MPLA-induced anticholesterol antibodies may potentiate gp41-MPLA liposomal vaccine
Shawn J. Green, Triple Tree
26 November 2012
Katinger and colleagues may want to include anti-cholesterol to their immunogenicity list. The vaccine adjuvant, liposomal MPLA, can elevate naturally-occurring anti-cholesterol titers and an unintended consequence of elevating anti-cholesterol with gp41-MPLA liposomes may prove to be beneficial. (1,2)
Because of the strong immune stimulating properties found in liposomal MPLA, Maytyas and Alving at Walter Reed Army Institute of Research took a look at whether liposomal MPLA elevated naturally occurring antibodies to cholesterol and liposomal-associated phospholipids. Stored for nearly 20 yrs, thawed serum samples from 23 volunteers who received the first liposomal MPLA malaria vaccine exhibited increased levels of antibodies to all the liposomal phospholipids, including the adjuvant, MPLA, as well as cholesterol. (1,3)
In our quest to identify a vaccine strategy directed against HIV, a series of papers have been suggestive that anti-cholesterol reactive antibodies may be players, but the story has yet to fully play out. Elevated titers of naturally-occurring anti-cholesterol -- that preferentially recognize `high-density cholesterol¿ microdomains in membranes and envelopes ¿ are found in HIV patients and anti-cholesterol antibodies were found to reduce the binding of HIV virions to cholesterol-coated plates. Others have found that the broadly neutralizing HIV antibody, 4E10, exhibit anti-cholesterol cross reactivity; unfortunately 4E10 is rare and all attempts to elicit them via current vaccine immunogens have failed. Eliciting adequate titers of anti-cholesterol reactive antibodies may be what is missing. (4-7)
A growing number of studies over the past decade have repeatedly shown that cholesterol is required for HIV to be infectious as demonstrated by cholesterol depletion of either the target host cell or HIV itself. The notion of targeting cholesterol, as well as, its synthesis, trafficking, and protein binding motifs all emerge as likely strategies to reduce HIV infectivity. Cholesterol-rich microdomains serve both as portals for HIV entry as well as a source of cholesterol for HIV to envelope itself upon departure. (8-10)
Boasso and colleagues at Imperial College, Johns Hopkins, and Milan have shown that cholesterol depleted from HIV's envelope prevents the viron from activating plasmacytoid dendritic cells (pDC); in doing so, immunosuppressive HIV-activated pDC is dampened, thereby allowing T cells to fight the virus more effectively. These results suggest that depleting or masking cholesterol-rich microdomains of HIV may be a critical precondition to effectively vaccinate against HIV. (11)
If one assumes that persistent infection maintains a heighten activated state of pDCs, thereby preventing T cell activation by a subunit vaccine, the solution may be as simple as 'two vaccines': the first, to tame the immune response, the second, to re-activate and re-direct it. Until cholesterol-driven pDC activation is eliminated first, T cell vaccination will remain unattainable.
It is tempting to speculate that elevated anti-cholesterol titers renders protection in a step-wise fashion: first, anti-cholesterol would masks HIV¿s cholesterol domains, thereby, dampening immunosuppressive HIV-activated pDC, and second, elevated anti-cholesterol titers would augment anti-gp41 by disrupting virus envelope-cell membrane interactions involved in cholesterol mixing during viron-cell fusion. As anti-cholesterol titers rise, immunosuppression recedes with a calming of the once activated pDC cells and restoration of T cell function. The thought that elevated anti-cholesterol antibody titers masking viron¿s cholesterol-rich microdomains and then synergizing with anti-gp41 by disrupting virus envelope-cell membrane interactions involved in lipid mixing during viron-cell fusion is reasonable.
Many have ascribed a `housekeeping¿ role for naturally-occurring anti-cholesterol antibodies, such as clearing cholesterol-rich VLDL particles. (2) If so, are elevated levels of naturally-occurring anti-cholesterol antibodies in HIV patients an attempt to clear other `cholesterol-rich particles¿? Would boosting anti-cholesterol titers mask HIV¿s cholesterol-driven immunosuppressive of pDC and enhance anti-gp41 subunit vaccine by disrupting virus envelope-cell membrane interactions involved in cholesterol mixing during viron-cell fusion? The gp41-MPLA liposomal vaccine by Katinger et al. provides an opportunity to explore these questions.
