Did Africans get HIV from chimps?

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제목 [AIDSHIVinASIAandAFRICAalternatives] Did Africans get HIV from chimps?
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http://www.rethinkingaids.com/Archive/1999/RA9908EleniOnMonkeys.html
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VOLUME 7, NUMBER 8 RETHINKING AIDS www.rethinkingaids.com AUGUST
1999
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Did Africans get HIV from chimps?
Not likely, asserts biophysicist Eleni
Papadopulos-Eleopulos in her latest paper rejected by Nature

The science journal Nature continues its de facto policy of rejecting
all submissions that question the HIV-causes-AIDS model. Its editors
recently rejected the following commentary composed by the AIDS
research team headed by Australian biophysicist Eleni Papadopulos-
Eleopulos.

The rejected article addresses a recently published letter by
scientists who claimed to have discovered the original human source
of HIV: a simian "immunodeficiency" virus (SIV) newly identified (by
them) from a particular subspecies of African chimpanzees. The
authors declared that the genetic sequencing of their new SIV closely
resembles that of HIV. And since the chimpanzees live in the same
region as some humans who test "HIV-positive," the authors concluded
that the humans there somehow contracted HIV (or what became HIV)
from those chimpanzees.

Not so fast, say the Australians. The published authors presented no
evidence that they had isolated any virus, so there's no basis for
claims of a new viral species or a viral genome. Nor did they
demonstrate a close similarity between the perported SIV and HIV gene
sequences. To the contrary, the published sequences differed
significantly. As for the possibility of trans-species transmission,
the Australians note that none of the presumably infected chimpanzees
had managed to transmit the purported virus to their own children or
sex partners.

Most scientists consider Nature the world's leading research
publication. Papadopulos-Eleopulos's carefully argued letter typifies
the high quality of dozens of AIDS reappraising submissions,
including several of hers, that Nature has rejected over the years.
and the sloppy, implausible letter she criticizes exemplifies the
poor quality of the dozens of pro-HIV submissions Nature publishes
each year. A comparison of the two suggests that when Nature's
editors consider the topic of AIDS, they practice poor judgment and
censorship. -- Editor


IN A LETTER to Nature (Feb. 4), Gao et al .claimed to have proven:

(i) the existence of a new simian immunodeficiency virus (SIVcpz), in
a chimpanzee, by identifying the virus's genome;

(ii) that the chimpanzees in which his group found this SIV belong to
a certain subspecies, P.t. troglodytes (their chimpanzee, Marilyn, as
well as two of the other three chimpanzees in which to date a SIVcpz
was reported, GAB1 and GAB2);

(iii) that these chimpanzees live in the same area of Africa with
humans who are said to be infected with certain genetic groups of HIV
("the natural range of P.t. troglodytes coincides uniquely with areas
of HIV-1 group M, N and O endemicity");

(iv) the humans there acquired their HIV from the chimpanzees ("HIV-1
infection of humans occurred as a result of cross-species
transmission of SIVcpz from P.t. troglodytes"); and

(v) those chimpanzees are the original source for humans of HIV
("P.t. troglodytes is the primary reservoir for HIV-1").

A close analysis of the evidence on which Gao's group bases its
claims raises several issues that contradict those claims:

(a) Marilyn was "wild-caught in Africa (country of origin unknown),
exported to the United States as an infant." [1]
Two of the chimpanzees, GAB1 and GAB2, originated in Gabon. GAB1, who
was 4 years old when reported HIV-1 positive, was caught when she
was "about 6 months" and was kept with another 49 wild-caught animals
at the International Centre of Medical Research (CIRM) in Gabon.
GAB2, who was also reported HIV-1 positive, was about 2 years old
when she was shot in the wild, kept in a village for 2 days and then
was brought to CIRM, "where it died of its wounds one week later." [2]

In the 1989 study, where the "HIV-1 seropositivity" of GAB1 and GAB2
was reported, the authors (which included one of Gao's co-authors,
Peeters) concluded: "...on examination, none of the people caring for
the animals and none of those living in the village showed antibodies
to HIV/SIV. Furthermore, the region where the chimpanzee was captured
is known to have a low seropreval‎ence rate.... It has been suggested
that human AIDS retroviruses originated from monkeys in Africa.
However, this study and other previous studies on SIV do not support
this suggestion." In other words, by the time that "HIV infection"
and AIDS had already reached their peaks in the US, Europe, and
Australia, the number of individuals proven HIV seropositive in Gabon
were few if any.

