Firstly, let me add my enthusiastic support to the views already expressed
by others for Valerie's valiant persistence and determination in pursuing
investigations on the patenting of components in human milk.  I am so glad
she is doing this, and hoping so hard that she is documenting it all
meticulously.  We all have our areas of special interest, and cannot have
the energy and time it takes to explore each avenue as thoroughly as it
deserves.  Of necessity, we have to depend on others to pursue these other
vital lines of enquiry, and this is one of the strengths of Lactnet - the
pooling of so much diverse expertise.

Secondly, Arly's recent post is the catalyst for this message, although
Valerie's discoveries have been noted and deeply appreciated for several
years.  Arly tells us about the recent startup company called Glycosyn,
founded by researcher David Newburg, to develop products synthesized from
the active components in human milk for future clinical applications.  This
re-reminded me all over again of the bewilderment I felt almost a decade
ago now  (at the start of looking at a topic which has since become my
special interest) at the inexplicable reaction of the world's policy-makers
to the apparent discovery that although HIV could be passed in breastmilk,
transmission was not consistent.  In fact, there seemed almost to be a
systematic exclusion of research showing that breastmilk might also contain
several important protective components.  Glycosamines would be one, as the
name of the above company, suggests.  The Human Milk Fat Globule is
another.  Time, and others' sleuthing, particularly Valerie's, have
subsequently helped to explain what might have happened.

In late 1995 circumstances eventually forced me to acknowledge that HIV was
posing a problem for breastfeeding promotion, and that I needed to look up
some of the literature.  In my ignorance, I thought I could get hold of a
few articles (as we do ....) synthesize a quick overview and provide an
"informed" sort of answer for a mother who needed to know whether she
should follow her doctor's advice to wean her eight-month-old
overnight.  Well!  The more I found, the more I realized that one answer
only led to a thousand more questions.  The subject was like a maze, going
round in circles and, for some inexplicable reason, the most promising
lines of enquiry - research which suggested that the components of human
milk itself would have antiviral effects - seemed to come to nothing, Why
was this?  Well ... what Valerie, and others have since discovered, seems
to provide an answer.  With the tincture of time, it seems not outside the
bounds of possibility that research results were diverted - not so that
breastmilk could be promoted for the protective effects it would confer on
the babies of HIV-infected mothers, but so that the components of
breastmilk could be isolated, synthesized and replicated as
formula-additives and/or pharmaceutical products, for commercial gain
-  while breastfeeding itself was demonised as a "significant" transmitter
of the virus.

Hindsight is always such a good thing, isn't it?  It sometimes points to
what evidence has been accumulating while we were napping.  The name
Newburg popped out at me. There are probably other names that we have
ignored, at our peril. Isaacs is certainly another.  By 1999 I finally
managed to get some of the questions down on paper in a semi-coherent
fashion;  here is a little excerpt from an article I wrote for
Breastfeeding Review about some of the antiviral research, citing Newburg
and others, which may be of interest to show how long some of these plans
for patents may have been germinating. Please note I have made a small
amendment [in square brackets] to correct an error in the original text
describing Newburg's research..

*********************
....PROTECTIVE PROPERTIES OF HUMAN MILK AGAINST HIV
..... Some milk factors may be specifically protective against postnatal
transmission of HIV.  Anti-HIV IgG and IgA antibodies have been identified
in colostrum from HIV+ women, but not from HIV- women. (Duprat et al,
1994).  Van de Perre et al (1993) suggest that HIV-1 IgM in breastmilk
could be protective against postnatal transmission of the virus  in three
ways (a) by compensating  for a defective secretory IgA response and
behaving in a similar way by directly coating viral particles, (b) that IgM
antibodies are strong potentiators of complement-mediated cytotoxicity, of
which at least nine components have been identified in human milk, and (c)
specific IgM could take part in the lysis of infected cells by a mechanism
of antibody-dependent lymphocyte cytotoxicity.  Human milk also contains
a  ...[glycosamine]  ... which is able to inhibit the binding of HIV [gp
120] to CD4,  which may block the first step that is critical for infection
of a target cell.   This inhibitory activity was found in colostrum and
mature milk samples from both HIV+ and HIV- populations of women. (Newburg
1992 and 1995)

.....ANTIVIRAL PROPERTIES OF HUMAN MILK
In the 1960s and 1970s a number of researchers looked at the antiviral
properties of breastmilk, which showed the dual nutritional and antiviral
role of lipids (Arnold 1993, Kabara 1980).   Lipid components that
inactivate enveloped viruses were described.  (Sarkar et al 1973, Welsh et
al 1979). In the late 80s and early 90s other researchers continued these
investigations. They looked at the inactivation of enveloped viruses by
different classes of free fatty acids in milk.   The most active free fatty
acids were the polyunsaturated long-chain fatty acids (C16-C22) and the
medium-chain saturated fatty acids (C10 - C14),  monoglycerides of  these
fatty acids being the most active, sometimes at concentrations much less
than the corresponding free fatty acids (Isaacs et al 1986, Thormar et al
1987, Orloff  et al 1993).

