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A Borsetti,
M T Maggiorella,
L Sernicola,
S Bellino,
F Ferrantelli, R Belli,
D Fulgenzi,
E T Mee,
N J Rose,
A Cafaro,
B Ensoli,
F Titti
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ABSTRACT: Mauritian cynomolgus macaques (MCM) are widely used in human immunodeficiency virus research because of their restricted major histocompatibility complex (MHC) diversity which provides the opportunity to address the influence of host factors on vaccine studies. We herein report the impact of MHC haplotype on the outcome of 21 MCM infections with the CCR5-tropic simian/human immunodeficiency virus (SHIV)(SF162P4cy). MCM were susceptible to SHIV(SF162P4cy) infection as shown by viremia and loss of CD4+ T cells. A significant association between haplotype M7 (class IA, IB, II) and persistent viremia was observed in chronic phase, whereas recombinant class IA haplotype was associated with a reduction of viral RNA during acute infection. Class IB M4 haplotype displayed significantly lower acute phase provirus copy numbers. In addition, statistical analysis indicated a detrimental effect of haplotype M4 (class IA, IB) on the course of infection as indicated by lower CD4+ T-cell levels during chronic infection. A decrease in post-acute phase CD4+ T-cell numbers was also observed in haplotype M2 animals. This is the first report that documents the effects of host MHC class I and II molecules on the SHIV(SF162P4cy) infection in MCM, particularly with regard to the association between recombinant class IA, M4, and M7 haplotypes and the dynamic of viral replication and level of CD4+ T cells.
Tissue Antigens 04/2012; 80(1):36-45. · 2.59 Impact Factor
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A Borsetti,
S Baroncelli,
M T Maggiorella,
S Bellino,
S Moretti,
L Sernicola, R Belli,
B Ridolfi,
S Farcomeni,
D R M Negri,
A Cafaro,
B Ensoli,
F Titti
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ABSTRACT: Simian-human immunodeficiency virus (SHIV) 89.6P is considered to be one of the most pathogenic chimeric viruses in rhesus macaques. However, when crossing from one to another species of monkeys the pathogenicity of this virus may be affected. By using SHIV-89.6P(cy243), a virus obtained by passaging SHIV-89.6P in cynomolgus macaques, we investigated the dynamics of viral replication and the impact of the inoculum size (from 10 up to 50 monkey infectious dose) on the progression of the infection in 22 cynomolgus macaques. SHIV-89.6P(cy243 )caused massive depletion of CD4+ T-cells within 4 weeks of the inoculum, followed by an irreversible immune deficiency in a high proportion of the infected monkeys. This study demonstrates that SHIV-89.6P(cy243) is pathogenic in cynomolgus macaques and that the dynamics of the viral replication and the rate of clinical progression depend on the size of the inoculum. Our findings provide unique and relevant data, particularly with regard to the value of the in vivo titration used to select the most appropriate infectious dose to study the "virus-host" interplay.
Archives of Virology 02/2008; 153(3):463-72. · 2.11 Impact Factor
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D R Negri,
S Baroncelli,
Z Michelini,
I Macchia, R Belli,
S Catone,
F Incitti,
P ten Haaft,
F Corrias,
M P Cranage,
N Polyanskaya,
S Norley,
J Heeney,
P Verani,
F Titti
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ABSTRACT: The efficacy of a multicomponent vaccination with modified vaccinia Ankara constructs (rMVA) expressing structural and regulatory genes of simian immunodeficiency virus (SIV(mac251/32H/J5)) was investigated in cynomolgus monkeys, following challenge with a pathogenic SIV. Vaccination with rMVA-J5 performed at week 0, 12, and 24 induced a moderate proliferative response to whole SIV, a detectable humoral response to all but Nef SIV antigens, and failed to induce neutralizing antibodies. Two months after the last boost, the monkeys were challenged intravenously with 50 MID50 of SIV(mac251). All control monkeys, previously inoculated with non-recombinant MVA, were infected by week two and seroconverted by weeks four to eight. In contrast a sharp increase of both humoral and proliferative responses at two weeks post-challenge was observed in vaccinated monkeys compared to control monkeys. Although all vaccinated monkeys were infected, vaccination with rMVA-J5 appeared to partially control viral replication during the acute and late phase of infection as judged by cell- and plasma-associated viral load.
