Transcript HIV-1 Diversity and Related Retroviruses

HIV-1 Diversity and Related Retroviruses
Dr. Matthew D. Marsden, Ph.D.
UCLA, Department of Medicine
[email protected]
Types of Viruses
(Baltimore Classification)
I: Double-stranded DNA (Adenoviruses; Herpesviruses; Poxviruses, etc)
Herpesviridae (Herpes, CMV, EBV), Poxviridae (Smallpox, Chickenpox,
Vaccinia), Papilloma virus, Adenovirus
II: Single-stranded (+) sense DNA (Parvoviruses)
Erythema infectiosum, Phages
III: Double-stranded RNA (Reoviruses; Birnaviruses)
Rotavirus, Reovirus
IV: Single-stranded (+) sense RNA (Picornaviruses; Togaviruses, etc)
Polio, SARS, Hep A, Hep C, Rubella, Yellow fever
V: Single-stranded (-) sense RNA (Orthomyxoviruses, Rhabdoviruses, etc)
Rubella, Influenza, Rabies, Measles, Mumps, Ebola
VI: Single-stranded (+) sense RNA with DNA intermediate (Retroviruses)
HTLV, HIV
VII: Double-stranded DNA with RNA intermediate (Hepadnaviruses)
Hep B
Classification of
Retroviruses:
• Divided into 3 subfamilies based primarily on
pathogenicity rather than genome relationships.
Subfamilies
Oncovirinae
Lentivirinae
Spumavirinae
Classification of
Retroviruses:
•Subfamilies are further divided based on:
1.Virion structure (types A-D)
2.Utilization of particular cell receptors
3.Lifestyle: whether endogenous or exogenous
4.Presence or absence of an oncogene
5.Other pathogenic properties
•When nucleotide sequences and genome
structure are considered, 7 groups (genus)
emerge.
Classification of
Retroviruses:
Subfamily
Genus
Isolates
Lentivirinae
Lentivirus
HIV-1
HIV-2
SIV
FIV
Visna/maedi
EIAV
CAEV
Lentivirus
•All Retroviruses contain gag, pol, pro* and env
•Lentiviruses are more complex:
Two regulatory genes: tat and rev
Accessory genes:
HIV-1 nef, vif, vpr, vpu
HIV-2 and SIV lack vpu and have vpx
*pro is sometimes contained within pol (HIV)
Diversity resulting
from base misincorporation
(clades: resemble each other across the
genome)
Reverse transcriptase
•
Lacks proofreading function
• 1000-fold higher rate of nucleotide substitutions
than seen with replication of viral DNA genomes
• 1 nucleotide change is introduced each time
provirus is synthesized
•
This results in quasispecies formation
HIV Life cycle
http://preprod.www.tibotec.com/content/backgrounders/www.tibotec.com/hiv_lifecycle.html
HIV Life cycle
• HIV mutates every time it replicates
• HIV replicates in billions of cells
simultaneously every day
• HIV therefore evolves around 1 MILLION
TIMES faster than mammalian genes
http://preprod.www.tibotec.com/content/backgrounders/www.tibotec.com/hiv_lifecycle.html
Comparison of HIV genetic variation with flu virus (longer lines mean more mutations)
http://www.nature.com/embor/journal/v4/n6s/fig_tab/embor857_F1.html
Comparison of HIV genetic variation with flu virus (longer lines mean more mutations)
http://www.nature.com/embor/journal/v4/n6s/fig_tab/embor857_F1.html
Comparison of HIV genetic variation with flu virus (longer lines mean more mutations)
http://www.nature.com/embor/journal/v4/n6s/fig_tab/embor857_F1.html
Comparison of HIV genetic variation with flu virus (longer lines mean more mutations)
http://www.nature.com/embor/journal/v4/n6s/fig_tab/embor857_F1.html
HIV “family tree”
http://www.avert.org/hiv-types.htm
Genetic subtypes of HIV-1
Groups
M
O
N
Clades or
A-H, J (9)
Subtypes
Limited Spread
Subclades F1 &F2
Strains or
isolates JR-CSF
P
1 infected person
Reported ‘09
2nd infected person
Reported ‘10
8 full, and 5 partial,
Genome sequences
Genetic subtypes of HIV
Groups (env sequences): M, O, N, P
M: Main, O: Outlier, N: New or Non-M-Non-O, P follows O
Subtypes or clades (env sequences): A-H, J
Equidistant env (25-30% a.a. differences)
Up to 20% a.a. sequence differences within a clade
Full length gene sequences required with no
evidence for recombination
Strains or isolates: e.g., HIV IIIb, HIV RF
Reasons For Genetic
Diversity Of HIV:
1. Zoonotic transmission from at least 3 sources:
Chimpanzees and Sooty Mangabees and
Gorillas on at least ten different occasions.
