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FJ
EXPRESS SUMMARY ARTICLE The Full-length version of this article is also available, published online December 8, 2000 as doi:10.1096/fj.00-0449fje. |
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* Rega Institute for Medical Research, Katholieke Universiteit Leuven, B-3000 Leuven, Belgium;
MIPS/GSF, Max-Planck-Institut für Biochemie, D-82152 Martinsried, Germany;
Department of Medical Microbiology, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin 4, Ireland;
§ Laboratoire Retrovirus, IRD, Montpellier, France; and
|| African Network of HIV variability, Senegal
2Correspondence: Rega Institute for Medical Research, Minderbroedersstraat 10, B-3000 Leuven, Belgium. E-mail: annemie.vandamme{at}uz.kuleuven.ac.be
SPECIFIC AIMS
Toinvestigate the time frame of the common ancestor of HIV-1 group M and its closest simian relative, SIVcpz, we developed a new method of molecular clock analysis, called site stripping for clock detection (SSCD). SSCD allows selection of nucleotide sites evolving at an equal rate in different lineages. We calculated that the origin of HIV-1 group M radiation dates back to the 1920s–1930s and that the coalescence time of HIV-1 group M and its simian counterpart occurred around the end of the XVII century.
PRINCIPAL FINDINGS
1. SSCD is a method of general applicability in
molecular evolution to calibrate clock-like phylogenetic trees
The time of origin of the most recent common ancestor for a clade
of contemporary virus strains can be estimated from a phylogenetic tree
provided that the molecular clock hypothesis holds. In such a tree, the
degree of sequence divergence, as measured by the number of
substitutions along a branch, is linearly proportional to the time of
divergence. Several factors, such as homoplasy, recombination and
positive selection can impair this linear relation, but not all the
sites in a set of aligned sequences deal with these problems. Our new
method, SSCD, helps detecting those sites that are more likely to
distort the molecular clock. These sites can be removed from an
alignment before calibrating a clock-like phylogenetic tree. The SSCD
procedure was validated by using a cohort of HCV-infected women, all
infected within a couple of months during 1977. The source of the
infection was identified as a contaminated anti-D immunoglobulin batch
prepared from a single blood donation from an HCV-genotype-1b positive
donor. We used the SSCD procedure on a set of aligned sequences of HCV
strains, sampled from the infected patients in 1998, and we calibrated
the evolutionary rate of HCV by using sequences sampled in 1994 from
other women infected in 1977 by the same batch. The origin of the
common ancestor of the viral strains sampled in 1998 was dated exactly
in 1977, with a standard error of 7 years. However, when the molecular
clock was calibrated without removing the clock-distorting sites, the
resulting estimated date was inaccurate (1955 ± 20).
2. The radiation of the HIV-1 group M
subtypes occurred around the 1920 and 1930s
Figure 1
shows the phylogenetic trees of HIV-1
pol strains sampled in 1998 and env strains
sampled in 1992. The trees are not fully resolved, and they should be
viewed as a consensus of the evolutionary history of the sequences. The
rationale behind using multi-furcating trees is that we are interested
mainly in dating the common ancestors of the clades indicated in Fig. 1
, for which all the phylogenetic analyses gave robust support. For both
trees the molecular clock hypothesis has to be rejected. However, by
using the SSCD procedure, we could find which sites in the
pol and env alignment are more likely to distort
the molecular clock. After removing these sites, we used the remaining
sites to calibrate clock-like branch lengths for the trees in Fig. 1
.
We estimated the evolutionary rate for the pol end
env clock-like evolving sites by using several HIV-1
sequences sampled between 1983 and 1999. The results are shown in
Table 1
.
The origin of subtype B radiation is estimated to be in the early 1970s
(1970 with pol, and 1972 with env). The most
recent common ancestor of subtypes B and D dates back between the end
of the 1940s and the early 1950s (1949 with pol, and 1954
with env), and the date of origin of group M radiation is
estimated to be during the 1920s and the 1930s; 1920 according to
pol, and 1937 according to env.
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3. HIV-1 group M and its closest
simian relative, SIVcpz, shared a common ancestor in 1675
Once the sites responsible for distorting the molecular clock were
removed, the clock could not be rejected for the trees in Fig. 1
,
including HIV-1 group M strains as well as SIVcpz strains. We estimated
that the most recent common ancestor of HIV-1 group M and SIVcpz (see
Fig. 1
) dates from around 1675 (99% c.i. 1590–1761). The estimation
was based on the pol gene only, as the env
dataset shows evidence of nucleotide substitutions saturation when the
SIVcpz strains are compared with the other HIV-1 group M strains. Using
sites that show saturation would result in an unreliable divergence
time.
CONCLUSIONS
The first goal of this study is to show that it is possible to apply molecular clock dating methods to a set of aligned nucleotide sequences for which the molecular clock is rejected. This objective is achievable by stripping from an alignment the sites that distort the clock and by retaining the clock-like sites that are used subsequently in the calculations. Our results show that upon identification and removal of the sites for which the molecular clock fails, the remaining sites can be used reliably to construct clock-like phylogenetic trees and to calculate divergence times at ancestral nodes, such as those illustrated by the HCV example.
We applied the new procedure in order to investigate the time of
origin of HIV-1 group M by using a dataset of pol and
env viral sequences, respectively. The date of the most
recent common ancestor of HIV-1 group M is not identical in the two
datasets, but they are in good agreement (see Table 1
). Also reassuring
is that the origin of the B/D node is placed around 1949–1954. This
result is fully consistent with the isolation of a HIV-1 strain from a
Congolese patient in 1959 that was phylogenetically placed near the
ancestral B/D node with a very short branch length and suggests a few
years prior to 1959 as the origin of the B/D node itself.
Our findings suggest that a zoonotic transmission responsible for the introduction of HIV-1 into our species must have occurred before the 1920s–1930s, because by that time the HIV-1 subtypes had already begun to diverge. The dating seems to exclude, or at least to make more unlikely, the theory that vaccination with oral polio vaccine batches contaminated with SIV, between 1957–1959 in the former Belgian Congo, is the origin of the HIV epidemics in humans.
Finally, SIV strains more closely related to HIV-1, other than the
SIVcpz from Pan troglodytes troglodytes, have not been found
thus far. Therefore, the separation of the HIV-1/SIVcpz lineages around
the end of the XVII century (see Table 1
) is the upper limit of the
time of the interspecies transmission responsible for the origin of
HIV-1 group M in humans. This finding does not necessarily mean that
the time of the interspecies transmission must have occurred more than
300 years ago; the date simply represents the coalescence time of the
simian ancestor of HIV-1 group M and its closest related SIVcpz
strains. However, it is important to realize that the lack of reported
cases of HIV-1-related disease during these years does not necessarily
imply an absence of infection in human populations, particularly when
this disease has occurred in remote geographical locations. The factors
contributing to a successful simian-to-human transmission and the
factors contributing to the expansion of the initial infection into
epidemic and then pandemic proportions are not necessarily the same.
The lack of sterile conditions in vaccination campaigns and the major
socio-cultural changes in Africa during the past century might have
contributed to the spread of the HIV epidemic, long after the
interspecies transmission had occurred.FIGURE 2
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FOOTNOTES
1 To read the full text of this article, go to http://www.fasebj.org/cgi/doi/10.1096/fj.00-0449fje To cite this article, use (December 8, 2000) FASEB J. 10.1096/fj.00-0449fje 
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