Journal of Medical Primatology 09/2001; 30(4):197-206. · 1.30 Impact Factor
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A Cafaro,
A Caputo,
M T Maggiorella,
S Baroncelli,
C Fracasso,
M Pace,
A Borsetti,
L Sernicola,
D R Negri,
P Ten Haaft,
M Betti,
Z Michelini,
I Macchia,
E Fanales-Belasio, R Belli,
F Corrias,
S Buttò,
P Verani,
F Titti,
B Ensoli
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ABSTRACT: The Tat protein of human immunodeficiency virus (HIV) is produced very early after infection, plays a key role in the virus life cycle and in acquired immunodeficiency syndrome (AIDS) pathogenesis, is immunogenic and well conserved among all virus clades. Notably, a Tat-specific immune response correlates with non-progression to AIDS. Here, we show that a vaccine based on the Tat protein of HIV blocks primary infection with the simian/human immunodeficiency virus (SHIV)89.6P and prevents the CD4 T cell decline and disease onset in cynomolgus monkeys. No signs of virus replication were found in five out of seven vaccinated macaques for almost 1 year of follow-up. Since the inoculated virus (derived from rhesus or from cynomolgus macaques) is shown to be highly pathogenic in cynomolgus macaques, the results indicate efficacy of Tat vaccination in protection against highly pathogenic virus challenge. Finally, the studies of the Tat-specific immunological responses indicate a correlation of protection with a cytotoxic T cell response. Thus, a Tat-based vaccine is a promising candidate for preventive and therapeutic vaccination in humans.
Journal of Medical Primatology 09/2000; 29(3-4):193-208. · 1.30 Impact Factor
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S Di Fabio,
D Trabattoni,
A Geraci,
S Ruzzante,
G Panzini,
M L Fusi,
F Chiarotti,
F Corrias, R Belli,
P Verani,
A Dalgleish,
M Clerici,
F Titti
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ABSTRACT: The potential therapeutic utility of thalidomide (Thd), an effective inhibitor of tumor necrosis factor (TNF)-alpha in vitro, was investigated in cynomolgus monkeys (Macaca fascicularis) at 10 months after infection with simian immunodeficiency virus (SIV). Thd-treated macaques (n = 8) received an oral dose (10 mg) daily for 7 days, followed by a wash-out period of 5 weeks. A 2nd cycle of treatment was performed on the same animals at higher doses (20 mg Thd/day) for 14 days. The control monkeys (n = 7) received a placebo for the same period of time. In the present study, we show that Thd, in addition to inhibiting TNF-alpha production after in vitro mitogen stimulation of peripheral blood mononuclear cells (PBMCs), was able to restore the proliferative responses to SIV peptides in monkeys that were infected with SIV. Interestingly, we found that such effects are associated with an increased expression of CD28 cell surface receptors on CD4+ T-cells paralleled by a decrease on CD8+ T-cells. At the same time, significant reduction in either cell-associated viral load or plasma viral RNA was not observed among the SIV-infected monkeys during the two treatment cycles, when compared with the placebo group.
Journal of Medical Primatology 03/2000; 29(1):1-10. · 1.30 Impact Factor
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S. Di Fabio,
D. Trabattoni,
A. Geraci,
S. Ruzzante,
G. Panzini,
M.L. Fusi,
F. Chiarotti,
F. Corrias, R. Belli,
P. Verani,
A. Dalgleish,
M. Clerici,
F. Titti
[show abstract]
[hide abstract]
ABSTRACT: The potential therapeutic utility of thalidomide (Thd), an effective inhibitor of tumor necrosis factor (TNF)-αin vitro, was investigated in cynomolgus monkeys (Macaca fascicularis) at 10 months after infection with simian immunodeficiency virus (SIV). Thd-treated macaques (n=8) received an oral dose (10 mg) daily for 7 days, followed by a wash-out period of 5 weeks. A 2nd cycle of treatment was performed on the same animals at higher doses (20 mg Thd/day) for 14 days. The control monkeys (n=7) received a placebo for the same period of time. In the present study, we show that Thd, in addition to inhibiting TNF-α production after in vitro mitogen stimulation of peripheral blood mononuclear cells (PBMCs), was able to restore the proliferative responses to SIV peptides in monkeys that were infected with SIV. Interestingly, we found that such effects are associated with an increased expression of CD28 cell surface receptors on CD4+ T-cells paralleled by a decrease on CD8+ T-cells. At the same time, significant reduction in either cell-associated viral load or plasma viral RNA was not observed among the SIV-infected monkeys during the two treatment cycles, when compared with the placebo group.
Journal of Medical Primatology 01/2000; 29(1):1 - 10. · 1.30 Impact Factor
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A Cafaro,
A Caputo,
C Fracasso,
M T Maggiorella,
D Goletti,
S Baroncelli,
M Pace,
L Sernicola,
M L Koanga-Mogtomo,
M Betti,
A Borsetti, R Belli,
L Akerblom,
F Corrias,
S Buttò,
J Heeney,
P Verani,
F Titti,
B Ensoli
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ABSTRACT: Vaccine strategies aimed at blocking virus entry have so far failed to induce protection against heterologous viruses. Thus, the control of viral infection and the block of disease onset may represent a more achievable goal of human immunodeficiency virus (HIV) vaccine strategies. Here we show that vaccination of cynomolgus monkeys with a biologically active HIV-1 Tat protein is safe, elicits a broad (humoral and cellular) specific immune response and reduces infection with the highly pathogenic simian-human immunodeficiency virus (SHIV)-89.6P to undetectable levels, preventing the CD4+ T-cell decrease. These results may provide new opportunities for the development of a vaccine against AIDS.