The fatty acids were found to affect the viral envelope, causing leakage
and, at higher concentrations, a complete disintegration of the envelope
and the viral particles.  They also caused disintegration of the plasma
membranes of tissue culture cells resulting in cell lysis and death.   All
enveloped viruses exposed to antiviral milk lipids or milk stomach contents
were inactivated, including vesicular stomatitis virus (VSV), herpes
simplex virus type 1 (HSV-1),  visna virus and HIV-1.  The antiviral
activity, which reduced titers of virus by as much as 10 000-fold only
affected enveloped viruses and was localized in the milk lipid
fraction.  Its appearance in stored milk was apparently due to fatty acids
released by the activity of milk lipases, particularly lipoprotein
lipase.  Antiviral activity in the infants' stomach most likely resulted
from the activity of gastric and lingual lipases on milk triglycerides and
caused the release of antiviral fatty acids.    Milk and stomach contents
that were antiviral also lysed cultured cells by disruption of their plasma
membrane.  Cell lysis was also caused by purified linoleic acid, which is a
normal constituent of human milk triglycerides.  (Isaacs,  l986).  The
HIV-1 inactivating property is heat stable and remains after heating at
temperatures consistently used by milk banks    (Orloff, 1993). Nduati et
al (1995)  note that culture detection of replicating HIV-1 virus in
breastmilk remains a challenge because of inhibitory factors in human milk.

........McDougal (1990) noted the antiviral activity of  milk lipids
against HIV in spiked milk samples that sat on the counter as controls
while other samples were being heat-treated.   Orloff (1993) noted that
input HIV-1 titer  could not be recovered from control human milk
preparations that were innoculated with HIV, but not heated.  He states
that this was due to inactivation of HIV-1 infectivity by the human milk,
rather than to cellular toxicity or interference with detection of viral
replication.  Isaacs and Thormar  (1990) state that the appearance of this
antiviral activity is lipoprotein-lipase dependent and occurs only in
stored milk in which the lipase has had a chance to break lipids down into
free fatty acids.  The activity of the free fatty acids is cumulative (the
more that are present, the more effective the antiviral activity) and viral
killing is rapid when the free fatty acids come into contact with the
envelope of the virus.  In cases such as HIV infection, in which the virus
may be found in the acellular fraction of the milk as well as the cellular
fraction, these antiviral lipids may reduce the risk of viral transmission
by destroying the free virus.  Milk concentrations as low as 10% had some
anti-viral activity. Titer reduction occurred rapidly, within 5 - 10
minutes and was more efficient at 37 degrees C and 22 degrees C than when
HIV-1 was mixed with milk at O degrees C (Orloff , Wallingford & McDougal
1993).   Although the study was done to assess the effectiveness of  Holder
pasteurization in destroying the HIV virus in  human milk, the researchers
stated that the magninitude of inactivation cannot be attributable to heat
alone although required concentration for maximum viral inactivation
varies......

  Refs:
Arnold LDW 1993,   Currents in Human Milk Banking,: HIV and Breastmilk:
What it means for milk banks. J Hum Lact 9(1): 47-48.

Isaacs, CE and Thormar, H;  Human milk lipids inactivate enveloped
viruses.  In Atkinson, SA, Hanson, LA and Chandra, RK, eds: Breastfeeding,
nutrition, infection and infant growth in developed and emerging countries,
St John's Newfoundland, Canada, 1990, ARTS Biomedical Publisher,
Canada:161-174.

Isaacs C, Thormar H, Pessolano T. 1986. Membrane-disruptive effect of human
milk;  inactivation of enveloped viruses. J Infect Dis 154:966-71.

Kabara JJ 1980, Lipids as host-resistance factors of human milk.  Nutr Rev
38:65-73.

McDougal JS, Martin LS, Cort SP, et al 1985, Thermal inactivation of the
acquired immunodeficiency syndrome virus, human T lymphotropic virus
III/lymphadenopathy-associated virus, with special reference to
antihemophilic factor. J Clin Invest 76:875-7.

Newburg, DS & Yolken  RH 1992, Anti-HIV components of human milk, in
Picciano MF, Lonnerdal B: Mechanisms regulating Lactation and Infant
Nutrient Utilization.  New York: Wiley-Liss:189-210.

Newburg, D et al 1995,  Human milk glycosaminoglycans inhibit HIV
glycoprotein gp 120 binding to its host cell CD4 receptor. J Nutr 125:419-24.

Newburg DS, Viscidi RP, Ruff A, Yolken RH 1992,  A human milk factor
inhibits binding of human immunodeficiency virus to the CD4
receptor.  Pediatr Res 31(1):22-28.

Sarkar NH, Charney J, Dion AS, Moor DH 1973,  Effect of human milk on the
mouse mammary tumor virus. Cancer Res 33:626-29.

Thormar H, Isaacs CE, Brown HR, Bashatzky MR, et al 1987,  Inactivation of
enveloped viruses and killing of cells by fatty acids and monoglycerides.
Antimicrob Agents Chemother 31:27-31.

Welsh JK, Arsenakis M, Coelen RJ et al 1979,  Effect of antiviral lipids,
heat and freezing on the activity of viruses in human milk. J Infec Dis
140:322-28.

*********************

Pamela Morrison IBCLC
(formerly in Zimbabwe, now Australia)

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