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Biomedical subjects

G Franchini

Publications and source records attributed to G Franchini.

At least 73 records · Page 4Linked to original sources
PubMed1996

Insights on the pathogenicity of human T-lymphotropic/leukemia virus types I and II.

Human T-lymphotropic/leukemia virus types I and II (HTLV-I and HTLV-II) are phylogenetically and immunologically related viruses that differ in their pathogenicity in vivo. HTLV-I is the etiologic agent of adult T-cell leukemia/lymphoma, as well as a chronic progressive myelopathy, HTLV-I-associated myelopathy/tropical spastic paraparesis. In contrast, HTLV-II has not been conclusively associated with specific diseases. Both HTLV-I and HTLV-II transform CD4+ T-cells in vitro, but their in vivo target cells appear to differ. HTLV-I is found mainly in CD4+ cells, whereas HTLV-II has been demonstrated mainly in CD8+ cells. Clearly the definition of the viral genetic determinants responsible for the different tropism and pathogenicity in vivo may provide the basis of our understanding of the HTLV-I oncogenicity. In this short review we emphasize two aspects of viral infection of T cells: (1) the influence of viral infection on the major proteins involved in the G0-G1 phase of the cell cycle and (2) the effect of viral infection on the S phase of the cell cycle, i.e., the interleukin-2 receptor pathway.

Alternative Splicing↗
PubMed1996

Interspecies transmission of macaque simian T-cell leukemia/lymphoma virus type 1 in baboons resulted in an outbreak of malignant lymphoma.

An outbreak of malignant lymphoma has been observed in one of the baboon (Papio hamadryas) stocks of Sukhumi Primate Center. More than 300 cases in this "high-lymphoma stock" have been registered since 1967. Human T-cell lymphotropic virus type 1 (HTLV-1)-related virus was implicated as the etiologic agent of Sukhumi baboon lymphoma. The origin of this virus remained unclear. Two possibilities were originally considered: the origin could be baboon simian T-cell leukemia/lymphoma virus type 1 (STLV-1) or HTLV-1 (before the outbreak started, some Sukhumi baboons were inoculated with human leukemic material). The third possibility entered recently: interspecies transmission of rhesus macaque STLV-1 to baboons. It was prompted by the finding of very close similarity between STLV-1 991-1cc (the strain isolated from a non-Sukhumi baboon inoculated with material from a Sukhumi lymphomatous baboon) and rhesus STLV-1. To test this hypothesis, we investigated 37 Sukhumi STLV-1 isolates from baboons of high-lymphoma stock by PCR discriminating rhesus type and baboon type STLV-1 isolates. All of them were proved to be rhesus type STLV-1. In contrast, all six STLV-1 isolates from baboons belonging to other stocks or populations were of baboon type. The PCR results were fully confirmed by DNA sequence data. The partial env gene gene sequences of all four STLV-1 isolates from Sukhumi lymphomatous baboons were 97 to 100% similar to the sequence of known rhesus STLV-1 and only 85% homologous with the sequence of conventional baboon STLV-1. Thus, interspecies transmission of STLV-1 from rhesus macaques (or closely related species) to baboons occurred at Sukhumi Primate Center. Most probably this event initiated the outbreak of lymphoma in Sukhumi baboons.

Animals↗
PubMed1996

The human T-cell leukemia/lymphotropic virus type 1 p12I proteins bind the interleukin-2 receptor beta and gammac chains and affects their expression on the cell surface.

p12I is a small hydrophobic protein encoded by the human T-cell leukemia/lymphotropic virus type 1 (HTLV-1) that interacts with the 16-kDa component of the H+ vacuolar ATPase and cooperates with bovine papillomavirus 1 E5 oncoprotein in cell transformation. Just as an important step in E5 action appears to be its binding to the platelet-derived growth factor receptor, it was found that p12I binds specifically to both the beta and gamma(c) chains of the interleukin-2 receptor (IL-2R). The IL-2R beta and gamma(c) chains associated with p12I are endoglycosidase-H sensitive, suggesting that their interaction occurs in a pre-Golgi compartment. p12I stabilizes the immature forms of the IL-2R beta and gamma(c) chains and decreases their cell surface expression. The interactions of p12I with IL-2R beta and gamma(c) may have important implications in the immunosuppressive effect of HTLV-1 in vivo as well as in the ligand-independent HTLV-1-mediated T-cell proliferation.