2. Rapid rate of mutation due to:
Reverse transcriptase (~1 error per genome)
and fast turnover in humans.
3. Recombination events
Zoonosis = Cross-species transmission event
http://what-when-how.com/medical-microbiology-and-infection/zoonoses-systemic-infection/
Phylogeny of lentiviruses.
Sharp P M , and Hahn B H Cold Spring Harb Perspect Med
2011;1:a006841
©2011 by Cold Spring Harbor Laboratory Press
©2011 by Cold Spring Harbor Laboratory Press
Sharp P M , and Hahn B H Cold Spring Harb Perspect Med
2011;1:a006841
Where did HIV come from?
HIV entered the human population from primates, which harbor a related virus known as SIV
(simian immunodeficiency virus). This probably occurred during the butchering and
consumption of monkey meat in Africa.
HIV “family tree”
http://www.avert.org/hiv-types.htm
Where did HIV come from?
HIV entered the human population from primates, which harbor a related virus known as SIV
(simian immunodeficiency virus). This probably occurred during the butchering and
consumption of monkey meat in Africa.
HIV “family tree”
HIV-1 group M, which
is the most prevalent
HIV strain, jumped
from chimpanzees
into humans.
http://www.awf.org/content/wildlife/detail/chimpanzee
http://www.avert.org/hiv-types.htm
Where did HIV come from?
HIV entered the human population from primates, which harbor a related virus known as SIV
(simian immunodeficiency virus). This probably occurred during the butchering and
consumption of monkey meat in Africa.
HIV “family tree”
HIV-1 group M, which
is the most prevalent
HIV strain, jumped
from chimpanzees
into humans.
http://www.awf.org/content/wildlife/detail/chimpanzee
http://www.avert.org/hiv-types.htm
HIV-2 originated in sooty
mangabeys and is
responsible for fewer
infections than HIV-1
http://pin.primate.wisc.edu/factsh
eets/entry/sooty_mangabey
New viruses are still being transferred from primates to humans, and have the potential to
cause new diseases and epidemics.
Origins of human AIDS viruses.
Sharp P M , and Hahn B H Cold Spring Harb Perspect Med
2011;1:a006841
©2011 by Cold Spring Harbor Laboratory Press
HIV and SIV Hosts
Virus
Host
Natural
Pathogenic
Origin
HIV-1
Humans
No
Yes
Africa
SIVcpz
Chimpanzees
Yes ?
No ?
Africa
HIV-2
Humans
No
Yes
Africa
SIVmac
Macaques
No
Yes
Asia
Yes
No
Africa
African Green Monkeys Yes
No
Africa
SIVsm
SIVagm
Sooty Mangabees
SIVmnd
Mandrills
Yes
No
Africa
SIVsyk
Sykes Monkeys
Yes
No
Africa
SIV gor
Gorillas
Yes
?
Africa
Source: Adapted from Atlas of Infectious Diseases, Mandell & Mildvan (ed.), pp. 2.3
Cross Species Transmission
of SIVcpz
•SIVcpz and HIV-1 are identical in genomic organization. Only two lentiviruses to contain vpu.
•Sequence of SIVcpz suggests HIV-1 transmission
from P. t. troglodytes.
•Observed natural infection of P. t. troglodytes with
isolates more closely related to SIVcpzUS and
YBF30 (group N) than any other HIV-1/SIV.
Origins of HIV-1
•West Equatorial Africa is the only location where M, N,
and O co-circulate, and where P. t. troglodytes is
infected with closely related viruses.
•Group M appears to originate from SIVcpzPtt in South
Central Cameroon.
•Group N most likely originated in southeastern
Cameroon as N sequences are highly related to
SIVcpzPtt in that region.
Origins of HIV-1
• Infection of Gorillas and Chimpanzees in Cameroon
with viruses closely related to Group O HIV.
• Although sequences suggest chimpanzee
transmission to Gorillas, it’s unclear which animal is
responsible for transmission to humans.
• Gorilla transmission to one woman in Cameroon
resulted in group P
• Greatest diversity of group M is observed in
Cameroon.
Geographic distribution of SIVcpz and SIVgor infections in sub-Saharan Africa.
Sharp P M , and Hahn B H Cold Spring Harb Perspect Med
2011;1:a006841
©2011 by Cold Spring Harbor Laboratory Press
HIV-1 origins.
