-PBL and lack of rescue of infectious HIV in most animals. Furthermore, PTX-B injection 2 h before and twice after infection prevented HIV-1 infection and replication in all (10/10) tested animals. Thus, PTX-B potently inhibited virus infection and replication in hu-PBL-SCID mice, supporting the hypothesis that it may represent a new pharmacological agent against HIV-1 infection.

Animals↗
PubMed2005

Role of cytokines and chemokines in the regulation of innate immunity and HIV infection.

The earliest defense against microbial infection is represented by the responses of the innate (or natural) immune system, that also profoundly regulates the adaptive (or acquired) T- and B-cell immune responses. Activation of the innate immune system is primed by microbial invasion in response to conserved structures present in large groups of microorganisms (LPS, peptidoglycan, double-stranded RNA), and is finely tuned by different cell types (including dendritic cells, macrophages, natural killer cells, natural killer T cells, and gammadelta T cells). In addition, several soluble factors (complement components, defensins, mannose-binding lectins, interferons, cytokines and chemokines) can play a major role in the regulation of both the innate and adaptive immunity. In this review, we will briefly overview the regulation of some cellular subsets of the innate immune system particularly involved in human immunodeficiency virus (HIV) infection and then focus our attention on those cytokines and chemokines whose levels of expression are more profoundly affected by HIV infection and that, conversely, can modulate virus infection and replication.

Chemokines↗
PubMed2005

Dendritic cells and natural killer cells in the pathogenesis of HIV infection.

Dendritic cells (DC) and natural killer (NK) cells, the main cellular components of the innate immune system, participate in the most ancient first line of defense against infections. Both types of cells patrol peripheral tissues, whereas their rapid recruitment and activation at mucosal surfaces [the major entry point for the human immunodeficiency virus (HIV)] is a hallmark of acute inflammatory response. The ability of HIV to survive and replicate in the human host relies upon several molecular mechanisms eluding the immune surveillance of both adaptive immunity and of DC and NK cells beginning with the acute phase of primary HIV infection. DC and NK cells, unlike CD4+ T cells, are impaired more functionally rather than being depleted by HIV infection. In this article we will review some of the aspects of DC/NK cells interaction with HIV infection both in vitro and in vivo, and we will also speculate on the potential consequence for HIV pathogenesis and for the capacity of the virus to escape the surveillance of the innate immune system.

Dendritic Cells↗
PubMed2005

Bacterial toxins: potential weapons against HIV infection.

Natural toxins are the product of a long-term evolution, and have captured crucial events in the most essential and vital processes of living organisms. They can attack components of the protein synthesis machinery (as in the case of Diphteria and Shiga toxins, and Ribosome inactivating proteins), actin polymerization (Clostridium botulinum type C, C2, toxins and Enterotoxin A), signal transduction pathways (Cholera toxin, Heat-labile enterotoxins, Pertussis and Adenylate cyclase toxins), intracellular trafficking of vesicules (for Tetanus and Botulinum neurotoxin type C) as well as immune and/or inflammatory responses (Pyrogenic exotoxins, Cholera and Pertussis toxins). Of interest is the fact that several bacterial and vegetal toxins can either kill selectively cells infected with the human immunodeficiency virus (HIV) or exert inhibitory effects on its life cycle. In particular both pertussis toxin (PTX) and its nontoxic B-oligomeric component (PTX-B) can block the infectious process in vitro at multiple levels, by preventing the entry of CCR5-dependent (R5) HIV strains and by inhibiting both R5 and CXCR4-dependent HIVs at post-entry level(s). In addition, some toxins possess immunostimulating properties that have been exploited in terms of adjuvancy and induction of specific cytotoxic T lymphocytes responses to different vaccine preparations, including some experimental vaccine against HIV infection. Thus, toxins may represent a relatively unexplored exhibition of powerful biological agents that could either prevent infection or attack HIV-infected cells.

Animals↗
PubMed2004

Inhibition of HIV-1 replication in monocyte-derived macrophages by Mycobacterium tuberculosis.

Controversial results have been obtained in studies of the effect of Mycobacterium tuberculosis on human immunodeficiency virus type 1 (HIV-1) replication in cells of the macrophage lineage. In the present study, monocyte-derived macrophages (MDMs), previously incubated for 2 days with heat-inactivated M. tuberculosis, were infected with HIV-1. M. tuberculosis consistently inhibited viral replication, and a similar result also was observed in the presence of supernatants from M. tuberculosis-stimulated MDMs, which indicates that this effect was mediated by soluble factors. Although CCR5-binding chemokines were induced by M. tuberculosis stimulation, the results of neutralization experiments indicated that it is unlikely that they were responsible for viral suppression. Inhibition occurred mainly after viral entry (demonstrated by use of a vesicular stomatitis virus G-pseudotyped HIV-1 and by analysis of HIV-1 early and late reverse-transcription products). Therefore, M. tuberculosis-induced factors may inhibit in vitro HIV-1 replication in macrophages by affecting an early postentry step in the HIV-1 cycle.