Golgi Apparatus↗
PubMed1995

Constitutively activated Jak-STAT pathway in T cells transformed with HTLV-I.

Human T cell lymphotropic virus I (HTLV-I) is the etiological agent for adult T cell leukemia and tropical spastic paraparesis (also termed HTLV-I-associated myelopathy). HTLV-I-infected peripheral blood T cells exhibit an initial phase of interleukin-2 (IL-2)-dependent growth; over time, by an unknown mechanism, the cells become IL-2-independent. Whereas the Jak kinases Jak1 and Jak3 and the signal transducer and activator of transcription proteins Stat3 and Stat5 are activated in normal T cells in response to IL-2, this signaling pathway was constitutively activated in HTLV-I-transformed cells. In HTLV-I-infected cord blood lymphocytes, the transition from IL-2-dependent to IL-2-independent growth correlated with the acquisition of a constitutively activated Jak-STAT pathway, which suggests that this pathway participates in HTLV-I-mediated T cell transformation.

Base Sequence↗
PubMed1995

Expression and characterization of proteins produced by mRNAs spliced into the X region of the human T-cell leukemia/lymphotropic virus type II.

In previous studies we showed that human T-cell leukemia/lymphotropic virus type I (HTLV-I) may produce novel proteins encoded in the X region. To investigate a possible correlation between expression of viral genes and different biologic properties of HTLV-I and HTLV-II, we analyzed expression of HTLV-II in the chronically infected cell line MoT. Reverse transcription-polymerase chain reaction analyses revealed that the virus produces several mRNAs singly or doubly spliced into the X region. Corresponding cDNAs were cloned and transfected into a HeLa cell line; resulting proteins were designated according to their sizes and coding open reading frames (ORFs). p10xI and p11xV were produced by a dicistronic doubly spliced mRNA. p10xI was generated by translation of the first exon of rex linked to the x-I ORF; p11xV was translated from the tax initiation codon linked to the x-V ORF. Two singly spliced polycistronic mRNAs produced p28xII, coded by the x-II ORF, and several isoforms generated by initiation within the x-III ORF. Studies of the proteins' subcellular localization revealed that they exhibited distinct targeting patterns. Comparison of these proteins with their HTLV-I counterparts indicated intriguing differences between these two viruses, suggesting that further study of the X region products may aid in defining genetic determinants of pathogenicity.

Alternative Splicing↗
PubMed1995

Biological and immunogenic properties of a canarypox-rabies recombinant, ALVAC-RG (vCP65) in non-avian species.

A canarypox-based (ALVAC) recombinant expressing the rabies G glycoprotein has been utilized to assess in vitro and in vivo biological properties of the canarypox virus vector system. In vitro studies have shown that no replication of the virus can be detected on six human-derived cell lines, nor can the virus be readily adapted to replicate on non-avian cells. Expression of the rabies G can be detected on all cell lines analyzed in the absence of productive viral replication. Analysis of viral-specific DNA accumulation indicated that the block in the replication cycle in the human cell lines analyzed occurred prior to DNA replication. The exact nature of the block, however, remains unknown. The concept of using a non-replicating immunization vehicle has been demonstrated through extensive in vivo studies in a range of species including non-human primates and humans. The results of such in vivo studies have exemplified the safety and immunogenicity of the ALVAC vaccine vector.

Animals↗
PubMed1995

The natural history and evolution of human and simian T cell leukemia/lymphotropic viruses.

The past five years have seen significant advances in understanding the origin and evolution of human T-cell leukemia/lymphotropic virus types I and II. The highlights include the identification of human T-cell leukemia/lymphotropic virus types I and II genotypic variants in remote human populations and the discovery of widely divergent simian T-cell leukemia virus in African and Asian non-human primates.

Animals↗
PubMed1995

Human T-cell leukaemia virus.

