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Biomedical subjects

Genoveffa Franchini

Publications and source records attributed to Genoveffa Franchini.

At least 37 records · Page 2Linked to original sources
PubMed2005

Attenuated poxvirus-based simian immunodeficiency virus (SIV) vaccines given in infancy partially protect infant and juvenile macaques against repeated oral challenge with virulent SIV.

An infant macaque model was developed to test pediatric vaccine candidates aimed at reducing HIV transmission through breast-feeding. Infant macaques were given multiple immunizations during the first 3 weeks of life with recombinant poxvirus vaccines expressing simian immunodeficiency virus (SIV) structural proteins Gag, Pol, and Env (ALVAC-SIV or modified vaccinia virus Ankara [MVA]-SIV). After repeated daily oral inoculations with virulent SIVmac251 at 4 weeks of age, significantly fewer ALVAC-SIV-immunized infants were infected compared with unimmunized infants. Monkeys not infected after oral challenge in infancy were rechallenged at 16 months of age or older by repeated weekly oral SIV exposure; unimmunized animals were infected after fewer SIV exposures than were animals vaccinated with ALVAC-SIV or MVA-SIV. When infected, ALVAC-SIV- and MVA-SIV-vaccinated animals also had reduced viremia compared with unimmunized animals. The results of these investigations suggest that immunization of human infants with poxvirus-based HIV vaccine candidates may offer protection against early and late HIV infection through breastfeeding.

Administration, Oral↗
PubMed2005

Smallpox vaccine does not protect macaques with AIDS from a lethal monkeypox virus challenge.

It is unknown whether smallpox vaccination would protect human immunodeficiency virus type 1 (HIV-1)-infected individuals, because helper CD4(+) cells, the targets of HIV-1 infection, are necessary for the induction of both adaptive CD8(+) cell and B cell responses. We have addressed this question in macaques and have demonstrated that, although smallpox vaccination is safe in immunodeficient macaques when it is preceded by immunization with highly attenuated vaccinia strains, the macaques were not protected against lethal monkeypox virus challenge if their CD4(+) cell count was <300 cells/mm(3). The lack of protection appeared to be associated with a defect in vaccinia-specific immunoglobulin (Ig) switching from IgM to IgG. Thus, vaccination strategies that bypass CD4(+) cell help are needed to elicit IgG antibodies with high affinity and adequate tissue distribution and to restore protection against smallpox in severely immunocompromised individuals.

Animals↗
PubMed2004

Functional simian immunodeficiency virus Gag-specific CD8+ intraepithelial lymphocytes in the mucosae of SIVmac251- or simian-human immunodeficiency virus KU2-infected macaques.

The vaginal and rectal mucosae are the first line of cellular immune defense to sexually transmitted human immunodeficiency virus type 1 (HIV-1) entry. Thus, intraepithelial lymphocytes (IELs) may be important in the immune response to HIV infection. Here we investigated whether functional IELs in mucosal compartments could be visualized by direct staining with a tetrameric complex specific for the simian immunodeficiency virus (SIV) immunodominant Gag epitope in either separated IEL cells or tissues of macaques infected with SIVmac251. Of the 15 Mamu-A*01-positive macaques studied here, eight were chronically infected with either SIVmac251 or simian-human immunodeficiency virus (SHIV) KU2 and the remaining seven were exposed mucosally to SIVmac251 and sacrificed within 48 h to assess the local immune response. Gag-specific CD8+ T-cells were found in separated IELs from the rectum, colon, jejunum, and vagina of most infected animals. Direct staining of tetramers also revealed their presence in intact tissue. These Gag-specific IELs expressed the activation marker CD69 and produced IFN-gamma, suggesting an active immune response in this locale.

Animals↗
PubMed2004

Avipox-based simian immunodeficiency virus (SIV) vaccines elicit a high frequency of SIV-specific CD4+ and CD8+ T-cell responses in vaccinia-experienced SIVmac251-infected macaques.

