Prevention of infection 2 : immunisation. How infection influences the host : viruses. Peter

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1 Prevention of infection 2 : immunisation How infection influences the host : viruses Peter Balfe,

2 Let s have some LO s just for fun 1. Define the Immune response to viruses, using vaccines as an example 2. Use HIV-1 as an example of how viruses interact with their hosts at a local level 3. Use CCR-5 as an example of pathogen driven host evolution. 4. Use HERVs as an example of how viruses have been co-opted by the immune system

3 Innate and Adaptive Immunity (Innate) (Adaptive) Image from: Understanding Viruses, 2nd Edition Jones & Bartlett Learning

4 The benefit of vaccination and B cell memory Vaccine Infection Immunological memory normally develops during/after an infection Vaccines are artificial ways of introducing memory against a pathogen

5 Live- attenuated The pathogenic virus is isolated and grown in nonpermissive cells to encourage mutations that attenuate growth in the original host From: Principles of Virology: Flint 2 nd Ed

6 Attenuation of Measles From Principles of Virology 2 nd ed: Flint

7 The reasons for loss of pathogenesis Sabin type 3 polio vaccine From Principles of Virology 2 nd ed: Flint

8 Inactivated Virus is inactivated with UV, chemicals or heat e.g. inactivated polio vaccine (IPV) and then injected UV and chemicals (e.g. formalin, phenol and β-propiolactone) are more commonly used than heat because heat often destroys surface exposed antigens, reducing immunogenicity Image from: Understanding Viruses, 2nd Edition Jones & Bartlett Learning

9 Attenuated or Inactivated Vaccine? Technical Not all pathogens can be grown in alternative hosts often the yield of virus grown in culture is low, increasing cost Both of these vaccine types have a limited shelf life and often require refrigeration Safety issues Incomplete inactivation is a potential risk Reversion of attenuated virus to virulence Duration of immunity Attenuated more enduring than inactivated

10 Responses to Live or Inactivated Vaccine From: Principles of Virology: Flint 2 nd Ed

"Well, in our country," said Alice, still panting a little, "you'd generally get to somewhere else if you run very fast for a long time, as we've been doing. "A slow sort of country!" said the Queen.

11 "Well, in our country," said Alice, still panting a little, "you'd generally get to somewhere else if you run very fast for a long time, as we've been doing. "A slow sort of country!" said the Queen. "Now, here, you see, it takes all the running you can do, to keep in the same place. If you want to get somewhere else, you must run at least twice as fast as that!" The Red Queen hypothesis The parasite (HIV) is in a constant arms race with it s host (the human immune system) in order to maintain itself. This interplay of host and parasite can persist in a meta-stable state for years (for HIV, until the host immune system fails). Slide 11

12 HSV - the perfect game of hide n seek An Aside about Herpes Simplex HSV infection leads to skin lesions and spread to new hosts. However a successful immune response to infection eliminates the virus from the skin. HSV evades the immune response by becoming quiescent. In LATENT infection the HSV genome resides in the nucleus of the host cell and produces NO proteins, just controlling mrna transcripts called Latency Associated Transcripts (LATs) Immune recognition REQUIRES protein, latent HSV doesn t make any. Slide 12

13 The LATs of HSV produce a spectrum of micro RNAs (mirnas) which act to control the host cell, even though the virus produces no protein There is a long list of factors recognised by the host immune system. Problem is, nothing on that list is present in latent HSV infection Image from: Umbach et al, MicroRNAs expressed by herpes simplex virus 1 during latent infection regulate viral mrnas Nature 454: Slide 13

14 Phylogenetic analysis of sequences obtained from animal T353 over time: Speed! WEEK: DNA & RNA Inoculum RNA substitutions/site Balfe et al Virology, sequences

15 Investigation of viral evolution in HIV-1 seroconverters 1. The number of viral particles required to initiate a new HIV-1 infection is very small 2. At the time of infection, HIV-1 goes through a genetic bottleneck, where all sequence variation is lost 3. The very first virus samples obtained are invariant 4. Seroconverting patients identified by discordant diagnostic assay results 5. Virological and immunological parameters monitored 6. Sequence changes measured at two different timepoints to assess rate of viral evolution at the start of infection 7. All sequence changes seem to matter

16 Acute viraemia and seroconversion Viral Load (copies/ml) Seroconversion p Day

17 Establishment of the asymptomatic state A relatively stable viral load set point is established early after seroconversion. This set point is due to the equilibration of immune response (CTL and Ab) with viral production. Individuals in whom this set point is lower are thought to have a better prognosis. Viral load 10 6 Set point vrna 0 0 Weeks Years 15 Time