HTLV-I has a complex and finely regulated mechanism of replication, which can be used as a model to study both cellular and viral regulation pathways in T-cells. Understanding of the underlying mechanisms involved in the pleiotropic effects of HTLV-I in the host represents a real challenge. Immunological regulation likely plays a central role in HTLV-I induced neurological disease, uveitis, and perhaps arthritis, implicating the importance of host factors as well. Viral proteins, including tax and p12' might play a role in T-cell proliferation, but the event(s) that result in the late leukaemic phase are unknown. The lack of effective therapy against HTLV-I-induced leukaemia renders prevention of viral infection the best means to eliminate HTLV-I associated diseases. Elimination or reduction of breast feeding from seropositive mothers in Japan has already produced encouraging results. In developing countries, probably only a vaccine will prevent the spread of HTLV-I infection. The molecular epidemiology of HTLV and STLV will help understand not only the phylogeny of these viruses but also the migration of human populations in the past. Episodes of horizontal transmission in the past and probably the present, indicates that nonhuman primates are the natural reservoir of HTLVs. New related viruses will likely be discovered in monkeys (and humans) in the future.

Animals↗
PubMed1995

HIV-1 recombinant poxvirus vaccine induces cross-protection against HIV-2 challenge in rhesus macaques.

Rhesus macaques were immunized with attenuated vaccinia or canarypox human immunodeficiency virus type 1 (HIV-1) recombinants and boosted with HIV-1 protein subunits formulated in alum. Following challenge with HIV-2SBL6669, three out of eight immunized macaques resisted infection for six months and another exhibited significantly delayed infection, whereas all three naive controls became infected. Immunizations elicited both humoral and cellular immune responses; however, no clear correlates of protection were discerned. Although more extensive studies are now called for, this first demonstration of cross-protection between HIV-1 and -2 suggests that viral variability may not be an insurmountable problem in the design of a global AIDS vaccine.

AIDS Vaccines↗
PubMed1995

Highly attenuated HTLV type Ienv poxvirus vaccines induce protection against a cell-associated HTLV type I challenge in rabbits.

The entire envelope protein of the human T cell leukemia/lymphoma virus type I (HTLV-I)1711, obtained from the DNA of a West African healthy HTLV-I-infected patient, was expressed in the highly attenuated poxvirus vaccine vectors ALVAC and NYVAC. These live recombinant vaccine candidates were used to immunize New Zealand White rabbits. Immunization regimens included inoculation of the poxvirus recombinant alone as well as prime/boost protocols using gp63 HTLV-I envelope precursor protein in Alum as the subunit boost. All animals were exposed to an HTLV-I cell-associated challenge (5 x 10(4) cells) from a primary culture of the HTLV-IBOU isolate. The results indicated that two inoculations of the ALVAC-based HTLV-Ienv vaccine candidate protected animals against viral challenge 5 months following the last immunization. However, a combination protocol with ALVAC-env and two additional boosts of gp63 surprisingly failed to confer protection, suggesting that administration of the subunit preparation might be deleterious. Further, in the case of the NYVAC HTLV-Ienv recombinant, protection was afforded as early as 2 months following the first immunization. Last, all the protected animals in the NYVAC and ALVAC trials were challenged 5 months following the initial challenge exposure with 5 ml of blood from an HTLV-IBOU-infected animal, and subsequently became infected. Protection conferred by the attenuated HTLV-Ienv recombinant poxvirus vaccine in the rabbit model might be instrumental for optimizing the immunogenicity of poxvirus-based vaccine candidates against human immunodeficiency virus (HIV), particularly because of the need to enhance protection against cell-to-cell transmission.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Humoral and cellular immune responses in rhesus macaques infected with human immunodeficiency virus type 2.

Eighteen rhesus macaques were inoculated with either an infectious molecularly cloned human immunodeficiency virus type 2 (HIV-2)SBL/ISY, or with one of eight mutants defective in one or more accessory genes. The immune responses generated by the macaques were monitored for up to 2 years postinfection. All the macaques except those that received mutants lacking the vpr or vif genes demonstrated low to moderate antibody titers. Macaques inoculated with vpx- mutants exhibited a persistent serological response, suggesting continuous virus expression even in the absence of detectable virus in the peripheral blood mononuclear cells (PBMCs). Neutralizing antibodies developed in only four macaques. In general, low-level cytotoxic T lymphocyte (CTL) activity, not clearly HIV-2 specific, was detected in PBMCs. However, one virus-negative macaque exhibited significant HIV-2-specific CTL activity in an enriched CD8+ cell population from PBMCs, suggesting clearance of the viral infection. In addition, CTL activity against the Env and Gag/Pol epitopes of HIV-2 by CD8+ lymphocytes from the spleens and lymph nodes of two infected macaques, in one case requiring CD8+ T cell enrichment and in the other clearly evident in unfractionated tissue lymphocytes, was demonstrated for the first time. This sequestration of tissue CTLs occurred in the absence of significant levels of circulating CTLs in the blood. Our results suggest that routine monitoring of PBMCs may sometimes be inadequate for detecting cell-mediated immune responses. Elucidation of immune correlates of vaccine protection may therefore require sampling of lymphoid tissues and assessment of enriched CD8+ populations.