A 1990 study published in Nature by researchers from CIRM and the
Pasteur Institute, including Wain-Hobson, where the authors
described "the molecular cloning and sequencing" of SIVcpzGAB1,
states: "In Gabon, only 2 out of 83 chimpanzees tested were
seropositive, indicating that SIVCPZ is not widely dispersed in this
region.... Of more than 250 chimpanzees caught over the last 15-20
years in West Africa, none was seropositive. This might explain the
absence of naturally infected chimpanzees in captivity in the US as
virtually all are of West African origin." [3]

How is it possible to espouse "preval‎ence in the natural
host," "geographic coincidence," and "plausible routes of
transmission" as evidence to substantiate the claims that HIV-1
originated in P.t. troglodytes and that this sub-species is the
natural reservoir for HIV-1?

(b) The three P.t. troglodytes -- GAB1, GAB2 and Marilyn -- were said
to be infected with HIV-1/SIVcpz on the basis of an antibody test.
However, given that:

(i) as Philip Mortimer points out, "...it may be impossible to relate
an antibody response specifically to HIV-1 infection." [4]
(ii) when the blood was collected none of the animals was perfectly
healthy although none had AIDS.
(iii) the only way to prove the specificity of an antibody test is to
use the virus isolation as a gold standard. Although no effort has
been spared, no SIVcpz could be isolated either from GAB2 or Marilyn
(see comments below for GAB1).

(c) How is it possible to claim proof for infection on the basis of
an antibody test?


(i) If GAB1 and Marilyn were infected then, given that the animals
were brought to the colony as infants where no other animals or
humans working there were infected and, according to
Weiss, "Chimpanzees in captivity are mostly taken from the wild
before they become sexually active and so rarely harbor SIV," how did
these two chimpanzees become infected? [5]


(ii) Since the three chimpanzees found positive were all female, and
since HIV/SIV is acquired following sexual maturity, how did they
become infected?


(iii) If the animals were infected with a virus SIVcpz and this was
transmitted to humans, why was this not transmitted to any other of
the 49 animals at CIRM where GAB1 was kept or to the 93 animals in
the colony where Marilyn was kept, not even to her 6 living offspring
or her mates? (By the age of 26 she had a total of 14 pregnancies).
[6]

(d) The additional "lines of evidence" that Gao used to substantiate
transmission are based on genomic studies. Gao claimed to have shown
that "All HIV-1 strains known to infect man, including HIV-1 groups
M, N, and O, are closely related to just one of these SIVcpz
lineages, that found in P.t. troglodytes." Indeed, if all these HIV-1
and SIVcpz strains represented one and the same virus, then their
genomes will have to be "closely related." In fact they should
represent a unique molecular entity. Even in the genomes of RNA
viruses, including influenza, which are considered to be most
variable, a 1% sequence difference is considered to
represent "extreme variability." [7] This is because small genetic
differences lead to significant phenotypic differences. For example
the difference between the human and the chimpanzee genome is less
than 2%.


In the 1989 study of SIVcpzGAB1 Peeters wrote: "Nucleic acid
hybridization experiments appear to indicate that the virus is
different from HIV-1 and HIV-2." A 1990 Nature paper by researchers
from CIRM and the Pasteur Institute, including Wain-Hobson,
states: "Several regions of the chimpanzee sequences were more than
50% divergent with respect to HIV-1BRU. Some parts of the gag gene
were almost as varied as the hypervariable regions in env.... The vpu
gene found only in the type 1 viruses was particularly different (64%
divergent to HIV-1BRU).... It is also apparent that the SIVCPZ genome
was not simply a more diverged HIV-1 isolate.... It is not possible
to conclude that SIVCPZ was the precursor to HIV-1, if indeed
infection ever passed in that direction. Even given this premise the
vpu data indicates that SIVCPZ was not the immediate precursor." [3]


In a 1994 study of the SIVcpzGAB2, Peeters wrote: "The genetic
distance between SIVcpz-gab [SIVcpz GAB1) and SIVcpz-gab2 is 14.1%.
Genetic distances to the HIV-1 genotypes A, B and D strains are 13.7
to 16.3%, whereas distances to group O HIV-1 strains are 15.4 to
18.5%." Contrary to Gao, in 1994 Peeters concluded: "On the basis of
their respective distances to each other and to the HIV-1 strains,
SIVcpz-gab and SIVcpz-gab2 can be assigned as representative for two
distinct genetic lineages of HIV-1-related chimpanzee lentiviruses."
[8]


