Post a new comment on this article
Post Your Discussion Comment
Please follow our guidelines for comments and review our competing interests policy. Comments that do not conform to our guidelines will be promptly removed and the user account disabled. The following must be avoided:
- Remarks that could be interpreted as allegations of misconduct
- Unsupported assertions or statements
- Inflammatory or insulting language
Why should this posting be reviewed?
See also Guidelines for Comments and Corrections.
Thank you for taking the time to flag this posting; we review flagged postings on a regular basis.close
Could a vaccine to cholesterol cause a wrinkle in the HIV-1 envelope?
Posted by pbio on 07 May 2009 at 22:14 GMT
Author: Shawn J. Green
Institution: Origo Biosciences
Submitted Date: November 16, 2006
Published Date: November 22, 2006
This comment was originally posted as a “Reader Response” on the publication date indicated above. All Reader Responses are now available as comments.
In reminding us of the critical role cholesterol plays in HIV assembly and infectivity, Mujawar, Bukrinksy, Sviridov and colleagues (PLoS Biology 4 (11): e365) suggests that HIV-infection triggers the formation of cholesterol-laden macrophages which contribute to the advancement of atherosclerosis in HIV-infected individuals.
The instigator in HIV-driven atherosclerosis is Nef, a HIV protein required for viral replication and infection. Here, Nef disables the macrophage's cholesterol transporter, ABCA1, thereby, preventing the efflux of cholesterol from HIV-infected macrophages. The dire consequences are two-fold: cholesterol accumulation in HIV-infected macrophages provides a rich source of cholesterol that is necessary for new HIV virion assembly, and two, cholesterol accumulation results in the formation of inflammatory foam cells -- macrophages filled with cholesterol-rich lipid droplets -- which accelerates the progression of atherosclerotic plaques.
In light of this report, a remedy to dampen both HIV-driven atherosclerosis and HIV replication is to increase the cholesterol efflux in HIV-infected macrophages (PLoS Biology 4 (11): e400). Unfortunately, our limited understanding in selectively stimulating cholesterol efflux leaves us with a daunting challenge. However, an alternative anti-HIV strategy is to target membrane cholesterol itself.
The idea of targeting cholesterol in HIV is not without merit. A series of studies have clearly shown that cholesterol is required for HIV to be infectious as demonstrated by cholesterol depletion of either the target cells or HIV itself.
Using various compounds to change cholesterol levels, such as beta-cyclodextrin, cells become resistant to HIV infection or released non-infectious HIV particles [1,2]. Cholesterol's pivotal role is further implicated in lipid raft diseases, which are characterized by membrane surface microdomains rich in phospholipids and/or sphingolipids and cholesterol; lipid rafts reportedly serve as portals of entry for various toxins, particles, and pathogens, such as HIV-1, among other viruses. Assuming cholesterol is a critical component in these lipid rafts, could anti-cholesterol antibodies be a membrane disruptor as cholesterol is being incorporated, rearranged, and concentrated into the HIV envelope?
Although data is limited on the lipid rearrangement of cholesterol and phospholipids within the HIV envelope during budding, binding, and fusion, it is tempting to speculate that switching of cholesterol from the mammalian cell membrane to the virus envelope renders cholesterol immunogenic [3,4]. Numerous reports, over the past 80 years, have shown that anti-cholesterol antibodies, as well as, other anti-lipid and anti-phospholipids, can be induced in animals with beneficial outcomes. In pre-clinical studies, vaccination against cholesterol has resulted in high titers of anti-cholesterol antibody levels with a significant reduction of both diet-induced hypercholesterolemia and atherosclerotic lesions [3-8].
In humans, anti-cholesterol antibodies are elevated in HIV patients and anti-cholesterol serum reduces the binding of HIV virions to cholesterol-coated plates [3,4]. Although the role of naturally-occurring anti-cholesterol antibodies remains unclear, these antibodies have been suggested to play a regulatory or "housekeeping" role in clearing harmful oxidized cholesterol and cholesterol-rich particles, such as LDL and VLDL, from circulation [5,6]. If so, are elevated levels of naturally-occurring anti-cholesterol antibodies in HIV patients an attempt to clear virion particles? Would boosting anticholesterol have a beneficial outcome by reducing viral load and plaque formation?