Sharp P M , and Hahn B H Cold Spring Harb Perspect Med
2011;1:a006841
©2011 by Cold Spring Harbor Laboratory Press
HIV-1 origins.
Likely independent
transmission
events into humans
Sharp P M , and Hahn B H Cold Spring Harb Perspect Med
2011;1:a006841
©2011 by Cold Spring Harbor Laboratory Press
HIV-2 origins.
Sharp P M , and Hahn B H Cold Spring Harb Perspect Med
2011;1:a006841
©2011 by Cold Spring Harbor Laboratory Press
HIV-2 origins.
Likely independent
transmission
events into humans
Sharp P M , and Hahn B H Cold Spring Harb Perspect Med
2011;1:a006841
©2011 by Cold Spring Harbor Laboratory Press
When did HIV first jump into humans?
Maximum clade credibility topology inferred using BEAST v1.4.7 under a Bayesian skyline plot
tree prior.
M Worobey et al. Nature 455, 661-664 (2008) doi:10.1038/nature07390
The strain of HIV responsible for the majority of global infections (HIV-1 Group M) probably
jumped into humans in western Africa sometime between 1884 and 1924.
From there it then spread throughout the world.
Origin and Spread of HIV
Genetic subtypes of HIV
Groups (env sequences): M, O, N, P
M: Main, O: Outlier, N: New or Non-M-Non-O
Subtypes or clades (env sequences): A-H, J
Equidistant env (20-30% a.a. differences)
Up to 10-15% a.a. sequence differences within a
clade
Full length gene sequences required with no
evidence for recombination
Strains or isolates: e.g., HIV IIIb, HIV RF
Group M (1959 [1910 – 1950])
•Arose from one cross-species transmission event.
•Most prominent group worldwide with 11
subtypes or clades: A-K
•Of these only 9 are true clades, E and I appear
to be recombinants.
•G clade has accessory genes that resemble clade
A but it is otherwise distinct.
•Are some unclassified clades.
Group M cont.
•Has four subclades: F1, F2, B and D
•F diverged into F1 and F2 and divergence
between these two subclades is not much
greater than between other clades.
•B and D show the same extent of divergence
but for historical reasons continue to be
classified as clades, not subclades.
•Clade B is the most common clade in North
America and Europe.
Evolutionary relationships among non-recombinant HIV-1 group M
clades based on near-full length genome sequences.
Peeters and Sharp AIDS 2000, 14
(Suppl 3): S129-S140.
Spira et al. J. of Antimicrobial Chemotherapy 2003, 51: 229-240
Group O (1963)
•First described in ~1990 in Camaroon, France
and Gabon
•Highly divergent from group M with only ~50%
homology to M in env.
•Represents a minority of infections in those
regions, ~2-5%.
•Has no subtypes which may be the result of slow
and limited spread, although with more
sequencing of genomes, subtypes may be found.
Group N
•More recently identified (1995)
•~12 confirmed infections all in Camaroon
•Sequences suggest this group is mosaic
•5’ half distantly related to M, 3’ half more
closely resembles SIVcpzus
Group P
• 1st known infection (seropositive 2004,
reported 2009)
• Woman in Paris, France recently emigrated
from Cameroon
• Sequences suggest SIVgor was responsible
• Cannot detect by PCR using M or O
primers
Group P
• 2nd individual identified in Camerron
• HIV-seropositive male hospital patient
• Screening of 1,736 HIV-seropositive
suggest group is rare ~ only 0.06% of HIVinfections
• Reported 2010 Vallari et al. J.V. Nov. 17th
Diversity due to
recombination
(mosaics: genes derived from
more than one parental strain)
Nature Reviews Immunology 6,
930-939 (December 2006)
Mechanism(s) For Recombination
A
B
A
B
http://www.hiv.lanl.gov/content/se
quence/HIV/REVIEWS/hahn.html
Recombinants or
Mosaics
•Eg. MAL: one of the first African HIV-1 isolates
characterized.
•1994: first multiply infected individual identified.
• ~10-20% of newly characterized strains.
•Identified by discrete breakpoints in genomic
regions.
•Isolated in regions where both parental strains
are found.
Recombinants or Mosaics
(cont.)
•Similar breakpoints reflect common ancestry.
•Designated ‘circulating recombinant forms: (CRF)
•CRFs are given identifying numbers followed by
letters reflecting the parental clades: CRF01-AE
•If more than three clades are parental, the CRF
is followed by cpx for ‘complex’. CRF01-CPX
Evolutionary relationships of CRFs, CRF01-AE and CRF02-AG.
