Toulon 2004 :
Abstracts
13th International Symposium on HIV
& Emerging Infectious Diseases
(all abstracts on <http://www.isheid.com/>)
6 abstracts
for Toulon :
Authors :
TRAN
M.K.G.1,
5, KIRKIACHARIAN
S.2, MAURISSON G.3, 5, CAPRANI A.4, 5
1 University Paris-Sud
XI ; correspondence: 31 Av du Bois, Châtenay-Malabry,
France.
2 Therapeutic Chemistry, Faculty Pharmacy, University
Paris-Sud XI, Châtenay-Malabry.
3 Centre Médical Europe, 44 rue d'Amsterdam,
Paris
4 CNRS UMR, University 7-Denis Diderot, CNRS UMR 7057, 2
Place Jussieu, Paris Cedex 05.
5 Positifs Association, BP 230 75865 Paris Cedex
18.
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2 AGREE
ABSTRACTS
Poster's
form
MOLECULAR HOMOLOGY BETWEEN ALPHA-DEFENSIN
AND SCRUB TYPHUS RICKETTSIA ORIENTIA TSUTSUGAMUSHI
56KD
TYPE SPECIFIC ANTIGEN
TRAN
M.K.G.1, 3, KIRKIACHARIAN S.2, MAURISSON G.3, CAPRANI A.3
1
Univ
Paris-Sud,
2 Therap
Chem, Fac Pharm, 92290 Chatenay-Mb, 3 Positifs Association
1) Zhang L.(2002) discovered an
a-defensin isotype [differing by
isoleucine 28 (Ileu 28 or I 28), instead of phenylalanine
(Phe or F) in classical commercial a-defensin] as the natural
protective factor against HIV-1 in long-term nonprogressors
remaining a life without treatment.
2) Watt G (2000, 2001) remarked a
beneficial effect of sera from scrub typhus Rickettsia (Orientia Tsutsugamushi)
[Rick.Or.Tsu.]-infected HIV-1+ patients on HIV-1
replication, suggesting a protective cross-reactive
antibody.
3) Tran M.K.G. described a molecular
homology between Nef and a
-defensin (Warsaw
Conf., Poland, 2003), then between Nef and Rick.Or.Tsu. 56
Kd type specific antigen (tsa 56) (this Toulon Conf., 2004)
centered on the common tetrapeptide GIRY. It is noteworthy
that Zhang's a-defensin variant (I 28) is 20
times more protective against HIV-1 than commercial
a-defensin (F 28), pointing to an
important role for this isoleucine 28 residue.
METHODS: We compared the amino acid
sequence and tridimensional (3D) structure of a-defensin (I 28) and
Rick.Or.Tsu.
tsa 56.
RESULTS:
DISCUSSION AND
CONCLUSION:
Rick.Or.Tsu tsa 56 is a perfect molecular
mimicry of Zhang's a -defensin on the tetrapeptide IAWL,
with a significant homology spanning 8 residues, suggesting
that protection may be mediated by a cross-reactive antibody
against HIV Nef sequence IWKFDSA. The trilogy (Nef, Zhang's
a -defensin and Rick.Or.Tsu tsa 56) defines 2 homologous
linear epitopes (centered respectively on IAWL and GIRY)
located in proximity in a 3D space. For clade B and Thailand
clade AE, vaccines with these Nef epitopes, or an anatoxine
with Rick.Or.Tsu tsa 56, and passive immunotherapy
(sera, monoclonal antibodies, Fab, Fv,É) could be designed
as an interesting anti-HIV-1 therapy, as this Nef region is
relatively conserved inside each clade.
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HIV-1 Protease Is A Metalloproteinase
Containing A Copper-Binding Motif Gly His Lys
(GHK)
At Residues 68-70
INTRODUCTION:
Antiproteases are
very efficient molecules, however they rapidly induce
cross-reactive chemoresistence with occurrence of multiple
mutations (L10FIRV, K20MR, L24I, D30N, V32I, L33F, M36I,
M46IL, I47V, G48V, I50V, I54VML, L63APQ, A71TV, G73SA, V77I,
V82AFTS, I84V, N88DS, L90M), rendering their long term
efficacy problematic.