By 1993 it was reported that "in the A-G HIV-1 genotypes the intra-
genotypic gag distances averaged 7%, whereas the inter-genotypic
distances averaged 14%.... The maximum level of variability in gag is
still well below that observed for the envelope region of HIV-1." [9]


The HIV-1 group O has "65% similarity to HIV-1 and 56% similarity to
HIV-2 consensus sequences. The env gene of MVP-5180 [HIV-1 group O]
had similarities to HIV-1 and HIV-2 of 53 and 49% respectively....
Comparison of the MVP-5180 amino acid sequences with that of the
Gabon chimpanzee virus showed similarities of 70, 78 and 53% in the
gag , pol and env genes, respectively." [10]


As far as the genomic differences between HIV-1 group N, on the one
hand, and group M and O on the other is concerned, it suffices to
quote from the 1998 study where its existence was first
reported. "Proviral DNA amplification with several sets of HIV-1
group M and O primers was attempted on pelleted end-cultured cells.
Amplification was negative with eight different group M env, gag or
pol primers and five group O env or gag primers." [11] How is it
possible to claim proof for the existence of a unique molecular
entity which constitutes the genome of a unique retrovirus HIV-
1/SIVcpz?

(e) The only way to prove that an RNA (and its cDNA) is the genome of
a retrovirus is to demonstrate that it comes from a retrovirus
particle and such RNA codes for its proteins. This can be done only
by obtaining the particles separate from everything else, purifying,
isolating them. [12]


In the 1989 study, where Peeters reported the isolation of
SIVcpzGAB1, stimulated peripheral blood lymphocytes "from healthy
human donors" were co-cultured with the same type of cells from the
chimpanzees. Supernatant from the co-culture was centrifuged for 10
minutes at 400.000g. Detection in the pellet of reverse transcriptase
activity, using An(dT) [12-18] as template primer, was considered
proof for SIVcpzGAB1 isolation. Such a method for viral isolation is
no different from claiming that elevations in serum liver enzymes
proves the existence of gallstones and, moreover, that the gallstones
have been isolated from the patient and are in the surgeon's hands
separate from everything else. The SIVcpzGAB1 "genome" was obtained
either by hybridizing the RNA present in the pellet (they presented
no proof that the pellet contained even retrovirus-like particles),
where one would expect to find ample cellular RNA, with probes "from
HIV-1oyi, a Gabonese HIV-1 strain," or from "SIVCPZ-infected human
lymphocytes," again using HIV-1oyi as a probe. The "genome" thus
obtained was compared with the genome of HIV-1BRU.


We could find no details as to how the HIV-1oyi "genome" was
obtained. HIV-1BRU is the "HIV-1" which, according to Weiss,
was "discovered by Barre-Sinoussi and her colleagues in 1983." The
senior author of the 1983 Barre-Sinoussi study, Luc Montagnier, in
1997 not only acknowledged that they did not isolate HIV-1BRU, but
their "pure" virus from where they chose some RNA and called it HIV
RNA, did not even contain particles with "morphology typical of
retroviruses." [13]
The only evidence ever presented as proving the existence of the
SIVcpzGAB2 genome was reported by Peeters and his associates. They
write: "From this chimpanzee we have been unable this far to isolate
a lentivirus, but some of the primary peripheral blood mononuclear
cells (PBMCs) have remained available in a frozen state. To
investigate the genetic relationship to the SIVcpz-gab isolate
[SIVcpzGAB1], proviral DNA was extracted from these primary PBMCs [no
mention is made how it was possible to extract the proviral DNA from
the chimpanzee DNA], and a 280-base pair (bp) fragment of the pol
gene was amplified by a nested polymerase chain reaction (PCR).
Subsequently, PCR fragments were cloned and sequenced." [8] No
mention is made as to how they obtained the PCR primer. Gao et al
used "consensus sequences" as primers and the following method: "Here
we used the polymerase chain reaction (PCR) to amplify HIV- or SIV-
related DNA sequences directly from uncultured (frozen) spleen and
lymph-node tissue obtained at autopsy in order to characterize the
infection responsible for Marilyn's HIV-1 seropositivity.
Amplification and sequence analysis of subgenomic gag (508 base pairs
(bp)) and pol (766 bp) fragments revealed the presence of a virus
related to, but distinct from, known SIVcpz and HIV-1 strains.
Because virus isolation from the autopsy tissues was unsuccessful, we
used PCR to amplify and sequence four overlapping subgenomic
fragments that together comprised a complete proviral genome, which
we termed SIVcpzUS."