MPLA-induced anticholesterol antibodies may potentiate gp41-MPLA liposomal vaccine
26 November 2012
Katinger and colleagues may want to include anti-cholesterol to their immunogenicity list. The vaccine adjuvant, liposomal MPLA, can elevate naturally-occurring anti-cholesterol titers and an unintended consequence of elevating anti-cholesterol with gp41-MPLA liposomes may prove to be beneficial. (1,2)
Because of the strong immune stimulating properties found in liposomal MPLA, Maytyas and Alving at Walter Reed Army Institute of Research took a look at whether liposomal MPLA elevated naturally occurring antibodies to cholesterol and liposomal-associated phospholipids. Stored for nearly 20 yrs, thawed serum samples from 23 volunteers who received the first liposomal MPLA malaria vaccine exhibited increased levels of antibodies to all the liposomal phospholipids, including the adjuvant, MPLA, as well as cholesterol. (1,3)
In our quest to identify a vaccine strategy directed against HIV, a series of papers have been suggestive that anti-cholesterol reactive antibodies may be players, but the story has yet to fully play out. Elevated titers of naturally-occurring anti-cholesterol -- that preferentially recognize `high-density cholesterol¿ microdomains in membranes and envelopes ¿ are found in HIV patients and anti-cholesterol antibodies were found to reduce the binding of HIV virions to cholesterol-coated plates. Others have found that the broadly neutralizing HIV antibody, 4E10, exhibit anti-cholesterol cross reactivity; unfortunately 4E10 is rare and all attempts to elicit them via current vaccine immunogens have failed. Eliciting adequate titers of anti-cholesterol reactive antibodies may be what is missing. (4-7)
A growing number of studies over the past decade have repeatedly shown that cholesterol is required for HIV to be infectious as demonstrated by cholesterol depletion of either the target host cell or HIV itself. The notion of targeting cholesterol, as well as, its synthesis, trafficking, and protein binding motifs all emerge as likely strategies to reduce HIV infectivity. Cholesterol-rich microdomains serve both as portals for HIV entry as well as a source of cholesterol for HIV to envelope itself upon departure. (8-10)
Boasso and colleagues at Imperial College, Johns Hopkins, and Milan have shown that cholesterol depleted from HIV's envelope prevents the viron from activating plasmacytoid dendritic cells (pDC); in doing so, immunosuppressive HIV-activated pDC is dampened, thereby allowing T cells to fight the virus more effectively. These results suggest that depleting or masking cholesterol-rich microdomains of HIV may be a critical precondition to effectively vaccinate against HIV. (11)
If one assumes that persistent infection maintains a heighten activated state of pDCs, thereby preventing T cell activation by a subunit vaccine, the solution may be as simple as 'two vaccines': the first, to tame the immune response, the second, to re-activate and re-direct it. Until cholesterol-driven pDC activation is eliminated first, T cell vaccination will remain unattainable.
It is tempting to speculate that elevated anti-cholesterol titers renders protection in a step-wise fashion: first, anti-cholesterol would masks HIV¿s cholesterol domains, thereby, dampening immunosuppressive HIV-activated pDC, and second, elevated anti-cholesterol titers would augment anti-gp41 by disrupting virus envelope-cell membrane interactions involved in cholesterol mixing during viron-cell fusion. As anti-cholesterol titers rise, immunosuppression recedes with a calming of the once activated pDC cells and restoration of T cell function. The thought that elevated anti-cholesterol antibody titers masking viron¿s cholesterol-rich microdomains and then synergizing with anti-gp41 by disrupting virus envelope-cell membrane interactions involved in lipid mixing during viron-cell fusion is reasonable.
Many have ascribed a `housekeeping¿ role for naturally-occurring anti-cholesterol antibodies, such as clearing cholesterol-rich VLDL particles. (2) If so, are elevated levels of naturally-occurring anti-cholesterol antibodies in HIV patients an attempt to clear other `cholesterol-rich particles¿? Would boosting anti-cholesterol titers mask HIV¿s cholesterol-driven immunosuppressive of pDC and enhance anti-gp41 subunit vaccine by disrupting virus envelope-cell membrane interactions involved in cholesterol mixing during viron-cell fusion? The gp41-MPLA liposomal vaccine by Katinger et al. provides an opportunity to explore these questions.
1. Green SJ. (2012) Liposomal lipid A adjuvants and naturally occurring antibodies to cholesterol. Vaccine 30(12):2039
2. Green SJ. (2008) Clinical development of TLR agonists as adjuvants: "post-alum adjuvant" candidates may reach beyond their intended purpose. Clin Pharmacol Therapeutic. 83: 813-814
3. Maytyas GR, Alving CR, (2011) Antigen-specific enhancement of natural human IgG antibodies to phosphatidylcholine, phosphatidylglycerol, phosphatidylinositol-4-phosphate, cholesterol, and lipid A by a liposomal vaccine containing lipid A. Vaccine 29: 5137-5144
4. Horváth A, BÃró A (2003) Anti-cholesterol antibodies in human sera. Autoimmun Rev 5: 272-277
5. Beck Z, Balogh A, Kis A, Izsépi E, Cervenak L, et al. (2010) New cholesterol-specific antibodies remodel HIV-1 target cells' surface and inhibit their in vitro virus production. J Lipid Res. 51: 286-96.
6. Haynes BF, Fleming J, St Clair EW, et al. (2005) Cardiolipin polyspecific autoreactivity in two broadly neutalzing HIV-1 antibodies. Science 308: 1906.
7. Matyas GR et al. (2009) Lipid binding properties of 4E10, 2F5, and WR304 monoclonal antibodies that neutralize HIV-1. Biochim Biophys Acta. 1788: 660.
8. Nguyen DH, Hildreth JEK (2000) Evidence for budding of HIV-1 selectively from glycoplipid-enriched membrane lipid rafts. J. Virol. 74: 3264.
9. Ono A, Freed EO (2001) Plasma membrane rafts play a critical role in HIV-1 assembly and release. Proc. Natl. Acad. Sci. 98: 13925.
10. Could a vaccine to cholesterol cause a wrinkle in the HIV-1 envelope? (2009) plosbiology http://www.plosbiology.org/annotation/listThread.action?root=10175
11. Boasso A, Royle CM, Doumazos S, Aquino VN, Biasin M, et al. (2011) Over-activation of plasmacytoid dendritic cell inhibits anti-viral T-cell responses: a model for HIV immunopathogenesis. Blood, 11(19): 5152.
Competing interests
No financial or non-financial interests.