18 Persistent HIV-1 Infection Measurement vrna CD4 CTL vabs 0 0 Weeks Years 15 Time

19 Two major types of HIV polymorphism Length polymorphism Substitutional polymorphism V1 V2

$Monitoring early infection 180,000 160,000 140,000 120,000 100,000 \ 80,000$ 24 28 32 36 40 Seroconversion Defined as: PCR +ve (DNA/RNA) but Fuji,

20 Monitoring early infection 180, , , , ,000 \ 80,000 60,000 40,000 20,000 0 Viral load during seroconversion (EJ5) Seroconversion Defined as: PCR +ve (DNA/RNA) but Fuji, Wellcozyme, Vidas -ve Sampling: 0 and 3 days, then 1, 2, 3, 4, 8, 12, 16, 24, 36 and 52 w

21 Degree of sequence change Almost no variation at 1st timepoint Genetic bottleneck Increase in polymorphism with time Change in sequence length between two timepoints (V1, V2, V4 loops) No. of changes on average in gp120:

22 Rapid sequence replacement during seroconversion Positions which are completely REPLACED between 1st and 2nd sampling Gp120 has a mix of conserved (C) and Variable (V) domains V1 V2 V3 V4 V5 Patient 1 Patient 2 These positions have ALL been mapped to either CTL or neutralizing antibody epitopes

23 Rapid sequence replacement during seroconversion Several previously described immunological targets are seen to change gp120 CTL (Borrow et al 1997) V3 loop sequence EJ7.2.1 EJ7.2.2 EJ7.2.3 EJ EJ EJ AEKLWVTVYY TEKLWVTVYY TEKLWVTVYY TEKL-VTVYY TEKLWVTVYY TEKLWVTVYY :***.***** AENLWVTVYY EJ7.2.1 EJ7.2.2 EJ7.2.3 EJ EJ EJ CTRPNNNTRKSIHMGPGGALYTTGAIIGDIREAHC CTRPNNNTRKSIHMGPGGALYTTGAIIGDVREAHC CTRPNNNTRKSIHMGPGGALYTTGAIIGDIREAHC CTRPNNNTRKGIHLGPGGAFFTTGAIIGDIREAHC CTRPNNNTRKGIHLGPGGAFFTTGAIIGDIREAHC CTRPNNNTRKGIHTGPGGALYTTGAIIGDIREAHC **********.**.*****::********:*****

24 Early humoral responses to HIV infection Autologous serum recognition of gp120 proteins derived from a Seroconvertor quasispecies Antigen Recognition by: Patient Serum (day) QC g 10.46c Mock LAI MN V3 peptide

25 General Summary The HIV-1 seroconvertor cohort as an example of mutation and change Viral evolution allows escape from selective forces Viral change happens faster than the immune system can respond No convergent changes are seen (5 patients), evolution is blind

26 gp41 Virus CCR5 32 gp120 2 trimeric viral spike 1 3 GAG CD4 Cell Chemokine receptor CCR-5

27 CCR5 and the Black death Cline of CCR5 32 mutations in Europe

28 gp41 Virus CCR5 32 gp120 2 trimeric viral spike 1 3 GAG CD4 Cell Chemokine receptor CCR-5

29 CCR5 32 In the European population there is a variant of the CCR5 gene which has lost 32 nucleotides in the ORF 32/3 = a frame shift mutation leading to loss of CCR5 protein CCR5 32 heterozygotes express lower levels of CCR5, homozygotes express none and are resistant to HIV-1 infection The lack of CCR5 is protective against infection by yersinia pestis CCR Survivors of the Black death The further north in Europe you go the higher the incidence of the gene. ~20% of the population of Finland carry CCR5 32

30 Timothy Brown,- the Berlin patient Received bone marrow transplant from CCR5 32 homozygote donor in Stopped HAART before operation. HIV undetectable after 7 years. 30

31 HERVs Is this where HIV is heading? Slide 31

32 HERVs The best adapted retroviruses incorporate themselves into the germ-line by getting into the gametes. They become self in the second generation. A large part of your genome (8-9%!) consists of these Slide 32

HERVs can be useful TI-2 recognition of carbohydrate antigens and genesis of IgM is mediated by endogenous retroviruses expressed in response

33 HERVs can be useful TI-2 recognition of carbohydrate antigens and genesis of IgM is mediated by endogenous retroviruses expressed in response to BCR engagement MAVS, cgas, and endogenous retroviruses in T-independent B cell responses Zeng et al. Science, 2015, 346: Slide 33

Lecture 11. Immunology and disease: parasite antigenic diversity

Lecture 11. Immunology and disease: parasite antigenic diversity Lecture 11 Immunology and disease: parasite antigenic diversity RNAi interference video and tutorial (you are responsible for this material, so check it out.) http://www.pbs.org/wgbh/nova/sciencenow/3210/02.html