The ability of ALVAC- or fowlpox-based simian immunodeficiency virus (SIV) vaccines to boost SIV-specific CD4+ and CD8+ T-cell responses was tested in 10 vaccinia-experienced macaques infected with SIVmac251. The CD8+ T-cell response to the dominant Gag(181-189) CM9 was quantitated in seven Mamu-A*01-positive macaques by tetramer staining, by ex vivo cytotoxic T-lymphocyte (CTL) activity, and by intracellular cytokine staining (ICS) with the specific Gag(181-189) CM9 peptide. The overall CD8+ T-cell response to Gag was assessed using a peptide pool encompassing the entire Gag protein followed by measurement of TNF-alpha production in ICS assay. Similarly, virus-specific CD4+ T-cell responses were measured by ICS for TNF-alpha following stimulation with the Gag-overlapping peptide and by proliferative response following stimulation with purified p27 Gag. The two vaccine modalities effectively boosted both CD4+ and CD8+ SIV-specific T-cell response despite prior exposure to the vaccinia-derivative NYVAC vector, suggesting that sequential boosting with either avipox-based vector vaccine candidate is a realistic approach in immune therapy of human immunodeficiency virus type 1 (HIV-1)-infected individuals.

Animals↗
PubMed2004

HTLV-1-encoded p30II is a post-transcriptional negative regulator of viral replication.

Human T-cell leukemia/lymphoma virus type 1 (HTLV-1) persists despite a vigorous virus-specific host immune response, and causes adult T-cell leukemia and lymphoma in approximately 2% of infected individuals. Here we report that HTLV-1 has evolved a genetic function to restrict its own replication by a novel post-transcriptional mechanism. The HTLV-1-encoded p30(II) is a nuclear-resident protein that binds to, and retains in the nucleus, the doubly spliced mRNA encoding the Tax and Rex proteins. Because Tex and Rex are positive regulators of viral gene expression, their inhibition by p30(II) reduces virion production. p30(II) inhibits virus expression by reducing Tax and Rex protein expression.

Cell Line↗
PubMed2004

T cell receptor recognition motifs govern immune escape patterns in acute SIV infection.

Escape from adaptive T cell immunity through transmutation of viral antigenic structure is a cardinal feature in the pathogenesis of SIV/HIV infection and a major obstacle to antiretroviral vaccine development. However, the molecular determinants of this phenomenon at the T cell receptor (TCR)-antigen interface are unknown. Here, we show that mutational escape is intimately linked to the structural configuration of constituent TCR clonotypes within virus-specific CD8(+) T cell populations. Analysis of 3416 SIV-specific TCR sequences revealed that polyclonal T cell populations characterized by highly conserved TCRB CDR3 motifs were rendered ineffectual by single residue mutations in the cognate viral epitope. Conversely, diverse clonotypic repertoires without discernible motifs were not associated with viral escape. Thus, fundamental differences in the mode of antigen engagement direct the pattern of adaptive viral evolution. These findings have profound implications for the development of vaccines that elicit T cell immunity to combat pathogens with unstable genomes.

Acute Disease↗
PubMed2004

Recombinant interleukin-7 induces proliferation of naive macaque CD4+ and CD8+ T cells in vivo.

Interleukin-7 (IL-7) regulates T-cell homeostasis, and its availability is augmented in lymphopenic hosts. Naive CD8+ T cells transferred to lymphopenic mice acquire a memory-like phenotype, raising the possibility that IL-7 is the biological mediator of this effect. Here, we provide direct evidence that IL-7 induces the acquisition of memory-cell markers not only in CD8+ T cells but also in CD4+ T-cell subsets in immune-competent Indian rhesus macaques. The increase of these memory-like populations was dependent on the dose of the cytokine, and these cells were found in the blood as well as secondary lymphoid organs. Memory-like CD4+ and CD8+ T cells acquired the ability to secrete tumor necrosis factor alpha and, to a lesser extent, gamma interferon following stimulation with a cognate antigen. The phenotypic change observed in naive T cells was promptly reversed after discontinuation of IL-7. Importantly, IL-7 induced cycling of both CD4+ and CD8+ central memory and effector memory T cells, demonstrating its contribution to the maintenance of the entire T-cell pool. Thus, IL-7 may be of benefit in the treatment of iatrogenic or virus-induced T-cell depletion.

Animals↗
PubMed2004

Repression of human T-cell leukemia virus type 1 and type 2 replication by a viral mRNA-encoded posttranscriptional regulator.