Acquired Immunodeficiency Syndrome↗
PubMed1995

Highly attenuated HIV type 2 recombinant poxviruses, but not HIV-2 recombinant Salmonella vaccines, induce long-lasting protection in rhesus macaques.

Immunization schemes employing priming with vector-based vaccine candidates followed by subunit booster administrations have been explored and shown to have merit in the human immunodeficiency virus type 1 (HIV-1) and simian immunodeficiency virus systems. In this study, we have assessed the priming capacity of highly attenuated poxvirus vector (NYVAC and ALVAC)-based HIV-2 recombinants, as well as Salmonella typhimurium HIV-2 recombinants in rhesus macaques. ALVAC- and NYVAC-based vaccine candidates expressing the HIV-2 gag, pol, and env genes or NYVAC-based recombinants expressing either gp160 or gp120 were used to immunize rhesus macaques in combination protocols with alum-adjuvanted HIV-2 rgp160. Following intravenous challenge exposure with 100 infectious doses of the HIV-2SBL6669 parental virus genotype mixture, seven of eight animals were protected from infection. The seven protected animals were rechallenged 6 months postprimary challenge, without additional booster inoculations, with the same dose of the HIV-2SBL6669 parental virus. Five of the seven animals remained protected against HIV-2 infection at 6 months following the second challenge. In contrast, oral immunization with recombinant Salmonella expressing the HIV-2 gag and the gp120 portion of the envelope either alone or in combination with alum-adjuvanted rgp160 failed to confer protection. These results suggest that the NYVAC- and ALVAC-based recombinants may confer long-lasting protection and that these two highly attenuated poxvirus vaccine vectors may represent promising candidates for developing an acquired immunodeficiency syndrome vaccine.

Amino Acid Sequence↗
PubMed1995

Mapping of the intermolecular association of human T cell leukaemia/lymphotropic virus type I p12I and the vacuolar H+-ATPase 16 kDa subunit protein.

The p12I protein, a small hydrophobic protein encoded by the human T cell leukaemia/lymphotropic virus type I pX region, contains a proline-rich region located between two putative transmembrane (TM) domains. The p12I protein is associated with cellular endomembranes, and physically binds to the 16 kDa subunit of the vacuolar H+-ATPase proton pump. To investigate the nature of the 16 kDa and p12I interaction and to determine the oncogenic domain of p12I, we constructed p12I mutant proteins in which various portions of the TM domains were deleted, as well as p12I mutant containing a single amino acid substitution. These mutants were tested for binding to the 16 kDa subunit of the vacuolar H+-ATPase in HeLa/Tat cells and for the capability to potentiate transformation by bovine papillomavirus type 1 E5 oncoprotein in mouse C127 cells. The results indicated that both TM domains of the p12I protein were dispensable for its interaction with the 16 kDa protein, whereas partial or complete deletion of the proline-rich region resulted in decreased or no binding of the p12I protein to the 16 kDa subunit. Immunofluorescence analysis of HeLa/Tat cells transfected with the p12I mutants showed that deletion of the proline-rich region did not alter the subcellular localization of these mutant p12I proteins, suggesting direct involvement of the proline-rich domain in binding rather than the failure of these p12I mutants to reach the appropriate cellular compartment. Mapping of 16 kDa subunit mutants in binding with p12I protein suggested that molecular determinants located between the second and third TM domain of the 16 kDa protein might be involved in this interaction. Finally, most of the p12I mutants lost the ability to potentiate transformation of C127 cells indicating that binding of p12I to the 16 kDa subunit does not directly correlate with oncogenicity.

