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Lecture 1
Origin and progression of HIV-1
Adelajda Zorba
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HIV is the causative agent of AIDS
- 60 million infected people
- 25 million deaths
- 14 million orphaned children in South Africa alone
UNAIDS 2009 report
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AIDS does not develop in monkeys where HIV originated from.
How come?
Did it really?
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HIV is a zoonotic (can be transmitted from non-human animals to
humans)
lentivirus (lt. lenti=slow, virus=poison)
Found in chimpanzees today is SIVcpz (<-misnomer)http://www.avert.org/hiv-types.htm
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HIV-2 origin : Sooty mangabey
HIV-1 origin: chimpanzee
http://www.prn.org/index.php/progression/article/origin_of_the_aids_pandemic_58http://monkeysphotos.blogspot.com/2008/10/white-collared-mangabey.html
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Humans acquired HIV-1 from chimpanzees:
1990
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Evolutionary relationship of SIVcpz and HIV-1 based on envelope protein sequence analysis
Sharp et al., J. of Vir., 79 (7), 3891, (2005)
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Four chimpanzee subspecies based on mtDNA sequence differences
Sharp et al., J. of Vir., 79 (7), 3891, (2005)
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Two important observations
P.t.troglodytes
P.t.shweinfurthii
2. Three separate introductions of SIVcpz in the human population
1.
Sharp et al., J. of Vir., 79 (7), 3891, (2005)
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Spot-nosed monkeysRed-capped mangabeys
Humans acquired HIV-1 from cross-species transmission of SIVcpz from chimpanzees
Chimpanzees acquired SIVcpz from:
http://cercopan.wildlifedirect.org/tag/red-capped-mangabey/https://chrisdixonstudios.com/wildprints/top-wildlife-prints/apex0002934_Lesser%20Spot%20Nosed%20Monkey-Close-up.jpg
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How to go about studying chimpanzees?
Gombe National Park (Tanzania)
Keele et al., Nature, 460, 515, (2009)
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How to go about studying chimpanzees?
Gombe National Park (Tanzania)- non-invasive (urine and fecal-based Western blots assays)
- RT PCR
Sharp et al., J. of Vir., 79 (7), 3891, (2005)
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AIDS does not develop in monkeys where HIV originated from.
How come?
Did it really?
Yes!
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Not only SIVcpz but also HIV-1 infected chimpanzees do not
develop AIDS
Which model system should be used to research AIDS?
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A new model system: Rhesus Macaques(develop AIDS-like symptoms when infected with SIVcpz not HIV-1)
http://barelyimaginedbeings.blogspot.com/2008_09_01_archive.html
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An infectious, even-closer mimic of HIV-1: SHIV(contains HIV-1 envelope glycoproteins)
Li et al., J. of Acq. Imm. Def. Syn., 5, 639, (1992)
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SIVcpz = harmless
HIV-1 = harmless
SIVcpz = harmful
HIV-1 = harmless
SHIV = harmful
SIVcpz = ?
HIV-1 = harmful
Chimpanzees Rhesus Macaques Humans
Why?http://www.prn.org/index.php/progression/article/origin_of_the_aids_pandemic_58http://barelyimaginedbeings.blogspot.com/2008_09_01_archive.htmlhttp://thelaughingstork.com/2009/03/funny-baby-pictures-bah-humbug-edition/
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1. Viral Entry Level: An incompatible receptor in the Old World Monkey cells?
No, because SHIV can replicate at a high titer in rhesus macaques
SHIV
from HIV-1
Rest is SIVcpz
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2. Post-Entry Events: A block that targeted the viral capsid prevented permanent infection?
VSV (vesicular stomatitic virus) envelope proteins
Infect cells with
cDNA from rh.mac. into HeLa cells
-look for GFP-negative colonies-check for infection with SIVcpz
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(it must not work on the particle-recognition level, but at an even more atomistic level)
TRIM5αrh inhibits HIV-1 infection but not SIVcpz or SHIV-based infection 2004
Stremlau et al., Nature, 427, 848, (2004)
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Although rhesus macaque TRIM5αrh inhibits HIV-1, human TRIM5αhu does not inhibit HIV-1
Why not?
Stremlau et al., Nature, 427, 848, (2004)
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Study the infectivity of chimeric TRIM5α proteins
Stremlau et al., J. of Vir., 79 (5), 3139, (2005)
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What we know so far..
1.Humans contracted HIV-1, the virus responsible for AIDS, from chimpanzees and sooty mangabeys.
2.Both SIVcpz and HIV-1 are harmless to chimpanzees.
3.SIVcpz is harmful to rhesus macaques, but HIV-1 is harmless.
4.TRIM5α could explain why this is the case.
5.We need to understand what capsids are…
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What are those ?
…to be continued in Lecture 2