Human T-cell leukemia virus type 1 (HTLV-1) and HTLV-2 are complex retroviruses that persist in the host, eventually causing leukemia and neurological disease in a small percentage of infected individuals. In addition to structural and enzymatic proteins, HTLV encodes regulatory (Tax and Rex) and accessory (open reading frame I and II) proteins. The viral Tax and Rex proteins positively regulate virus production. Tax activates viral and cellular transcription to promote T-cell growth and, ultimately, malignant transformation. Rex acts posttranscriptionally to facilitate cytoplasmic expression of viral mRNAs that encode the structural and enzymatic gene products, thus positively controlling virion expression. Here, we report that both HTLV-1 and HTLV-2 have evolved accessory genes to encode proteins that act as negative regulators of both Tax and Rex. HTLV-1 p30(II) and the related HTLV-2 p28(II) inhibit virion production by binding to and retaining tax/rex mRNA in the nucleus. Reduction of viral replication in a cell carrying the provirus may allow escape from immune recognition in an infected individual. These data are consistent with the critical role of these proteins in viral persistence and pathogenesis in animal models of HTLV-1 and HTLV-2 infection.

Cell Line↗
PubMed2004

Poxvirus-based vaccine candidates for HIV: two decades of experience with special emphasis on canarypox vectors.

Poxvirus vectors have emerged as important vectors for licensed veterinary vaccines and candidate vaccines for humans. Vaccinia, highly-attenuated vaccinia strains and avipoxviruses have been assessed extensively in preclinical models, as well as in humans, to determine their immunogenicity and protective efficacy against HIV. The attenuated vaccinia strains and avipoxviruses have been shown to be safe and able to carry HIV genes and express their proteins to induce both antibodies and cellular immune responses. Preclinical studies show protection against HIV challenge. When using a live attenuated vector system, one must be cognizant of the potential for immune dampening because of vector-specific immunity. In this regard, avipoxviruses, such as canarypox, appear free of the inhibitory effects of vector immunity and repeated use. Unlike vaccinia-based vectors derived from classical vaccine strains, NYVAC and modified vaccinia Ankara may be less susceptible to this effect. In the coming 5 to 10 years, we will certainly know whether this class of vaccine candidates, either alone or in a prime-boost format with other vectors or proteins, will contribute to HIV disease management either from a preventive or therapeutic perspective. Additional Phase I and II studies, as well as human efficacy trials will provide new information. Furthermore, it is hoped that this body of data will contribute to a better understanding of the relevance of specific immunogenicity end points to protection and the predictive value of available animal models in HIV vaccine development.

AIDS Vaccines↗
PubMed2003

Species-specific transformation of T cells by HV(MNE).

HV(MNE) is an Epstein-Barr virus (EBV)-like lymphocryptovirus (LCV) originally isolated from a Macaca nemestrina with CD8(+) T cell mycosis fungoides/cutaneous T cell lymphoma (Blood 98 (2001), 2193). HV(MNE) transforms rabbit T cells in vitro and causes T cell lymphoma in New Zealand white rabbits. Here we demonstrate that HV(MNE) also immortalizes T cells from mustached tamarins but not those from owl monkeys, common marmosets, squirrel monkeys, black-capped capuchins, and humans. Cytogenetic and FACS analysis revealed the true origin and T cell lineage of the transformed tamarin T cell lines. Tamarin T cells contained HV(MNE) DNA sequence and displayed a decreased requirement for the IL-2 cytokine for growth. Thus, this EBV-like virus from M. nemestrina differs from the other EBV-like viruses found in nonhuman primates inasmuch as it appears to preferentially transform T cells.

Animals↗
PubMed2003

Modeling a safer smallpox vaccination regimen, for human immunodeficiency virus type 1-infected patients, in immunocompromised macaques.

We have modeled smallpox vaccination with Dryvax (Wyeth) in rhesus macaques that had depletion of CD4(+) T cells induced by infection with simian immunodeficiency virus or simian/human immunodeficiency virus. Smallpox vaccination induced significantly larger skin lesions in immunocompromised macaques than in healthy macaques. Unexpectedly, "progressive vaccinia" was infrequent. Vaccination of immunocompromised macaques with the genetically-engineered, replication-deficient poxvirus NYVAC, before or after retrovirus infection, was safe and lessened the severity of Dryvax-induced skin lesions. Neutralizing antibodies to vaccinia were induced by NYVAC, even in macaques with severe CD4(+) T cell depletion, and their titers inversely correlated with the time to complete resolution of the skin lesions. Together, these results provide the proof of concept, in macaque models that mirror human immunodeficiency virus type 1 infection, that a prime-boost approach with a highly attenuated poxvirus followed by Dryvax increases the safety of smallpox vaccination, and they highlight the importance of neutralizing antibodies in protection against virulent poxvirus.