METHODS:
We undertook a systematic screening of the complete amino
acid sequence of HIV-1 protease, looking for some specific
motifs which could have escaped to previous investigators.
RESULTS:
There is a classical typical copper-binding motif Glycine
Histidine Lysine (Gly His Lys, or GHK) [K stems for Lysine]
(Pickart L, 1980) at HIV-1 protease residues 68-70. For
example, GHK is found in collagen I sequence, and released
after proteolysis as a copper tripeptide (Maquart F.X.,
1988). This 68-GHK-70, located far from the catalytic site,
classified HIV-1 protease as a member of metalloproteinase
family, with 2 symmetrical coppers. The function of copper
seems important: Only rarely His 69 is mutated to Tyrosine
(Tyr or Y) (treatment by lopinavir) and even then, the
replacement of His by Tyr could be non functional, because
both residues bind copper, although the copper affinity for
His is higher. As HIV-1 Gag contains also GHK, and is the
target of HIV-1 protease, it may be that copper, as a metal
bridge, could contribute to gag proteolysis.
DISCUSSION AND
CONCLUSION:
A chemical design of new anti-proteases generation must take
in account the chelation by the motif 68-GHK-70 of the 2
symmetrical coppers in protease dimer, to enhance efficacy
and perhaps avoid chemoresistence, as far as copper is
necessary for HIV-1 functional enzymatic activity. As a
metalloproteinase, HIV-1 protease may be attacked by
adequate antiprotease simultaneously at this copper
Achilles' heel, what has never been done until now.
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4 NON AGREE ABSTRACTS
The Scorpion Venom Model Of Aids:
Scrub Typhus Rickettsia Orientia Tsutsugamushi 56kd Type
Specific Antigen Has
A Common Motif With HIV-1 Nef In The Alpha-defensin-like
Region
TRAN
M.K.G.1,3, KIRKIACHARIAN S.2, MAURISSON G.3, CAPRANI A.3
1 University Paris-Sud
XI ; correspondence : 31 Av du Bois, Châtenay-Malabry,
France.
2 Therapeutic Chemistry, Faculty Pharmacy, University
Paris-Sud XI, Châtenay-Malabry.
3 Positifs Association, BP 230 75865 Paris Cedex
18.
INTRODUCTION:
Watt G. (2001,
2000) found in Thailand that scrub typhus rickettsial
infection by Orientia Tsutsugamushi (Or.Tsu.)
was beneficial for
HIV-1+ patients, by a cross-reactive immunity involving
antibodies to a common epitope between HIV-1 and
Or.Tsu. Elsewhere, HIV-1 Nef was found
mimicking a member of the scorpion venom family:
Alpha-defensin (Tran M.K.G., E.A.C.S. Warsaw Eur. Conf.,
2003), the natural protective protein in long-term
nonprogressors (Zhang L., 2002). We tried to determine
precisely this protective cross-reactive
epitope.
METHODS:
Comparison of
amino acid (aa) sequences between HIV-1 proteins (Los Alamos
databanks) and Or.Tsu. surface proteins [56 kD type
specific antigen (tsa 56)].
RESULTS:
We found a common
motif GIRY (or GVRY) between clade E Thailand
HIV-1 Nef and Or.Tsu. tsa 56 (513-521):
P and S are commonly found on
the tip of a loop; L and F are hydrophobic semi-conserved, A
and G are space providing aa. The length is 9 aa, which is
significant. Interestingly, this epitope is located exactly
in the Nef region which mimicks a
-defensin (Tran MKG,
Warsaw 2003), suggesting a crucial functional role. A second
epitope is published in this Toulon conference (Tran MKG,
2004).
