Download C62-5th IAS( International AIDS Society)conference onAIDS and

C62-5th IAS( International AIDS Society)conference onAIDS and HIV
infection
Captown, South Africa, 22-24 July 2009.
“Positifs” n’a pu être present physiquement”à cette conference, faute de
moyens financiers. Un abstract en présentation CD a cependant été retenu
(CDA009) et nous la présentons in extenso dans cet article. Pour une
excellente synthèse objective, mais où l’information off que Positifs
rapporte systématiquement n’apparait pas, nous vous conseillons de
consulter:< http://www.nam.org.uk/cms1290216.aspx> .
Parmi les points que nous pouvons souligner:
-quasi consensus sur une mise sous traitement rapide, c’est à dire à 350
CD4, en faisant l’impasse sur les effets indésirables à long terme des
traitements!
- Débat non clos sur les risques cardiovasculaires de l’abacavir
-Simplification des traitements. Monothérapie au Kalétra validé.
Monothérapie au darunavir/ritonavir possible. Atanazavir boosté ou non
boosté presentent la meme efficacité.
L’aciclovir reduit les risques de progression de la maladie et le taux de
mortalité.
Enfin rien de vraiment nouveau sur les vaccins et l’éradication par accès
aux reservoirs.
Communication de “Positifs”
Molecular mimicry between aphthous diseases viruses: HIV-1 Gag p24,
Human Foot-and-Mouth Disease Virus (HMFDV) and Parvovirus B19
(Behcet’s disease) centred on a hexapeptide VDRFYK. Thalidomide
mechanism of action on Gag.
Tran M.K.G. 1*, Caprani A. 2*, Gerbaud L.1
1 University Auvergne. Public Health (Pr Gerbaud L.), Hospital Hotel Dieu, Clermont-Ferrand,
France. E-mail : [email protected]
2 University Paris VII, CNRS, France. E-mail : [email protected]
* Association Positifs, Paris, France.
BACKGROUND
Thalidomide is used in AIDS aphthous ulcers (Jacobson J.M., 1999) and Behcet’s bipolar
aphthous disease, but the link between the 2 diseases is not clear. After the outbreak of cattle mouthand-foot disease in France and Great-Britain, we tried to prevent for the future such a catastrophe
for agricultural economics by studying a vaccine containing a critical epitope. In Behcet’s disease,
Parvovirus B19 was found in 15, 7% cases versus 0% in controls (p = 0, 03) (Kiraz S., 1996).
Parvovirus B19 DNA was detected by polymerase chain reaction in the lesional skin of Behçet's
disease (Baskan E.B., 2007). Streptococcus Sanguinis and human herpesvirus simplex have also
been implicated in Behcet’s disease (Suzuki Kurokawa M., 2004).
We try to understand the mechanism of aphthous ulcer formation in AIDS, Behcet’s disease
and cattle mouth-and-foot disease.
METHODS
We analyse amino acid sequences of Parvovirus B19, HIV-1 (Los Alamos databanks),
Coxsackieviruses A and B/Human Foot-and-Mouth Disease Virus (HFMDV), Streptococcus and
human herpesvirus simplex 1 and 2.
Parvovirus B19 non structural protein (nsp) amino acid sequence was read from the COOHterminus to the NH2-terminus (in retro-inverso sense, in Italics).
RESULTS
There is a molecular homology (VDRFYKTL, 8 residues) between HIV-1 gag p24 and
HFMDV capsid VP2 (VNRFYTL) (one gap), which is significant: There is roughly only 1 chance
out of 208 (20 x 20 x 20 x 20 x 20 x 20 x 20 x 20) that this occurs by simple chance.
Interestingly, a Streptococcus Sanguinis SK36 [gbABN43890] (Xu P., 2007) transcriptional regulator
AcrR (and TetR family) has almost the same sequence 119-YVLDRFYHRLCER-131 than HIV-1
Gag YVDRFYKTLRAEQ.
