Avid Bioservices Inc (CDMO)

[jazzbeerman]

from Bart Haynes WIPO patent application -------------


.........Thus, HTV virions and HIV envelope can directly induce T cell death in AHI, soluble TRAIL can bind to uninfected cells and induce death in AHI, and with both HTV infection of cells and with massive apoptosis, high levels of phosphatidylserine containing cells and particles likely abound in AHI. It has recently been shown that PD-I (programmed death molecule- 1) is present on the surface of human B cells in chronic HIV infection. This suggests that human B cells are primed for apoptosis in HIV infection (Figure 6). HIV specific CD8+ T cell PD-I expression correlates with a CD8+ T cell response to poorly controlled chronic HIV infection (Petrovas et al, JEM 203: 2281 (2006)). Phosphatidylserine (PS) on the surface of HIV infected cells and virions has been found (Figure 7) and Callahan et al have found PS is a cofactor for HIV infection of monocytes (Callahan, J. Immunol 170:4840 (2003)). PS-dependent ingestion of apoptotic cells promotes TGF-beta secretion (Huynh et al, J. Clin. Invest. 109:41 (2002)) and interaction between PS and PS receptor inhibits antibody responses in

vivo (Hoffman et al, J. Immunol. 174:1393 (2005)) [ (jazzbeerman's "required reading #1") ] . INF-alpha, an anti-viral cytokine, sensitizes lymphocytes to apoptosis (Carrero et al, JEM 200:535 (2004)). There are increases in PS+ shed membrane particles in chronic HIV infection (Aupeix et al, J. Clin. Invest. 99:1546 (1997).........

Thus, the massive apoptosis that occurs with acute HIV infection with resulting release of TRAIL, mediation of apoptosis via FAS-FASL interactions, and release of PS containing viral and other particles all conspire to initially immunosuppress the host, preventing rapid protective B cell responses.

The present invention includes strategies to prevent apoptosis that include, but are not limited to, the use of PS-containing HIV immunogens, such as PS liposomes, either with or without CON-S or CON-T gpl40 or HTV env epitopes associated with the liposomes, such as 2F5-GTH1 peptide lipid conjugates (Figures 8A and 8B) administered with adjuvants to break tolerance and induce anti-PS antibodies that inhibit PS-CD36 interactions. Alternatively, recombinant CD36 can be targeted in order to raise anti-CD36 antibodies, preferably, both anti-PS or anti-CD36 antibodies are induced at mucosal sites to prevent apoptotic mediated immune suppression.



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