DISCUSSION AND
CONCLUSION:
A protective
specific vaccine or immunotherapy (serotherapy, monoclonal
antibodies or Fab, etc...) strategy may be developed on the
basis of a homology between Thailand HIV-1 Nef and
Or.Tsu. tsa 56 centered on the GIRY (or
GVRY), with a better fitness between the corresponding HIV-1
Nef and Or.Tsu. strains than a blind serotherapy
(as did Watt G. in 2001). The relatively conserved Nef
sequence may be presented by heat shock proteins to
dendritic cells (Srivastava P, 2002). This also confirms our
scorpion venom model of AIDS and the efficacy of Tacrine.
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Aids and Atherosclerosis: Homology Between
Atherogenic Chicken Marek's Disease Herpes Virus
and LDL Receptor
TRAN
M.K.G.1,3, KIRKIACHARIAN S.2, MAURISSON G.3, CAPRANI A.3
1 University Paris-Sud
XI ; correspondence : 31 Av du Bois, Châtenay-Malabry,
France.
2 Therapeutic Chemistry, Faculty Pharmacy, University
Paris-Sud XI, Châtenay-Malabry.
3 Positifs Association, BP 230 75865 Paris Cedex
18.
INTRODUCTION:
Hypercholesterolemic,
hypertriglyceridemic, diabetic, lipodystrophic AIDS patients
are particularly prone to atherosclerosis, WHO's first cause
of mortality in the world. Atherosclerosis may be of viral
herpetic origin: Paterson (1950) discovered a link between
Marek's disease virus (MDV) a poultry herpesvirus and
coronary sclerosis in chickens. Fabricant CG (1973) found
cholesterol crystals in cell cultures infected by a feline
herpesvirus and in 1975 submitted chickens to a diet without
cholesterol but infected by MDV: They developed an
atherosclerosis of aortic, celiac, gastric, mesenteric and
coronary arteries with cholesterol deposition and spumous
cells. Chicken (Influenza, poliomyelitis) viruses may be
transmitted to humans. MDV p53 inhibitor Meq induced a
clonal arterial smooth muscle cell proliferation, coupled
with an accumulation of phospholipids, free fatty acid,
cholesterol and cholesterol esters. We try to elucidate MDV
role in cholesterol deposition
METHODS:
Amino acid (AA) sequence comparison and tri-dimensional
structure superimposition.
RESULTS:
We found in MDV genome a 132 base pair, 40 AA long, repeated
about 8 fold in some strains. A similar ~ 8 fold repetition
of a 42 AA sequence occurs in LDL (or bad) cholesterol
receptor (LDLR). In genetic familial hypercholesterolemia
& Watanabe rabbit model, mutations occurred precisely in
the LDLR. MDV & LDLR match spans the repeat:
In the LDLR flower
tri-dimensional structure, we superimposed the AA of MDV on
LDLR, by centering on cysteines C (C bridges ss).
DISCUSSION AND
CONCLUSION:
MDV contains a viral LDLR, present during infection in the
arterial (i.e. coronary) plaque, which captured and retained
the bad LDL cholesterol in situ (MDV antigens were detected
in arteries) provoking a fatty accumulation initiating
atherosclerosis. Alimentary chickens must be analyzed for
their safety (MDV absence) to avoid atherosclerosis,
especially in AIDS. Anti-herpetics [i.e. propolis, better
than aciclovir (Vinograd N, 2000)] and a vaccine (which
exists for poultry) may be developed against MDV.
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The Scorpion Venom
Model Of Aids: Feline Leukemia Virus (FeLV 61C Inducing
Aids)
Envelope Is Homologous To A Scorpion
Venom
TRAN
M.K.G.1,3, KIRKIACHARIAN S.2, MAURISSON G.3, CAPRANI A.3
1 University Paris-Sud
XI ; correspondence : 31 Av du Bois, Châtenay-Malabry,
France.
2 Therapeutic Chemistry, Faculty Pharmacy, University
Paris-Sud XI, Châtenay-Malabry.
3 Positifs Association, BP 230 75865 Paris Cedex
18.
INTRODUCTION:
Retrovirus-induced
AIDS has long-standing precedent in Feline Leukemia Virus
(FeLV)-associated immunodepression (designated as
FeLV-AIDS), occurring in cats with some isolates of FeLV.