Animals↗
PubMed1995

Molecular phylogeny and dissemination of human T-cell lymphotropic virus type I viewed within the context of primate evolution and human migration.

A renewed interest in the emergence and evolution of the primate T-cell lymphotropic viruses has followed the discovery of genetically distinct variants of human T-cell lymphotropic virus type I (HTLV-I) in Melanesia and Australia. Phylogenetic trees based on selected regions of the gag, pol, env and pX genes of HTLV-I from widely separated geographic regions and of simian T-cell lymphotropic virus type I (STLV-I) from African and Asian catarrhines, constructed using the neighbor-joining and maximum parsimony methods, indicated that the Australo-Melanesian and cosmopolitan strains of HTLV-I have evolved along separate geographically dependent lineages, with African STLV-I strains clustering with cosmopolitan HTLV-I strains and Asian STLV-I strains diverging from the common ancestral virus before the Australo-Melanesian HTLV-I strains. When viewed within the context of non-human primate evolution and human occupation of Australia and Melanesia, the rate of molecular change of HTLV-I and STLV-I is approximately 2.5-6.8 x 10(-7) substitutions per site per year. Overall, the sequence and phylogenetic analyses are in accord with interspecies virus transmission among non-human primates, as well as between non-human primates and humans, with independent evolution of HTLV-I in Southeast Asia and in Africa, and with dissemination of HTLV-I by forced or voluntary movements of human populations. The immunosuppressive and T-cell activation properties of HTLV-I places at added risk these Australian Aboriginal and Melanesian populations, some of which are in imminent threat of infection with human immunodeficiency virus type 1.

Africa↗
PubMed1994

Phylogenesis and genetic complexity of the nonhuman primate retroviridae.

The three known groups of nonhuman primate retroviruses (simian immunodeficiency virus, simian T cell lymphotropic/leukemic virus type I, and simian foamy virus) are thought to have equivalent human counterparts. This is clearly the case with human immunodeficiency virus types 1 and 2, the causative agents of acquired immunodeficiency syndrome, and with human T cell lymphotropic/leukemia virus type I (HTLV-I), which causes T cell leukemia and a progressive form of myelopathy (tropical spastic paraparesis/HTLV-I-associated myelopathy), and HTLV-II. However, the presence of spumaviruses (foamy viruses) in humans remains uncertain. Data accumulated in the last 5 years suggest the possibility that the human retroviruses are indeed the result of transmission of simian retroviruses to humans. In this article we attempt to parallel the genetic features of the simian retroviridae with their human counterparts and argue for the possibility of horizontal transmission of these viruses from monkeys to humans.

Animals↗
PubMed1994

Cross-neutralizing antibodies against cosmopolitan and Melanesian strains of human T cell leukemia/lymphotropic virus type I in sera from inhabitants of Africa and the Solomon Islands.

The so-called cosmopolitan strains of human T cell leukemia/lymphotropic virus type I (HTLV-I) from Japan, Africa, the West Indies, and the Americas differ only slightly (< 3%) in their genomic sequence. On the other hand, the Melanesian strains of HTLV-I are somewhat more divergent, exhibiting only 93% sequence similarity with the cosmopolitan strains. Despite this difference, sera from individuals infected with Melanesian strains cross-react with T cells infected with cosmopolitan strains of HTLV-I, indicating an overall conservation of the B cell immunoprevalent epitopes. Neutralizing antibodies against HTLV-I in sera from virus-infected Africans and Melanesians were assayed by determining their ability to block the formation of syncytia in cocultures of 8166 and T cell lines harboring either cosmopolitan or Melanesian HTLV-I isolates. All six African sera blocked the formation of syncytia with cells infected with HTLV-IC91-PL, a viral isolate from the United States. Similarly, all six Melanesian sera inhibited syncytium formation with cells infected with HTLV-IMEL3, a virus isolate from the Solomon Islands. Although most of these sera inhibited syncytium formation in cell cultures carrying the cosmopolitan as well as the Melanesian HTLV-I strains, neutralizing antibody titers tended to be higher against the homologous virus. All sera failed to inhibit syncytium formation when cells were infected with HTLV-II. These data indicate the involvement of one or more epitopes in syncytial formation, some of which are conserved in all strains of HTLV-I.(ABSTRACT TRUNCATED AT 250 WORDS)

Africa↗