Animals↗
PubMed2003

Prior DNA immunization enhances immune response to dominant and subdominant viral epitopes induced by a fowlpox-based SIVmac vaccine in long-term slow-progressor macaques infected with SIVmac251.

A therapeutic vaccine for individuals infected with HIV-1 and treated with antiretroviral therapy (ART) should be able to replenish virus-specific CD4+ T-cells and broaden the virus-specific CD8+ T-cell response in order to maintain CD8+ T-cell function and minimize viral immune escape after ART cessation. Because a combination of DNA and recombinant poxvirus vaccine modalities induces high levels of virus-specific CD4+ T-cell response and broadens the cytolytic activity in naive macaques, we investigated whether the same results could be obtained in SIVmac251-infected macaques. The macaques studied here were long-term nonprogressors that naturally contained viremia but were nevertheless treated with a combination of antiviral drugs to assess more carefully the effect of vaccination in the context of ART. The combination of a DNA expressing the gag and pol genes (DNA-SIV-gp) of SIVmac239 followed by a recombinant fowlpox expressing the same SIVmac genes (FP-SIV-gp) was significantly more immunogenic than two immunizations of FP-SIV-gp in SIVmac251-infected macaques treated with ART. The DNA/FP combination significantly expanded and broadened Gag-specific T-cell responses measured by tetramer staining, ELISPOT, and intracellular cytokine staining and measurement of ex vivo cytolytic function. Importantly, the combination of these vaccine modalities also induced a sizeable expansion in most macaques of Gag-specific CD8-(CD4+) T-cells able to produce TNF-alpha. Hopefully, this modality of vaccine combination may be useful in the clinical management of HIV-1-infected individuals.

Animals↗
PubMed2003

Shared modes of protection against poxvirus infection by attenuated and conventional smallpox vaccine viruses.

The concern about bioterrorism with smallpox has raised the possibility of widespread vaccination, but the greater prevalence of immunocompromised individuals today requires a safer vaccine, and the mechanisms of protection are not well understood. Here we show that, at sufficient doses, the protection provided by both modified vaccinia Ankara and NYVAC replication-deficient vaccinia viruses, safe in immunocompromised animals, was equivalent to that of the licensed Wyeth vaccine strain against a pathogenic vaccinia virus intranasal challenge of mice. A similar variety and pattern of immune responses were involved in protection induced by modified vaccinia Ankara and Wyeth viruses. For both, antibody was essential to protect against disease, whereas neither effector CD4+ nor CD8+ T cells were necessary or sufficient. However, in the absence of antibody, T cells were necessary and sufficient for survival and recovery. Also, T cells played a greater role in control of sublethal infection in unimmunized animals. These properties, shared with the existing smallpox vaccine, provide a basis for further evaluation of these replication-deficient vaccinia viruses as safer vaccines against smallpox or against complications from vaccinia virus.

Animals↗
PubMed2003

Highly effective treatment of acquired immunodeficiency syndrome-related lymphoma with dose-adjusted EPOCH: impact of antiretroviral therapy suspension and tumor biology.

The outcome of acquired immunodeficiency syndrome-related lymphomas (ARLs) has improved since the era of highly active antiretroviral therapy, but median survival remains low. We studied dose-adjusted EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin) with suspension of antiretroviral therapy in 39 newly diagnosed ARLs and examined protein expression profiles associated with drug resistance and histogenesis, patient immunity, and HIV dynamics and mutations. The expression profiles from a subset of ARL cases were also compared with a matched group of similarly treated HIV-negative cases. Complete remission was achieved in 74% of patients, and at 53 months median follow-up, disease-free and overall survival are 92% and 60%, respectively. Following reinstitution of antiretroviral therapy after chemotherapy, the CD4+ cells recovered by 12 months and the viral loads decreased below baseline by 3 months. Compared with HIV-negative cases, the ARL cases had lower bcl-2 and higher CD10 expression, consistent with a germinal center origin and good prognosis, but were more likely to be highly proliferative and to express p53, adverse features with standard chemotherapy. Unlike HIV-negative cases, p53 overexpression was not associated with a poor outcome, suggesting different pathogenesis. High tumor proliferation did not correlate with poor outcome and may partially explain the high activity of dose-adjusted EPOCH. The results suggest that the improved immune function associated with highly active antiretroviral therapy (HAART) may have led to a shift in pathogenesis away from lymphomas of post-germinal center origin, which have a poor prognosis. These results suggest that tumor pathogenesis is responsible for the improved outcome of ARLs in the era of HAART.

