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[SANET-MG] tobacco with a transgene to control AIDS
August 11, 2006
Prof. Joe Cummins
Tobacco modified with a transgene to control AIDS
There are currently 20 anti-human immune deficiency virus (HIV)
drugs licensed for clinical use. The licensed drugs fall into five
catagories: nucleoside reverse transcription inhibitors, non-nucleoside
reverse transcription inhibitors, protease inhibitors and fusion
inhibitors (such inhibitors prevent fusion of vial and cell membranes
preventing viral entry into the cell). There are at least thirty drugs
in clinical trials (I,II or III). Among these is compound cyanovirin-N
a topical anti HIV microbiocide applied as a cream to vagina or
anus(1,2). Results of a phase I clinical tial of cyanovirin-N was
reported in 2006., 36 sexually abstaining women were tested in a double
blind study showing that cyanovirin-N gels did not have undesirable
side effects and retained protective levels of the biocide for at least
12 hours (3). Cyanovirin-N was first isolated from the from the
cyanobacterium, Nostoc, it is a peptide of 101 amino acids it is
resistant to degradation. It binds to N-linked mannose glycans such as
those found on the HIV gp120 surface protein (4,5). Cyanovirin-R also
prevents hepatitis C virus entry into cells (6).
Intravaginal and intrarectal biocides provide a relatively
inexpensive way of preventing AIDS transmission . Condom use prevents
spread of AIDS but use of such devices is erratic and not well suited
for poor counties. Microbiocides such as cyanovirin-R may be widely
distributed at relatively little cost and effectively control spread of
AIDS (7,8).
Production of cyanovirin-N has required recombinant
technology , first by production in recombinant microbes and later
using recombinant plants. Before describing the recombinant microbes
used to produce cyanovirin-N , the plant system will be discussed. The
patent for a DNA sequence producing a glycosylation resistant form of
cynaovirin-N protein (created by deleting 3 amino acid codons from the
native gene was assigned to the USA Deaprtment of Health and Human
Services)(9). That patented sequence was used to modify tobacco
plants. The modified tobacco contained a cauliflower mosaic virus 35S
promoter , a short mouse antibody (IgG) leader sequence to direct the
recombinant protein to endomembrane system and genes for resistance to
the antibiotics spectomycin and kanomycin, along with a nopaline
transcription terminator seuqence. Recombinant tobacco plants grown in
hydroponic solutions excreted cyanovirin-N into the culture medium. The
tobacco plants produced up to 130ng cyanovirin-N/mg of leaf tissue
(1.3g/Kg). The transgenic plants are expected to provide a high level of
microbiocide production at a relatively low cost (10).
It is worth pointing out that the tropical plant Dorstenia
contrajera a tropical plant used in traditional medicine was found to
produce a strong anti-HIV peptide as did the tropical plant Treculia
obovoidae (related to African breadfruit) (11). Such indigenous plants
can be used to produce anti-HIV biocides immediately and in doing so
can provide work for indigenous farmers. Lectins (sugar binding
proteins) from Hippeastrum hybrid (Amaryllis) and Galanthus nivalis
(snowdrop) were also found to potently inhibit HIV infection (12). Such
wild plants could provide a source of livelihood for indigenous
farmers while serving to alleviate the AIDS epidemic in developing
countries.
Turning to the use of recombinant bacteria to produce
cyanovirin-N , the recombinant bacterium Escherichia coli (E coli)
provides a means of mass producing cyanovirin-N in liquid culture (13).
Recombinant vaginal Lactobacilli for mucosal delivery of cyanovirin-N
have been developed. A human isolate of Lactobacillus jenenii was
modified with the cyanovirin-N gene to produce a biocide capable of
colonizing the human vagina. The live microbiocide is capapble of
producing a very inexpensive and stable protection against HIV infection
in women (14,15). A commensal bacterium Streptococcus gordonii was
modified with a cyanovirin-N gene and provided a system to deliver and
maintain an HIV biocide to the vaginal mucosa (16). As an alternative
approach, a portion of the HIV envelope glycoprotein (Env) protein
known to neutralize the activity of HIV was introduced into a
colonizing strain of E. coli. It blocks HIV entry by interfering with
the conformational changes that drive the membrane fusion mechanism for
HIV entry (17). Colonizing bacteria modified to become virus specific
microbiocides provide a possible long term protection from HIV infection
Inexpensive microbiocides offer a global solution to the
spread of HIV-AIDS to both men and women. Recombinant micro biocides ,
though appealing, are not yet tested adequately . In contrast , biocide
containing tropical plants have been used as folk remedies for ages. A
global strategy for implementing use of microbiocides to limit spread
of HIV is likely to fail unless it is based on diverse biocides.
Medicinal tropical plants shown to contain effective biocides can be
cultivated by indigenous farmers and the product distributed through
a local community at little cost and compelling immediacy. Once tested
adequately the colonizing microbial biocides may prove effective
provided that diversity to cope with viral mutation is respected. The
tobacco based recombinant cyanovirin-N based biocide is being promoted
to be a way of revitalizing the flagging tobacco industry. However, the
system is not yet tested adequately and lacks the diversity required
for long term AIDS protection. Implementing the use and global
distribution of microbiocides should be based on common sense , not on
corporate greed and public relations alone.
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