Tetherin-driven evolution of pandemic and non-pandemic HIV-1 strains [Elektronische Ressource] / Daniel Sauter

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• Gesundheit

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• Publié par: universitat_ulm
• Publié le: 01 janvier 2011
• Nombre de lectures: 49
• Langue: English
• Poids de l'ouvrage: 36 Mo

Extrait

Institute of Molecular Virology
Prof. Dr. Frank Kirchhoff




Tetherin-Driven Evolution
of Pandemic and Non-Pandemic HIV-1 Strains









Cumulative Dissertation
for the Doctoral Degree in Human Biology
at the Medical Faculty of the University of Ulm



Daniel Sauter
Überlingen am Bodensee
2011
Present Dean: Prof. Dr. Thomas Wirth

1st reviewer: Prof. Dr. Frank Kirchhoff
2nd reviewer: Prof. Dr. Karl Lenhard Rudolph

Date of graduation:
18.7.2011Contents III
Contents
List of Abbreviations.………………………………………………………………………………….……………………IV
1 Introduction ................................................................................................................... 1
1.1 Epidemiology and evolution of HIV-1 ..................................................................... 1
1.2 Host restriction factors ........................................................... 5
1.2.1 APOBEC ........................................................................................................... 5
1.2.2 TRIM5 ............ 5
1.2.3 Tetherin ........... 5
1.2.4 CAML ................................................................................................................ 7
1.3 Accessory proteins of HIV-1 .................... 7
1.3.1 Vif ..................................................................................................................... 8
1.3.2 Vpr ................... 8
1.3.3 Vpu 8
1.3.4 Nef ................................................................................................................... 9
2 Results.......................... 10
2.1 Tetherin but not CAML restricts retroviral release .............................................. 10
2.2 Tetherin poses a barrier for cross-species transmissions ..... 11
2.2.1 Counteraction of tetherin by Vpu is species-specific .................................... 11
2.2.2 SIVcpz and SIVgor employ Nef to counteract tetherin.. 12
2.3 Only pandemic HIV-1 group M evolved a fully functional Vpu ............................ 13
2.3.1 HIV-1 group O and P Vpus do not antagonize tetherin ................................. 13
2.3.2 HIV-1 group N Vpus do not downmodulate CD4 .......... 15
3 Discussion .................................................................................................................... 16
4 Summary ...................... 21
5 References ................................................................................................................... 22
6 Acknowledgements ..................................................................................................... 27
7 Publication Index ......... 28
8 Appendix…………………….…………………………………………………………………………………………..30 List of Abbreviations IV
List of Abbreviations
AIDS Acquired immunodeficiency syndrome
APOBEC Apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like
BST-2 Bone marrow stromal antigen 2
CAML Calcium-modulating cyclophilin ligand
CD Cluster of differentiation
CXCR4 C-X-C chemokine receptor type 4
enJRSV Endogenous Jaagsiekte sheep retrovirus
Env Envelope protein
Fig Figure
Gag Group-specific antigen
GPI Glycosylphosphatidylinositol
HeLa Henrietta Lacks
HHV-8 Human herpes virus 8
HIV Human immunodeficiency virus
HTLV-1 Human T-lymphotropic virus
ILT7 Immunoglobulin-like transcript 7
Int Integrase
JRSV Jaagsiekte sheep retrovirus
LTR Long terminal repeat
MHC Major histocompatibility complex
MLV Murine leukemia virus
mRNA Messenger ribonucleic acid
Nef Negative factor
NPC-A-7 Nasopharyngeal carcinoma associated 7
NTB-A Natural killer T cell and B cell antigen
PDCA-1 Plasmacytoid dendritic cell antigen 1
PERV Porcine endogenous retrovirus
Prot Protease
Ptt Pan troglodytes troglodytes
Rev Regulator of virion List of Abbreviations V
RING Really interesting new gene
RT Reverse transcriptase
siRNA Small interfering ribonucleic acid
SIV Simian immunodeficiency virus
SIVagm SIV from African Green Monkeys (Chlorocebus sabaeus)
SIVblu SIV from Blue Monkeys (Cercopithecus mitis)
SIVcpz SIV from Chimpanzees (Pan troglodytes)
SIVden SIV from Dent’s Mona Monkeys (Cercopithecus denti)
SIVgor SIV from Western Lowland Gorillas (Gorilla gorilla gorilla)
SIVgri SIV from Grivets (Chlorocebus aethiops)
SIVgsn SIV from Greater Spot-nosed Monkeys (Cercopithecus nictitans)
SIVlho SIV from L’Hoest’s Monkeys (Cercopithecus lhoesti)
SIVmac SIV from Macaques (Macaca spec.)
SIVmon SIV from Mona Monkeys (Cercopithecus mona)
SIVmus SIV from Mustached Monkeys (Cercopithecus cephus)
SIVrcm SIV from Red-capped Mangabeys (Cercocebus torquatus)
SIVsmm SIV from Sooty Mangabeys (Cercocebus atys)
SIVsyk SIV from Sykes’ Monkeys (Cercopithecus albogularis)
SIVwrc SIV from Western Red Colobus (Procolobus badius)
ß-TrCP beta-Transducin repeat containing protein
Tat Trans-activator of transcription
tMRCA Time of most recent common ancestor
TRIM Tripartite motif-containing protein
Vif Viral infectivity factor
Vpr Viral protein r
Vpu Viral protein unknown/Viral protein unique to HIV-1
VSV Vesicular stomatitis virus
XMRV Xenotropic murine leukemia virus-related virus
Introduction 1
1 Introduction
1.1 Epidemiology and evolution of HIV-1
In 1981, the term acquired immunodeficiency syndrome (AIDS) was established to
describe a disease of young men who displayed a marked depletion of
+CD4 T lymphocytes and suffered from various opportunistic infections that were often
1fatal . Two years later, a retrovirus was isolated from the blood of AIDS patients and
2demonstrated to be the causative agent of the syndrome . This virus was subsequently
named human immunodeficiency virus type 1 (HIV-1) and assigned to a new subfamily of
retroviruses: the lentiviruses.
2-5Four different groups of HIV-1 (M, N, O, and P) have been described to date , each of
them representing an independent cross-species transmission of simian
3,6,7immunodeficiency viruses (SIV) to humans (Fig. 1, Table 1). HIV-1 M (major) is by far
the most common group and accounts for more than 90 % of the 33.3 million HIV
8infections worldwide . It is further subdivided into nine subtypes (A-D, F-H, J and K) and
9,1048 circulating recombinant forms . The direct precursors of pandemic HIV-1 group M
and rare group N (non-M, non-O) which has been detected only in 15 Cameroonian
patients are SIVcpz strains found in the Central Chimpanzee (Pan troglodytes
4,11-17troglodytes) . SIVcpz itself is the product of successive cross-species transmission and
recombination events involving precursors of today’s SIVgsn/mon/mus infecting
18Cercopithecus species and SIVrcm from Red-capped Mangabeys (Cercocebus torquatus)
(Fig. 1). In contrast to HIV-1 groups M and N, group P viruses, which have only been
detected in two individuals, originated from SIVgor naturally infecting Western Lowland
3,19Gorillas (Gorilla gorilla gorilla) .The simian ancestor of HIV-1 group O (outlier), a strain
infecting several ten thousand people mostly in Western Central Africa is either SIVcpz or
11,20-24SIVgor . In contrast to HIV-1 group M, the prevalence of group O has remained
20,23stable or even declined during the last years .