Acquired Immunodeficiency Syndrome↗
PubMed2003

Emergence of cytotoxic T lymphocyte escape mutants following antiretroviral treatment suspension in rhesus macaques infected with SIVmac251.

Structured treatment interruption (STI) of antiretroviral drugs has been proposed as an alternative approach for managing patients infected with HIV-1. While STI is thought to spare drug-related side effects and enhance the HIV-1-specific immune response, the long-lasting clinical benefit of this approach remains uncertain, particularly in patients with long-standing HIV-1 infection. Here, we investigated the basis of unabated virological replication following different STI regimens in rhesus macaques that expressed the MHC class I Mamu-A*01 molecule treated during acute and long-standing infection with SIVmac251. An amino acid change at the anchor residue within the immunodominant Mamu-A*01-restricted Gag(181-189) CM9 epitope (T --> A) in one of six macaques with acute SIVmac251 infection and in three of four macaques with long-standing SIVmac251 infection (T --> A; T --> S; S --> C) was found in the majority of plasma virus. These amino acid changes have been shown to severely decrease binding of the corresponding peptides to the Mamu-A*01 molecule and, in the case of the T --> A change, escape from CTL. In one macaque with long-standing SIVmac251 infection, a mutation emerged that conferred resistance to one of the antiretroviral drugs (PMPA) as well. These results provide insights into the mechanism underlying the limited capacity of repeated interruption of antiretroviral therapy as an approach to restrain viral replication. In addition, these data also suggest that interruption of therapy may be less effective in chronic infection because of preexisting immune escape and that immune escape is a risk of interruption of therapy.

Animals↗
PubMed2003

T-cell control by human T-cell leukemia/lymphoma virus type 1.

Human T-cell leukemia/lymphoma virus type 1 (HTLV-1) causes neoplastic transformation of human T-cells in a small number of infected individuals several years from infection. Collective evidence from in vitro studies indicates that several viral proteins act in concert to increase the responsiveness of T-cells to extracellular stimulation, modulate proapoptotic and antiapoptotic gene signals, enhance T-cell survival, and avoid immune recognition of the infected T-cells. The virus promotes T-cell proliferation by usurping several signaling pathways central to immune T-cell function, such as antigen stimulation and receptor-ligand interaction, suggesting that extracellular signals are important for HTLV-1 oncogenesis. Environmental factors such as chronic antigen stimulation may therefore be of importance, as also suggested by epidemiological data. Thus genetic and environmental factors together with the virus contribute to disease development. This review focuses on current knowledge of the mechanisms regulating HTLV-1 replication and the T-cell pathways that are usurped by viral proteins to induce and maintain clonal proliferation of infected T-cells. The relevance of these laboratory findings is related to clonal T-cell proliferation and adult T-cell leukemia/lymphoma development in vivo.

Cell Transformation, Neoplastic↗
PubMed2003

Seizing of T cells by human T-cell leukemia/lymphoma virus type 1.

Human T-cell leukemia/lymphoma virus type 1 (HTLV-1) causes neoplastic transformation of human T-cells in a small number of infected individuals several years from infection. Several viral proteins act in concert to increase the responsiveness of T-cells to extracellular stimulation, modulate proapoptotic and antiapoptotic gene signals, enhance T-cell survival, and avoid immune recognition of the infected T-cells. The virus promotes T-cell proliferation by usurping several signaling pathways central to immune T-cell function. Viral proteins modulate the downstream effects of antigen stimulation and receptor-ligand interaction, suggesting that extracellular signals are important for HTLV-1 oncogenesis. Environmental factors such as chronic antigen stimulation are therefore important, as also suggested by epidemiological data. The ability of a given individual to respond to specific antigens is determined genetically. Thus, genetic and environmental factors, together with the virus, contribute to disease development. As in the case of other virus-associated cancers, HTLV-1-induced leukemia/lymphoma can be prevented by avoiding viral infection or by intervention during the asymptomatic phase with approaches able to interrupt the vicious cycle of virus-induced proliferation of a subset of T-cells. This review focuses on current knowledge of the mechanisms regulating HTLV-1 replication and the T-cell pathways that are usurped by viral proteins to induce and maintain clonal proliferation of infected T-cells in vitro. The relevance of these laboratory findings will be related to clonal T-cell proliferation and adult T-cell leukemia/lymphoma development in vivo.

Apoptosis↗