Similarly, Human Herpesvirus simplex-1 UL 24 [ACM622246] sequence RFYKALAEEVREFH is
similar to HIV-1 Gag RFYKTLRAEQASQEVK:
FQE -GDRFYK GKTTM
HIV-1 Gag capsid p24 GPkEPFRDYVDRFYKTLRAEQASQEVKGW
HFMDV capsid VP2 KPTRPDVS VNRFY -TLDTKL WEkSSKGW
Coxsackie B and A
Q
D
GKKWEATTKGW
FMDV (swine) capsid VP2
RFFKT
Human Herpesvirus Simplex 1 UL 24
RFYKAL- AEEV- REFH
Human Herpesvirus Simplex 2 UL 24
RFYKAF- AREV- REFN
Streptococus Sanguinis SK36 NRYVLDRFYHRL- CER
Calpain
RFFKTLDT
CDNF
KEFLNRFYKSL
Parvovirus B19 nsp
We looked for a human sequence similar to these pathogen epitopes by BLASTP and found
a sequence 687-RFFKTLDT-694 in the COOH-terminus of Calpain, which is activated by
Epidermal Growth Factor (EGF) and induced apoptosis of keratinocytes (Inoue A., 2004): Perhaps
this may be relevant to aphthous ulcers formation mechanism. Calpain is also implicated in
thrombosis formation (Kulkarni S., 2004), which may be correlated to thrombosis in Behcet's
disease. We found also a very significant homology with Conserved Dopamine Neurotropic Factor
(CDNF) [or Arginine-rich mutated in early tumor-like 1 (ARMETL1)] sequence KEFLNRFYKSL:
In neuro-Behcet, a schizophrenia-like clinical picture was described by Nkam I. (2006), and
schizophrenia is dopamine-related. There is a higher HIV infection rate in schizophrenia patients
(Koen L., 2007).
Schizophrenia and dopamine receptor type 2
In schizophrenia, anti-psychotics whether new or old target dopamine transmission.
Dopamine receptor type 2 (DRD2) polymorphism is associated with schizophrenia
(Corderio Q., 2009; Hanninen K., 2006).
There is a striking molecular homology (Tran G.M.K., unpublished) between Influenza virus
hemagglutinin 529-ILWISFTISCFLL-543 and DRD2 158-IVWVLSFTISCPLL-171, confirming
Brown's data about the role of Influenza virus in schizophrenia (Brown A.S., 2004) and the role of
dopamine receptor type 2.
We found also, in the same region, an homology of dopamin receptor type 2 sequence 160WVLSFTISCPL-170 with Toxoplasma Gondii GT1 conserved hypothetical protein [gb EEE20189] 83WLLSLFLVSCPL-94. Toxoplasmosis during pregnancy was also reported to produce schizophrenia
in infants (Brown A.S., 2006; Henriquez S.A., 2009):
Dopamin receptor type 2 (DRD2)
158-IVWVLS -FTI SCPLL-171
Influenza virus hemagglutinin
529-ILWI
Toxoplasma Gondii GT1 conserved hypothetical protein
- S -FTI SCFLL-543
83-WLLSLFLVSCPL-94
CONCLUSION
Although the viruses and bacteria associated or inducing aphthous diseases were unrelated,
at the molecular level, the mechanism seems the same. Thalidomide is probably efficient by a
common mechanism in these various unrelated diseases. We found the aphthogenous motif
VDRFYK in HIV-1 gag, and interestingly thalidomide and analogues in vitro reduces precisely Gag
mRNA expression (Moreira A.L., 1997). Another interesting alternative and efficient treatment of
aphthous ulcers is the grapefruit (Citrus maxima, Citrus grandis, Citrus paradisi) seed extracts
(Heggers J.P., 2002), which has a bitter taste. Propolis from bee is also interesting (Samet N., 2007).
Vitamin B12 is efficient (Volkov I., 2009).
A vaccine against FMDV in cattle can be designed on this epitope to prevent future epidemics: It
has the enormous commercial advantage to be recognized easily from infected cattles. A vaccine
against HIV-1 must include this epitope presented by heat shock protein to dendritic cells
(Srivastava P.K., 2009).
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