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formation? And how developmentally distant
can the cell of origin and the target cell be for
this approach to work? Exocrine cells and β-islet cells share a common precursor. WhenZhou
used the same factors to induce
transdifferentiation of more distantly relatedfibroblast cells or muscle cells into the β-islet-like cells, the approach failed. Could it be thatthe inclusion of other factors allows transdif-
ferentiation of more distantly related cells?
Considering the many problems associatedwith the use of viral vectors in gene therapy
,finding alternative ways to induce the expres-
sion of the three transcription factors in theexocrine cells of an organism
would beespecially useful. Can the virus-mediated
introduction of genes for Ngn3, Pdx1 and Mafa
be substituted with transient introduction of
non-DNA elements such as RNAs, recombinant
proteins or chemical mimics of these factors,
which may be safer? Indeed, the transdifferenti-ation process that Zhou
describe occurredrapidly and did not require ongoing expression
of the virally introduced genes, suggesting that
transient non-DNA-based approaches might
succeed. No matter what the answers to thesequestions are, the authors’ findings
that the field of regenerative medicine must pur-
sue several strategies to uncover the best thera-peutic solutions to degenerative diseases.
Robert Blelloch is at the Institute for RegenerationMedicine, Center for Reproductive Sciences,and Department of Urology, University ofCalifornia, San Francisco, San Francisco,California 94143–0525, USA.e-mail: firstname.lastname@example.org
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661–680 (2008).2. Zhou, Q., Brown, J., Kanarek, A., Rajagopal, J. & Melton,D. A.
627–632 (2008).3. Hochedlinger, K. & Jaenisch, R.
1061–1067(2006).4. Takahashi, K. & Yamanaka, S.
663–676 (2006).5. Park, I.-H.
et al. Cell
877–886 (2008).6. Dimos, J. T.
1218–1221 (2008).7. Rodic´ , N., Rutenberg, M. S. & Terada, N.
Trends Mol. Med.
93–96 (2004).8. Meivar-Levy, I. & Ferber, S.
Trends Endocrinol. Metab.
460–466 (2003).9. Ber, I.
J. Biol. Chem.
31950–31957 (2003).10. Kojima, H.
et al. Nature Med.
596–603 (2003).11. Oliver-Krasinski, J. M. & Stoffers, D. A.
1998–2021 (2008).12. Hasbrouck, N. C. & High, K. A.
Human immunodeficiency virus type 1 (HIV-1)
must have been spreading through the
human population long before AIDS was first
described in 1981, but very few strains from
this ‘prehistoric’ period (pre-1980s) have been
characterized. Viral sequences from earlier
times can provide insight into the early spreadof HIV-1, because the rapid rate of evolution of
this virus — up to a million times faster than
that of animal DNA — means that substan-tial amounts of sequence change occur in a
matter of decades
. On page 661 of this issue,
describe the sequences of par-tial genome fragments of HIV-1 from a lymph-
node biopsy collected in 1960 in Léopoldville
(now Kinshasa, Democratic Republic of the
Congo). They compare these sequences with
those of other HIV-1 strains, shedding light on
the early evolution and diversification of this
virus in Africa.
HIV-1 strains are divided into three groups,each of which was independently derived from
a simian immunodeficiency virus (SIV) that
naturally infects chimpanzees in west-central
. Whereas two of these groups are rare,the third, group M, has spread throughout the
world and is the cause of more than 95% of
HIV infections globally. Group M can be fur-
ther divided into many subtypes (A–K), which
seem to have arisen through founder events.
For example, subtype B, which encompasses
all the strains originally described in NorthAmerica and Europe, is very rare in Africa,and reflects such a founder event. Last year,Worobey and colleagues showed
that thissubtype probably arose from a single strainthat was carried from Africa to Haiti beforespreading to the United States and onwards.The newly described
1960 virus (DRC60)falls within, but close to the ancestor of,
DRC60 is not the first ‘ancient’ HIV-1 sam-ple to be characterized: viral sequences froma blood-plasma sample originally obtained in
1959 — also from Léopoldville — were pub-
lished 10 years ago
. The importance of DRC60
Prehistory of HIV-1
Paul M. Sharp and Beatrice H. Hahn
The origin of the current AIDS pandemic has been a subject of great interestand speculation. Viral archaeology sheds light on the geography andtimescale of the early diversification of HIV-1 in humans.
Origin of pandemic HIV-1. a
, Map of west-central Africa showing
major rivers, and citieswith explosive population growth in the twentieth century. Chimpanzees carrying the SIV strainsmost closely related to the viruses of HIV-1 group M, such as that described by Worobey
, havebeen found in southeast Cameroon (red ring).
Léopoldville in 1896
view from Mount Léopold)and
, around 1955
the commercial centre).(Photos F. L. Michel (
) and C. Lamote (
), collectionof the Royal Museum for Central Africa, Tervuren, Belgium.)
is that it is highly divergent from the 1959
sample (ZR59), which was most closely related
to the ancestor of subtype D, thus directly
demonstrating that, by 50 years ago, group M
HIV-1 strains had already undergone substan-
The ZR59 and DRC60 sequences differ by about 12%, a value similar to distances now
seen between the most divergent strains withinsubtypes. As the positions of ZR59 and DRC60within the group M phylogeny indicate that the
various subtypes already existed 50 years ago,
simple extrapolation suggests that these two
viral sequences had a common ancestor at least50 years before that. For a more robust estimate
of the date of the common ancestor of HIV-1
group M strains, Worobey and colleagues used
state-of-the-art statistical analyses, allowing a variety of models for the growth of the HIV-1
pandemic and variable rates of evolution.The different analyses gave broadly similar
2 October 2008
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