More cats die from the cytosuppressive consequences of FeLV
infections (AIDS and bone marrow aplasia) than from leukemia
itself. AIDS in cats is characterized by progressive weight
loss, intractable diarrhea, lymphoid hyperplasia,
lymphopenia, opportunistic infections (bacterial rhinitis,
pneumonia, necrotizing stomatitis). Sequencing of the
retrovirus envelope reveals a difference of 6 residues
(sequence NVKHGA) between the fatal AIDS-inducing strain
(FeLV 61C) and the benign strain (FeLV 61E) (Overbaugh J.,
Science, 1988: 906). Our objective is to understand why this
strain 61C was so pathogenic conducing to fulgurant lethal
AIDS.
METHODS:
Amino acid
sequences comparison.
RESULTS:
We discovered that
only AIDS-inducing strain 61C, but not benign strain 61E,
could be aligned with a scorpion venom toxin from
Centruroides sculpturatus Ewing (CsE). In the case of the
benign strain 1E, the hexapeptide NVKHGA insertion after SPT disrupted
completely the alignment:
A more extended alignment is
found if chimeras of scorpion venoms and FeLV envelope are
considered.
DISCUSSION AND
CONCLUSION:
In cats, FeLV can kill by a fulgurant fatal AIDS. The AIDS
inducing strain 61C differs from the benign strain 61E by an
hexapeptide deletion ; this deletion permitted to align 61C
with a scorpion venom, whereas 61E could not. Thus the
concept of scorpion venom of AIDS (Tran MKG, 1989 ; Werner
T., 1991) is found not only for HIV-1, but also for a
lymphocytotropic leukemia virus in cats. Tacrine, which
modifies the scorpion venom receptor (voltage dependent
Na+ channel), may be tried and be
beneficial in cat AIDS.
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Molecular Homology Between RANTES, MIP
1alpha, MIP 1beta Chemokines,
HIV-1,-2 SIV Envelope GP120 V2 Loop
And Scorpion Venom Tityus TS-VI
TRAN
M.K.G.1,3, KIRKIACHARIAN S.2, MAURISSON G.3, CAPRANI A.3
1 University Paris-Sud
XI ; correspondence : 31 Av du Bois, Châtenay-Malabry,
France.
2 Therapeutic Chemistry, Faculty Pharmacy, University
Paris-Sud XI, Châtenay-Malabry.
3 Positifs Association, BP 230 75865 Paris Cedex
18.
INTRODUCTION:
As chemokines
(RANTES, MIP 1alpha, MIP 1beta) were implicated in AIDS
physiopathology, we analyzed them in the context of scorpion
venom model of AIDS. We try to analyze RANTES, MIP 1alpha,
MIP 1beta mechanism of action.
METHODS:
The amino acid
sequences of RANTES, MIP 1alpha, MIP 1beta were compared to
those of eosinophilic chemotactic factor (ECF), scorpion
toxins and HIV Los Alamos databanks
RESULTS:
HIV envelope gp
120 V2 loop is a scorpion venom; the tri-dimensional
structures of RANTES and scorpion venom were similar with
one alpha-helix and 3 beta-strands in common. The RANTES
active site residue Y 27 is homologous to scorpion venom Y
5. The best fit was with Tityus Serrulatus Ts-VI, a scorpion
venom inducing a generalized allergy in mice. Asterisks *
are HIV-1 RF escape mutant Y177, T179.
DISCUSSION AND
CONCLUSION:
RANTES, MIP 1alpha, MIP 1beta chemokines were homologous to
HIV-1,-2 SIV envelope V2 loop, as well as to scorpion venom
Tityus serrulatus Ts-VI (which induced, like RANTES, an
allergy).Thus RANTES can be integrated a larger concept of
the scorpion venom model of AIDS (i.e. V3 loop, gp41, Nef;
scorpion receptor voltage-dependent Na+ sodium channel; and the drug
Tacrine, a modifier of Na+ channel).
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