Acquired Immunodeficiency Syndrome↗
PubMed2004

Inhibition of intra- and extra-cellular Tat function and HIV expression by pertussis toxin B-oligomer.

HIV-1-transactivating factor Tat contributes to virus replication and to the onset of AIDS-associated pathologies by targeting different infected and uninfected cell types. We previously demonstrated that the B-oligomer of pertussis toxin (PTX-B) inhibits HIV infection and replication in primary T cells and macrophages and Tat-dependent HIV-1 long terminal repeat (LTR) transactivation inT lymphoid Jurkat cells. Here we demonstrate that PTX-B inhibits Tat-dependent NF-kappaB activation and HIV-1 LTR-transactivation in non-permissive epithelial HL3T1 cells in a phosphatidylinositol 3'-kinase-dependent way. PTX-B exerts its inhibition both when Tat is produced endogenously in transfected cells and in cells incubated with the extracellular Tat protein. In this latter case, PTX-B does not interfere with extracellular Tat uptake by cells. PTX-B inhibited also interleukin-8 secretion and virus expression stimulated in chronically infected U1 promonocytic cells by intra- and/or extracellular Tat. The genetically modified holotoxin PT-9 K/129G retains the capacity to inhibit Tat transactivating activity and HIV replication in both HIV-permissive and non-permissive cells. Inconclusion, PTX-B acts as a "pleiotropic" inhibitor of Tat, and this may significantly contribute to the broad spectrum of anti-HIV-1 effects exerted by PTX-B in different cell types, and suggests PTX-B and its derivatives as prototypic for the development of anti-Tat drugs.

Chemokines, CXC↗
PubMed2004

Coronaviridae and SARS-associated coronavirus strain HSR1.

During the recent severe acute respiratory (SARS) outbreak, the etiologic agent was identified as a new coronavirus (CoV). We have isolated a SARS-associated CoV (SARS-CoV) strain by injecting Vero cells with a sputum specimen from an Italian patient affected by a severe pneumonia; the patient traveled from Vietnam to Italy in March 2003. Ultrastructural analysis of infected Vero cells showed the virions within cell vesicles and around the cell membrane. The full-length viral genome sequence was similar to those derived from the Hong-Kong Hotel M isolate. By using both real-time reverse transcription-polymerase chain reaction TaqMan assay and an infectivity plaque assay, we determined that approximately 360 viral genomes were required to generate a PFU. In addition, heparin (100 microg/mL) inhibited infection of Vero cells by 50%. Overall, the molecular and biologic characteristics of the strain HSR1 provide evidence that SARS-CoV forms a fourth genetic coronavirus group with distinct genomic and biologic features.

Animals↗
PubMed2004

Increased sensitivity of SARS-coronavirus to a combination of human type I and type II interferons.

There is currently an urgent need to identify effective antiviral agents that will prevent and treat severe acute respiratory syndrome coronavirus (SARS-CoV) infection. In this study, we have investigated and compared the antiviral effect of different interferons (IFNs) on SARS-CoV replication in the epithelial kidney monkey Vero cell line. The results showed that SARS-CoV grown in Vero cells is moderately sensitive to IFN-beta and only weakly sensitive to IFN-alpha and IFN-gamma, in comparison to other IFN-sensitive viruses, such as those for encephalomyocarditis, vesicular stomatitis and Newcastle disease. Simultaneous incubation of Vero cells with IFN-beta and IFN-gamma indicated that they may act synergistically against SARS-CoV replication. The IFN-induced MxA protein was detected in the IFN-treated Vero cells. The data, however, suggest that the antiviral activity of IFN against SARS-CoV virus is independent of MxA expression.

Animals↗
PubMed2003

Thymic function and immunoglobulin mutation genotype in B-cell chronic lymphocytic leukemia patients.

B-cell chronic lymphocytic leukemia (B-CLL) is characterized by a profound dysregulation of the host's immune system at both the humoral and cellular level. We investigated to see if this dysregulation could be due partly to thymus dysfunction by quantifying the number of signal joint T-cell receptor excision circles (sjTRECs) in peripheral blood mononuclear cells of 30 untreated B-CLL patients at diagnosis and in age-matched healthy controls. sjTRECs were found decreased, normal and elevated in 19, 9 and 2 patients, respectively, in comparison to age-matched controls. We next speculated that sjTREC levels might be related to an accredited B-CLL prognostic marker represented by the somatic hypermutation (SHM) status of the variable heavy chain (V(H)) genes. Eight of 17 patients with SHMs had sjTREC levels in the range of or higher than normal donors, whereas only 3 of the 13 patients lacking SHMs had normal sjTREC levels. After a 5-year observation period in 16 patients for whom a clinical follow-up was available, only 2 of 10 patients with SHMs progressed vs. 5 of 6 patients without SHMs and 3 of 7 patients with normal or higher sjTREC levels progressed vs. 4 of 9 with low sjTREC levels. Our study demonstrates that sjTREC levels are decreased in >60% of B-CLL patients and suggests a potential role of thymus in the immune dysfunction of these patients.

Base Sequence↗