However,

(i) The specificity of the PCR for HIV has never been proven. The
only way to obtain such proof is to use virus isolation as a gold
standard. Even if one accepts the claims for SIVcpzGAB1 isolation, it
is agreed that, although no effort has been spared, SIVcpz could not
be isolated from the other two animals. This means that the PCR
results obtained for the genomes of SIVcpzGAB2 and SIVcpzUS are false.

(ii) Even if they were specific for retroviruses; given that:
(a) The genome of all humans and animals contain retroviral
proviruses, i.e., genomes of the endogenous retroviruses. [14]
(b) There are homologies between the genomes of different
retroviruses, especially in the gag and pol genes. In fact, according
to Montagnier and Wain-Hobson, the gag and pol genes "are generally
conserved among retroviruses." [15]
(c) In not one of the studies which claimed proof for the existence
of the SIVcpz genomes did the authors use controls.

(iii) How is it possible to claim that the sequences detected in the
DNA "of SIVcpz-infected human lymphocytes," the PBMCs of GAB2 and in
Marilyn's "spleen and lymph-node tissue" were those of an exogenous
retrovirus which is transmitted from one chimpanzee to another and
from chimpanzee to humans and not those of an endogenous retrovirus?

(iv) Since there is no proof that the three chimpanzees ever came in
contact with HIV-1-infected humans or animals or that they
transmitted such a virus to other humans or animals, is it not
more "plausible" to conclude that if these animals did harbor a
retrovirus, the retrovirus was endogenous?In analyzing the "SIVcpz"
molecular biology one cannot help reflecting upon the words of Sir
John Maddox, "Is there a danger, in molecular biology, that the
accumulation of data will get so far ahead of its assimilation into a
conceptual framework that the data will eventually prove an
encumbrance? Part of the trouble is that the excitement of the chase
leaves little time for reflection. And there are grants for producing
data, but hardly any for standing back in contemplation." [16]

Signed,
Eleni Papadopulos-Eleopulos (1)
Valendar F. Turner (2)
John M. Papadimitriou (3)
David Causer (Senior Physicist) (1)
Bruce Hedland-Thomas (1)
Barry Page (1)
Charles Geshekter (4)
Etienne DeHarven (5)
Helman Alphonso(6)
Todd Miller (7)

1) Dept of Medical Physics, Royal Perth Hospital, Western Australia.
bruce.hedland-thomas@rph.health.wa.
gov.au;
2) Dept. of Emergency Medicine, Royal Perth Hospital, Western
Australia;
3) Dept of Pathology, University of Western Australia;
4) Dept. of History California State University, Chico, California;
5) Professor (Emeritus) of Pathology, University of Toronto, Canada.
6) Head, Department of Research, Universidad Metropolitana
Barranquilla, Colombia
7) Assistant Scientist,Department of Molecular and Cellular
Pharmacology, University of Miami School of Medicine, Florida, USA


Eleni Papadopulos-Eleopulos, Biophysicist, Department of Medical
Physics, Royal Perth Hospital, Wellington Street, Perth 6001, Western
Australia.
www.virusmyth.com/aids/perthgroup;vturner@cyllene.uwa.edu.au

REFERENCES
1. Gao, Nature 397, 436-441 (1999).
2. Peeters, Aids 6, 447-51 (1992).
3. Wain-Hobson, Nature 345, 356-9 (1990).
4. Mortimer, Med. Internat. 56, 2334-2339 (1989).
5. Weiss, Nature 397, 385-386 (1999).
6. Gilden, Lancet i, 678-679 (1986).
7. Steinhauer, Annual Rev. of Microbiology 41, 409-433 (1987).
8. Janssens, AIDS Res. and Human Retrov. 10, 1191-2, 1994.
9. Louwagie, AIDS 7, 769-780 (1993).
10. Gurtler, Journal of Virology 68, 1581-5 (1994).
11. Simon, Nature Medicine 4, 1032-7 (1998).
12. Toplin, Spectra , 225-235 (1973);
13. Tahi, Continuum 5, 30-34l; 1998 (available at:
www.virusmyth.com /aids/ data/dtinterviewlm.htm.
14. Lower, Proceedings of the Nat'l Academy of Sciences 93, 5177-
5184, 1996.
15. Wain-Hobson, Nature 313, 743 (1985).
16. Maddox, Nature 335, 11 (1988).

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