Introduction 2
It is still unknown why only one of four independent transmissions of SIVs to humans led
to a pandemic. Different time-points of the zoonotic events would provide an explanation
for the differences in spread. Although precise dating of the transmission events of SIV to
humans is almost impossible, sequence analyses provide a means to estimate the time of
the most recent common ancestors of the four current groups of HIV-1. According to
ththese estimations, HIV-1 M and O emerged at the beginning of the 20 century [1884-
1924 and 1890-1940, respectively], whereas the most recent common ancestor of HIV-1
25-27N was dated to 1963 [1948-1977] . Although only two HIV-1 P isolates have been
described so far, its time of emergence has been estimated to 1850-1980 (Gupta and
Sauter et al., in revision). These calculations suggest that a later introduction of HIV-1 O
and P into the human population is not the reason for their low prevalences in
comparison to HIV-1 M.
















Figure 1: Evolution of HIV-1. HIV-1 groups M, N, O, and P are the result of four independent cross-species
transmissions of simian immunodeficiency viruses from chimpanzees (SIVcpz) or gorillas (SIVgor) to
humans. SIVcpz itself is a recombinant virus involving precursors of today’s SIVgsn/mon/mus lineage
infecting Cercopithecus species and SIVrcm from Red-capped Mangabeys. Remarkably, only HIV-1 group M
spread worldwide, whereas the other groups remain largely restricted to Western Africa. Introduction 3
Table 1: Epidemiology of HIV-1 groups M, N, O, and P
HIV-1 Geographic Direct Date of
Prevalence Pathogenicity
group distribution precursor transmission

8 12More than 30 M Worldwide SIVcpz Ptt