Nature Medicine 07/1999; 5(6):643-50. · 22.46 Impact Factor
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L Sernicola,
F Corrias,
M L Koanga-Mogtomo,
S Baroncelli,
S Di Fabio,
M T Maggiorella, R Belli,
Z Michelini,
I Macchia,
A Cesolini,
L Cioè,
P Verani,
F Titti
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ABSTRACT: The infection of cynomolgus monkeys with an attenuated simian immunodeficiency virus (SIV) (C8) carrying a deletion in the nef gene results in a persistent infection associated with an extremely low viral burden in peripheral blood mononuclear cells. The aim of this study was to determine (1) the breadth of the protection after repeated challenges of monkeys with SIV homologous strains of different pathogenicity, (2) the genotypic stability of the live virus vaccine, (3) whether the protection might depend on cellular resistance to superinfection, and (4) whether immunogenic stimuli such as recall antigens could reactivate the replication of the C8 virus. To address these goals, the monkeys were challenged at 40 weeks after C8 infection with 50 MID50 of cloned SIVmac251, BK28 grown on macaque cells. They were protected as indicated by several criteria, including virus isolation, anamnestic serological responses, and viral diagnostic PCR. At 92 weeks after the first challenge, unfractionated peripheral blood mononuclear cells from protected monkeys were susceptible to the in vitro infection with SIVmac32H, spl. At 143 weeks after C8 infection, the four protected monkeys were rechallenged with 50 MID50 of the pathogenic SIVmac32H, spl grown on macaque cells. Once again, they were protected. The C8 virus remained genotypically stable, and depletion of CD4(+) cells was not observed during approximately 3 years of follow-up. In contrast, it was found that the infection with SIVmac32H, spl induced CD4(+) cell depletion in three of three control monkeys. Of importance, stimulation with tetanus toxoid, although capable of inducing specific humoral and T cell proliferative responses, failed to induce a detectable reactivation of C8 virus.
Virology 05/1999; 256(2):291-302. · 3.35 Impact Factor
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S Di Fabio,
D Trabattoni,
A Geraci,
S Ruzzante,
G Panzini,
M L Fusi,
F Chiarotti,
F Corrias, R Belli,
P Verani,
A Dalgleish,
M Clerici,
F Titti
AIDS 03/1998; 12(3):334-5. · 6.24 Impact Factor
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F Titti,
L Sernicola,
A Geraci,
G Panzini,
S Di Fabio, R Belli,
F Monardo,
A Borsetti,
M T Maggiorella,
M Koanga-Mogtomo,
F Corrias,
R Zamarchi,
A Amadori,
L Chieco-Bianchi,
P Verani
[show abstract]
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ABSTRACT: The ability of a live attenuated simian immunodeficiency virus (SIV) to protect against challenge with cloned SIVmac251/BK28 was evaluated in four cynomolgus macaques. The intravenous infection of the C8 variant of the SIVmac251/32H virus, carrying an in-frame 12 bp deletion in the nef gene, did not affect the CD4+ and CD8+ cell counts, and a persistent infection associated with an extremely low virus burden in peripheral blood mononuclear cells (PBMCs) was established. After 40 weeks, these monkeys were challenged intravenously with a 50 MID50 dose of SIVmac251/BK28 virus grown on macaque cells. Four naive monkeys were infected as controls. Monkeys were monitored for 62 weeks following challenge. Attempts to rescue virus from either PBMCs or bone marrow from the C8-vaccinated monkeys were unsuccessful, but in two cases virus was re-isolated from lymph node cells. The presence of the SIV provirus with the C8 variant genotype maintaining its original nef deletion was shown by differential PCR in PBMCs, lymph nodes and bone marrow. Furthermore, in contrast to the control monkeys, the vaccinated monkeys showed normal levels for CD4+ and CD8+ cells, minimal lymphoid hyperplasia and no clinical signs of infection. Our results confirm that vaccination with live attenuated virus can confer protection. This appears to be dependent on the ability of the C8 variant to establish a persistent but attenuated infection which is necessary for inducing an immune response, as suggested by the persistence of a strong immune B cell memory and by the over-expression of interleukin (IL)-2, interferon-gamma and IL-15 mRNAs in PBMCs of C8-vaccinated monkeys but not in those of control monkeys.
Journal of General Virology 11/1997; 78 ( Pt 10):2529-39. · 3.36 Impact Factor
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Journal of biological regulators and homeostatic agents 11(1-2):82-7. · 5.18 Impact Factor