Based on full length gag, 3’ end of pol, and gp120 sequences.
Peeters and Sharp AIDS 2000, 14
(Suppl 3): S129-S140.
Evolutionary relationships of CRFs, CRF01-AE and CRF02-AG.
Based on full length gag, 3’ end of pol, and gp120 sequences.
Peeters and Sharp AIDS 2000, 14
(Suppl 3): S129-S140.
Geographical distribution of predominant groups, clades and
CRF’s.
Peeters and Sharp AIDS 2000, 14
(Suppl 3): S129-S140.
Importance of CRFS
•Successful transmission of SIV to Chimpanzees and
humans, and subsequent human to human transmission,
required viral adaptation.
•Recombination increases the odds of “successful diversity”.
Indeed, transmission of SIV to Chimpanzees is thought to
have included a recombinant event.
•CRF01_AE is Southeast Asia and CRF02_AG in West
Africa are the fastest-spreading epidemic strains.
•Subtypes A, C and CRF02_AG now account for 75% of
the 14,000 estimated new daily infections worldwide.
Heeney et al. Science 2006, 313:462
Why is understanding
diversity important?
•Key to understanding the path of the epidemic.
•Diagnostic tests: mainly available for clade B,
and diversity can affect sensitivity.
•Antiretroviral drugs: mainly available for clade
B only. Group O and HIV-2 are naturally resistant
to NNRTs. Group M shows variation in drug
susceptibilities.
•Transmission and rates of disease progression
differ between HIV-1 and HIV-2.
Why is understanding
diversity important?
•Biological differences among groups and clades:
Virus or host factors?
•Vaccines: nAb and CTL may be clade specific
– or not. Implications are that conserved
regions must be included.
•Vaccines and gene therapy: Recombination
events are a concern. Endogenous retroviruses and infectious viruses must be
considered.
So, How Did Chimpanzees
Get Infected?
Chimpanzees are predatory animals.
Prey of chimpanzees are also infected with SIV
Infection was with a recombinant virus, an ancestor
of viral strains currently infecting red-capped
Mangabeys and the greater spot-nosed monkeys.
Both of these monkeys have overlapping ranges
with P.t. troglodytes in west and central Africa.
Origin of infection of P. t. schweinfurthii is not
currently clear.
So, How Did gorillas Get
Infected?
Gorillas are not predatory animals.
Share home range with chimpanzees who are also
infected with SIV
Route of infection is currently unclear
Origins of HIV: Some major take home points
Different strains of HIV have been independently transmitted into
humans from animals (Chimpanzee, Sooty mangabey, or Gorilla) on over
10 separate occasions.
The most common strain of HIV (HIV-1, group M), which is responsible
for over 90% of global infections, originated in chimpanzees (Pan
troglodytes).
This likely occurred in Cameroon (West Africa) approximately 100 years
ago.
Bushmeat (hunting monkeys for food) is the most likely source of these
transmissions of AIDS viruses into humans.
Mutation and recombination have shaped the HIV epidemic, and are
important for immune evasion, drug resistance, vaccine development
etc.
General References:
Sharp P M , and Hahn B H Cold Spring Harb
Perspect Med 2011;1:a006841
Publication Date: August 1, 2013 | ISBN-10:
0199641145 | ISBN-13: 978-0199641147 | Edition: 1
More References:
1. Hybrid origin of SIV in Chimpanzees Bailes et al.
Science 2003, 300:1713
1. Origins of HIV and the Evolution of Resistance to AIDS.
Heeney et al. Science 2006, 313:462
3. The Black Death and AIDS: CCR5-D32 in genetics and
history Q.J.Med 2006, 99:497
4. Chimpanzee Reservoirs of Pandemic and Nonpandemic
HIV-1 Keele et al. Science 2006, 313:523
More References
•
Molecular Epidemiology of Simian Immunodeficiency Virus Infection in Wildliving Gorillas
Neel C, Etienne L, Li Y, Takehisa J, Rudicell RS, et. Al.
J Virol. 2009 Nov 11. [Epub ahead of print]PMID: 19906908 [PubMed - as
supplied by publisher]
• Origin and Biology of Simian Immunodefiency Virus in Wild-Living Western
Gorillas
Takehisa J, Kraus MH, Ayouba A, Bailes E, Van Heuverswyn F, Decker JM,
Li Y, Rudicell RS, Learn GH, Neel C, Ngole EM, Shaw GM, Peeters M, Sharp
PM, Hahn BH.
J Virol. 2009 Feb;83(4):1635-48. Epub 2008 Dec 10.PMID: 19073717