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Aicardi-Goutieres (Trex1 mutation – DNA exonuclease)SpondyloenchondrodysplasiaISG15 deficiency (negative regulator of IFN signaling)SAVI (STING-associated vasculopathy with onset in infancy) - a gain-of-function STING mutation
Viruses attack common cellular defense pathways
Medina RA, A Garcia-Sastre, Influenza A viruses: new research developments. Nature Rev Microbiol 9:590, 2011.
Relevant Life Cycle Issues
1. An intestinal infection of wild waterfowl.
2. Crosses to mammals through close contact.
3. Multiple ‘crosses’ enhance capacity to establish
mutants and reassortment variants
adapted to mammalian hosts.
4. HA species specificity: sialic acid -2,3 galactose linkage (avian intestine; human LRT)
5. NA compatibility: human viruses gain -2,6 activity
stalk length (longer NA enhances activity in humans)
6.HA, NA Adaptations HA glycosylation; HA1/HA2 fusion domain (expanded basic amino acid repeat in highly pathogenic chicken H5/H7/H9 flu -HPAI- enhances spectrum of proteases that can activate HA fusion event; may explain pathogenicity of co-infection with bacteria)
Medina RA, A Garcia-Sastre, Influenza A viruses: new research developments. Nature Rev Microbiol 9:590, 2011.
Mutation and reassortment drive influenza A epidemics and pandemics
Influenza Pandemics
Year Common Name Subtype OriginDeaths
1889 - H2N2 ?Europe 6 million
1898 - H3N2 ?Europe 0.5 million
1918 Spanish Flu H1N1* ?Eurasia 40 million
1957 Asian Flu H2N2* China 4 million
1968^ Hong Kong Flu H3N2* China 2 million
1977^ Russian Flu H1N1+ China/Russia 1 million
2009^ Swine Flu H1N1* N. America >18,000
* Contained elements from avian viruses
+ Laboratory-derived from frozen stock (persons pre-’50s immune)
^Antigenic variants continue to co-circulate
Live chickens and ducks in same cages
Asian Live-Animal Markets -
The Great Zoonotic Mixer
A new pandemic influenza virus, H1N1/09
USA estimates: 22 million infected, 3900 deaths
Relevant Immunology
Innate immunity: Type 1 IFNs, TNF-, MxA, IFIT and IFITM proteins
HA antibodies: Neutralize infectivity, protective
NA antibodies: Restrict viral spread
Cytotoxic CD8 T cells: M2, PB2, HA, NP specificity common M2 specificity almost universal
CD8 TCR / chains
V17/V10.2
HLA-A2 (A*0201)
Influenza A Matrix Protein amino acids 58-66
Stewart-Jones et al. Nature Immunol 7:657, 2003
The Most Common Human TCR in the World
Why do they die?…
Human Immunodeficiency Virus
Worldwide: 35 million infected
29 million dead
14,000 new infections/day
2/3 infected persons in Africa
U.S.: ~1 million infected including 400,000 dead
(appeared 1983)
Worldwide Estimates of Numbers of HIV-Infected Persons
Origins of HIV(9 genes)
Chahroudi A, et al. Science 335:1188, 2012.
HIV Origins - Primate Lentiviruses
HIV-1
SIVcpz - West equatorial Africa = M group (chimps)
Cameroon = N group (chimps)
Gabon = O group (gorillas)
HIV-2
SIVsm (sooty mangabey)
Infection/Disease in areas of active bushmeat trade.
HIV Origins
SIVcpz - Asymptomatic infection of chimpanzees (up to 1% in areas of west Central Africa)
HIV-1: M group consists of 11 clades
Last common ancestor entered human population around 1890 (+ 30 yrs)
Spread and recombination among founder HIV clades
HIV is a primate lentivirus
Lentiviruses can infect nondividing cells
Replication driven from long terminal repeats
Structural genes - gag, pol, env
Regulatory genes - tat, rev
Accessory genes - vif, vpr, vpu, nef
HIV life-cycle
TRIM5, TREX1, SAMHD1
APOBEC Tetherin
Innate HIV Resistance by APOBEC3G
Arias JF et al., Frontiers Microbiol 3 (275):1-12, 2012.
HIV vif sequesters
APOBEC enzymes from
the budding virions
Martin-Serrano J, SJD Neil. Host factors involved in
retroviral budding and release. Nature Rev Microbiol 9:519,
2011.
HIV Pathogenesis
M
DC-SIGN
1. Entry at sites of M cells or trauma (STDs)
2. Transit to LN via C-type lectins* on dendritic cells
3. Peak CD4+ T cell infection days 4-7
4. Viremia peaks day 14
5. All lymphoid tissues infected by day 23
*DC-SIGN, MR, Langerin
HIV infection occurs predominantly at mucosa
Dendritic cells mediate transit of virus to regional lymph nodes via CLRs
Massive loss of mucosa-associated lymphocytes of the small intestine precedes systemic CD4 T cell loss
Proposed epithelial damage mediates sustained activation of mucosal T cells after HIV infection
Brenchley, Price & Douek, Nat Immunol 7:235, 2006
HIV Receptors
CD4
R5
X4
1o Infection: M-tropic, CCR5
Turnover 1010 virions/day
Progressive CD4 T cell destruction
CXCR4
T-tropic
Syncytium-forming
Natural History of Untreated HIV Infection
Natural HIV Resistance
1. CCR532 - slow progression if infected
20% W. European Caucasians heterozygous
1% homozygous
Successful bone marrow tx
2. HLA class I homozygosity - rapid progression
3. Rare HLA class I alleles - slow progression (suggests virus near mutational threshold)