Interestingly, the prerequisite for induction and binding of anti-cholesterol antibodies resides in increased cholesterol density, thereby, exposing cholesterol-rich microdomains on the membrane surface [6,9,10]. In healthy cells, cholesterol is somewhat cryptic and no such microdomains exist; instead, it is buried between the towering phospholipids that make-up the lipid membranes. However, by creating high density cholesterol liposomes, cholesterol was rendered immunogenic in the presence of the adjuvant, monophosphoryl lipid A [9,10]. Immunoreactive serum and a monoclonal antibody to cholesterol were found to react with membranes vesicles containing high density cholesterol consisting of >50 mole percent cholesterol. These observations partially explain why healthy mammalian cells, HDL, and low-density cholesterol-containing liposomes are protected from these antibodies, while LDL, VLDL, Mycoplasma, and high-density, cholesterol-rich liposomes are highly reactive to anti-cholesterol antibodies resulting in membrane destabilization [6,11]. In like fashion, the possibility exists that high-density, cholesterol-rich microdomains are found on infectious HIV-1 particles during budding, binding, and fusion; if so, HIV particles may be acutely sensitive to anti-cholesterol and other anti-phospholipid antibodies.
In our quest to identify a vaccine strategy directed against HIV-1, the unexpected observation by Haynes et al. revealed that the two broadly neutralizing human antibodies, 2F5 and 4E10, both have binding specificities directed towards phospholipids, including cardiolipin, phosphatidylserine, and other neutral phospholipids . Such observations provoke us to examine the merits of targeting lipid microdomains, in particular, those enriched with cholesterol, cholesterol oxides, and certain phospholipids uniquely displayed in the HIV envelope.
On a closing note, would a vaccine to cholesterol reduce the development of atherosclerosis in HIV-patients similar to that reported in hypercholesterolemic models? Are high-density, cholesterol-rich microdomains potential targets of HIV-1 during budding, binding, and fusion? If so, it may be worthwhile to consider "high-density, cholesterol-rich microdomains" as part-of-the-mix in designing a successful vaccine strategy against HIV-1 and HIV-driven atherosclerosis.
1. Nguyen DH, Hildreth JEK. (2000) Evidence for budding of HIV-1 selectively from glycoplipid-enriched membrane lipid rafts. J. Virol. 74, 3264.
2. Ono A, Freed EO. (2001) Plasma membrane rafts play a critical role in HIV-1 assembly and release Proc. Natl. Acad. Sci. 98, 13925.
3. Horvath, A., Biro A. (2003) Anti-cholesterol antibodies in human sera. Autoimmunity 2: 272.
4. Horvath A, Fust G. et al. (2001) Anti-cholesterol antibody levels in patients with different atherosclerotic vascular diseases. Characterization of human anticholesterol antibody. Atherosclerosis. 156:185.
5. Cheng HM, Sundram, K. (1999) Oxidized LDL, diet, and natural antibodies. Am. J. Clin. Nutr. 70: 104.
6. Dijkstra J, Swartz GM, Jr, Raney JJ, Aniagolu J, Toro, Green SJ. (1996) Interaction of anti-cholesterol antibodies with human lipoporteins. J. Immunol. 157, 2006.
7. Alving CR, Swartz GM Jr, Wassef NM, Ribas JL, Herderick EE, Virmani R, Kolodgie FD, Matyas GR, Cornhill JF. (1996) Immunization with cholesterol-rich liposomes induces anti-cholesterol antibodies and reduces diet-induced hypercholesterolemia and plaque formation. J Lab Clin Med.127:40-9.
8. Ordovas JM. (1996) Anticholesterol antibodies and plaque formation. Nutr Rev. 54:124.
9. Swartz GM Jr, Gentry MK, Amende LM, Blanchette-Mackie EJ, Alving CR. (1988) Antibodies to cholesterol. Proc Natl Acad Sci U S A. 85:1902.
10. Alving CR. (2006) Antibodies to lipids and liposomes: immunology and safety.
J Liposome Res. 16:157.
11. Agirre, A., et al. (2000) Induction of aggregation and fusion of cholesterol-containing membrane vesicles by an anti-cholesterol monoclonal antibody. J Lipid Res. 41: 621.
12. Haynes BF, Fleming J, St Clair EW, et al. (2005) Cardiolipin polyspecific autoreactivity in two broadly neutalzing HIV-1 antibodies. Science 308, 1906.