C.85-Thai AIDS Vaccine RV 144: Molecular Homology Between HIV-1 Gp 120 Envelope First Conserved Region C1, Which Induces IgA Antibodies Increasing AIDS Risk, And The Complement Receptor CR1

Thailand RV 144 vaccine, despite gp120 V1/V2 loops neutralizing IgG, has a low 31% efficacy, mitigated by IgA antibodies against the first conserved region C1 (odds ratio 3.15) (Haynes BF, 2012). We analyse the biological significance of C1 by Basic Local Alignment Search Tool Protein (BLASTP) and visual Amino Acid (AA) sequences comparison: We screened C1 of the vaccine 2 Thailand strains and all HIV-1 strains (HIV Sequence Compendium 2012 Kuiken C, Los Alamos) on Homo Sapiens and found a molecular homology between C1 (AA 112-122) and Complement Receptor type 1 CR1 (CD35) isoform S (AA 2089-2099), in the CCP 32 [NP_000642]; the  corresponding numbering of allotype F is  AA 1639-1649, in the Sushi 25 [P17927]:
C1                                 112-WDQSL KP CVKL-122
C1 (strain CRF 37_cpx) (Powell RL, 2007) 112-WGPKL KP CVKL-122
CR1 isoform S  CCP 32              2089-WGPKL(H,P)CS RV-2099

Domain structure of human complement receptor CR1 and its most common cell expression profile. Human CR1 F allotype contains 30 Short Consensus Repeats (SCRs), each depicted by spheres. Indicated in red are the SCRs mediating binding to the C3b fragment (Hea JQ, 2008).

The tip of the complement receptor CR1 loop (Proline P2095) is read in retro inverso : 2096-(H,P)-2095, instead of 2095-PH-2096.

Such tip inversion exists: Epidermal Growth Factor (EGF) and Transforming Growth Factor-alpha (TGF-a) bind to the same EGF Receptor, despite different tip linear sequence, but in 3D have superimposed loop tip AAs (E and V):
Rat EGF          24 - E S V - 26
TGF-alpha      26 -(E,Q,V)- 24
Anti-C1 IgA harmfulness is explained by Wagner C (2006): Anti-complement receptor CR1 antibodies profoundly inhibit T cell proliferation by inhibiting Interleukin-2 (IL-2)/Interferon-gamma synthesis and IL-2 efficacy, explaining IL-2 clinical trials failure despite T4 cell rise (Pett SL, 2010). CR1 is decreased in lung tuberculosis (Senbagavalli P, 2008). It acts on macrophages and dendritic cells.

Conclusion

An AIDS vaccine must avoid anti-C1 IgA antibodies, because C1 is a molecular mimetic of CR1 and therefore the cross-reactive anti-C1 IgA are anti-CR1 auto-antibodies which profoundly inhibit T cell proliferation. These auto-antibodies could also promote lung tuberculosis. We advocate an AIDS vaccine devoid of this envelope gp120 first constant region C1 deleterious epitope to ameliorate the 31% efficacy observed with the Thai RV 144 vaccine.

An AIDS therapeutic vaccine (as was the case for Pasteur anti-rabies vaccine) would be more rapid to develop, step by step, than a classical prophylactic vaccine: The rapidity of a therapeutic vaccine is calculated in months, whereas for a prophylactic vaccine, each trial would take dozen of years. The same therapeutic vaccine, when finally successful, can be then converted in a prophylactic vaccine (following the anti-rabies vaccine example).

BIBLIOGRAPHY

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