Scientific Basis

A wide range of preclinical results have been accumulated showing that a short conserved peptide, from HIV-1 gp41, named the 3S peptide, is at a key element in the pathogenisis of HIV-1 (i.e. the CD4 T cell depletion) as described below.
The pathogenicity of the gp41 3S peptide: The 3S peptide, within inactive viral particles, when entering into contact with CD4+ T lymphocytes lead to the translocation at the cell surface member of the CD4+ T lymphocytes of NKp44L, an NK cell ligand. Activated NK cells after NKp44-NKp44L recognition will lead to the depletion of CD4+ T lymphocytes.

The scientific evidences supporting the role of the 3S peptide in the HIV-1 pathogenicity includes in vitro, in vivo data in cynomolgus, and data from HIV-1 infected patients.

1. In vitro results show that the 3S peptide from HIV-1 gp41 is sensitizing human CD4+ T lymphocytes to NK cell-mediated lysis by inducing NKp44L (a ligand of the NK cell NKP44 receptor) cell surface expression on CD4+ T lymphocytes. Moreover, such effect could be counteracted by antibodies directed against the 3S peptide. These observations indicated the pathogenic role of the 3S peptide and were the basis of a totally new vaccine approach.These findings also led to propose that the absence of anti-3S antibodies in patients may be related to a faster CD4+ T lymphocytes depletion (Vieillard, Costagliola et al. 2006) and that CD4+ T lymphocytes depletion could be a consequence and not a cause of NKp44L expression.

2. A solid in vivo proof of concept of the vaccination with the 3S peptide has been achieved in cynomolgus macaques (Vieillard V et al. Proc.Natl. Acad. Sci. USA, 2008, 105:2100-4) infected with SHIV. An immunization against the 3S motif, which is highly conserved among HIV-1 variants, resulted in high level of anti-3S peptide antibodies. This resulted  to :

• The prevention of CD4+ T lymphocytes depletion as compared to the control cynomolgus group in which the decrease represented 50% of the normal level of CD4+ T lymphocytes ;  CD4+ T lymphocytes activation was also inhibited;

• The prevention of NKp44L expression at the surface of the CD4 cells,

• A decrease of the apoptosis rate of CD4+ T lymphocytes in peripheral blood and lymph nodes.

These data clearly show that anti-3S vaccination and the subsequent anti-3S antibody response resulted in the nearly complete inhibitionof all the downstream events/markers induced by the 3S peptide (CD4+ T lymphocytes level, NKp44L expression at the surface of CD4+ T lymphocytes, rate of apoptosis of CD4+ T lymphocytes)

These outstanding biological effects of the vaccine were observed during the whole duration of the experiment (200 day period).
Such results are unique in the way that the prevention of the onset of CD4+ T lymphocytes loss in a macaque model of HIV infection is obtained, thus demonstrating the value of this vaccine approach that InnaVirVax is developing with the forecast to obtain the same effect in man.

3. The in vivo data from cynomolgus macaques are in total agreement with data from HIV-infected patients.
For instance, in patients the anti-3S antibody titer, present naturally after the sero-conversion and for a variable duration from patient to patient, was shown to be inversely associated with NKp44L expression at the surface of CD4 T+ lymphocytes, suggesting the same effect as in the monkeys (i.e. when no anti-3S antibodies present, then presence of NKp44L at the surface of CD4+ T lymphocytes).
Most importantly, analysis of NKp44L at the surface of CD4+ T lymphocytes of patients has shown clearly that the percentage of CD4+ T lymphocytes expressing NKp44L is increasing as the level of CD4+ T lymphocytes is decreasing (Vieillard V., et al. 2006 AIDS 20:1795-1804), making a link in human with the effect of the 3S peptide. The preclinical proof of concept data obtained in vitro and in vivo in monkey is linked to observations in patients (concerning anti-3S antibodies, CD4+ T lymphocytes levels, and the presence of NKp44L at the surface of CD4 +T lymphocytes). The link between the human pathogenesis and data obtained in cynomolgus macaques strongly consolidates the role of the 3S peptide in the pathogenesis of AIDS.

Publications

1. Vieillard V., Strominger J., and P. Debré. 2005. NK cytotoxicity against CD4+ T cells during HIV-1 infection: A gp41 peptide induces the expression of an NKp44 ligand. Proc. Natl. Acad. Sci USA, 102:10981-10986.
2. Vieillard V., Costagliola D., Simon A., P. Debré and French Asymptomatiques à Long Terme (ALT) Study Group. 2006. Specific adapative humoral response against a gp41 motif inhibits CD4 T-cells sensitivity to NK lysis during HIV-1 infection. AIDS 20:1795-1804.
3. Vieillard V.,El Habib R., Brochard P., Delache B., Fausther Bovendo H., Calo J., Morin J., Picq I., Martinon F., Vaslin B., Le Grand R., and P. Debré. 2008. CCR5 or CXCR4 use influences the relationship between CD4 cell depletion, NKp44L expression and NK cytoxicity in SHIV-infected macaques. AIDS. 22:185-192.
4. Vieillard V., Le Grand R., Dausset J. and P. Debré. 2008. A new vaccine strategy against AIDS: A HIV gpg41 peptide immunization prevents NKp44L expression and CD4+ T cell depletion in SHIV-infected monkeys. Proc.Natl. Acad. Sci. USA, 105:2100-4.
5. Fauster-Bovendo H., N. Sol-Foulon, D. Candotti, H. Agut, O. Schwartz, P. Debré and V. Vieillard. HIV escape from natural killer cytotoxicity: nef inhibits NKp44L expression of CD4+ T cells. AIDS 2009, 23:1077-1087.
6. Viellard V., H Fausther-Bovendo, A. Samri, P. Debré and French Asymptomatiques à Long Terme (ALT) ANRS-CO15 Study Group. 2010. Specific Phenotypic and Functional Features of Natural Killer Cells From HIV-infected Long-Term Nonprogressors and HIV Controllers. J. Acquir. Immune Defic. Syndr. 53:564-573.
7. Fausther-Bovendo H., V. Vieillard, S. Sagan, G. Bismuth, P. Debre. 2010. HIV-1 gp41 Engages gC1qR on CD4+ T Cells to Induce the Expression of an NK Ligand Through the PIP3/H202 Pathway. PLoS Pathogens, 6:1-13.

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