Protective Immunity to HIV:
What Animal Models of HIV Infection
Can and Cannot Teach Us
Models of Protective Immunity to HIVXVI International AIDS Conference
August 13 – 18, 2006Toronto, Canada
Ruth Ruprecht, M.D., Ph.D.Dana-Farber Cancer Institute
Harvard Medical School, Boston
Vaccine-induced Protection Could be Due to…
• acquired immunity
• innate immunity
• both acquired and innate immunity
Vaccine-induced Protection Could be Due to…
• acquired immunity
• innate immunity
• both acquired and innate immunity
• viral interference (in the case of live attenuated SIV or SHIV)
Because rhesus monkeys are outbred and twin gestations are very rare, adoptive transfer of immune T cells is not feasible. Only the humoral arm of the immune system can be tested by passive immunization.
SHIV 1157ip: Summary• built from the SHIV-vpu+ backbone
• env was derived from an HIV clade C strain, HIV1157i, a primary R5 strain isolated from a six-month old Zambian infant who was HIV positive at birth
• replicates in rhesus macaque PBMC
• uses only CCR5 as coreceptor
• was adapted to rhesus monkeys by rapid animal-to-animal passage in five animals
• results in high peak viral RNA levels and persistent infection in infant and adult macaques
• was titrated orally in neonatal rhesus monkeys
• shows signs of pathogenicity in rhesus macaques: persistent viremia, depletion of memory T cells, loss of absolute numbers of CD4+ T cells, AIDS, thrombocytopenia
TM
gp120 gp41
SIVmac239
HXBc2
HIV1157i env
HIV1157i TM
LTRgag
pol
vifvpx
vpr vpu
1157i env
nef
LTR
tatrev
SHIV-1157i
oralSHIV-1157ip
mAbs
1hr
control (n=4)
treatment with 4x mAbs i.v. (n=4)
1 2 4
1 2 4d8
0
0
oralSHIV-1157ip
100 weeks
100 weeks
mAbs
Experimental Design
log
pla
sma
vira
l R
NA
lo
ad
(co
pie
s/m
l)
1
3
5
7
0 30 60 90
Weeks after inoculation
RPj-9
RTj-9
RWk-9
RZk-9
RPk-9
RSj-9
RTk-9
RVj-9
Week 40
Passive Immunization: 1h Post-Exposure Prophylaxis
The Correlates of Immune Protection
• The human anti-HIV mAbs used in the quadruple combination completely protected monkeys against mucosal virus challenge.
• These nmAbs, which recognize conserved epitopes and are active across clades, were the sole immune protective mechanism.
IgG1b12 : anti - CD4 binding site(b12)
2G12 : complex epitope on gp120 dependent on correct N-linked glycosylation
2F5 : linear gp41 epitope, ELDKWA
4E10 : linear gp41 epitope, NWFDIT
Epitope Specificity
Correlates of Immune Protection
IgG1b12 : anti - CD4 binding site(b12)
2G12 : complex epitope on gp120 dependent on correct N-linked glycosylation
2F5 : linear gp41 epitope, ELDKWA
4E10 : linear gp41 epitope, NWFDIT
Causes of Immune Protection
IgG1b12 : anti - CD4 binding site(b12)
2G12 : complex epitope on gp120 dependent on correct N-linked glycosylation
2F5 : linear gp41 epitope, ELDKWA
4E10 : linear gp41 epitope, NWFDIT
Protective Epitopes
IgG1b12 : anti - CD4 binding site(b12)
2G12 : complex epitope on gp120 dependent on correct N-linked glycosylation
2F5 : linear gp41 epitope, ELDKWA
4E10 : linear gp41 epitope, NWFDIT
In order to be as predictive as
possible, vaccine efficacy studies in
non-human primate models
should reflect the biology of HIV-1
transmission among humans as
closely as possible.
HIV-1 Transmission Among Humans
• 90% of all HIV-1 transmissions occur via mucosal exposure; this includes sexual transmission and mother-to-child transmission
• mucosal HIV-1 transmission involves R5 viruses almost exclusively, even if the source person harbors predominantly X4R5 and X4 strains
• recently transmitted strains of HIV-1 may be more sensitive to neutralization and encode shorter Env molecules than quasispecies that predominate in the source person (shown for clade C)1
1 Derdeyn et al., Science 2004; 303:2019-22; Li et al., J Virol 2006; 80:5211-8
Vaccine Challenge Studies in Primates:
Getting Real…
• mucosal route (intrarectal, intravaginal, oral) • R5-tropic virus• repeated low-dose vs. standard high-dose
challenges• neutralization-sensitive virus• virus lacking overwhelming, acute
pathogenicity• heterologous virus (with regard to vaccine)
Vaccine Challenge Studies in Primates:
Getting Real…
• mucosal route (intrarectal, intravaginal, oral) • R5-tropic virus• repeated low-dose vs. standard high-dose
challenges• neutralization-sensitive virus• virus lacking overwhelming, acute
pathogenicity• heterologous virus (with regard to vaccine)
Mucosal Challenge in Primates: Virus Dose Matters…
• The standard single high-dose virus challenge, designed to yield > 95% chance of infecting unvaccinated controls, does not reflect the HIV-1 inocula during sexual transmission
• High-dose challenge may overrun host defenses and set the bar for achieving protection too high
Repeated Low-dose Challenge: Lowering the Hurdle
• Example: using an R5 SHIV, Kim et al.1 performed weekly intravaginal challenges at low doses (10 TCID) in monkeys. Group 1 received the vaginal microbicide CAP 15 min prior to each virus inoculation; controls remained untreated. Whereas all controls became systemically infected after 3 to 4 weekly exposures, 3 out of 4 monkeys given CAP microbi-cide remained uninfected after 12 exposures (p = 0.015).
• CAP microbicide efficacy was 66% when tested against a single high-dose virus challenge; when tested against repeated low-dose challenges, efficacy was 92%.
1 J Med Primatol 2006; 35: 210-6 CAP = cellulose acetate phthalate.
Vaccine Challenge Studies in Primates:
Getting Real…
• mucosal route (intrarectal, intravaginal, oral) • R5-tropic virus• repeated low-dose vs. standard high-dose
challenges• neutralization-sensitive virus• virus lacking overwhelming, acute
pathogenicity• heterologous virus (with regard to vaccine)
Neutralization Sensitivity: Avoid “Stealth” Envelopes
• Late-stage viruses that have undergone multiple rounds of neutralizing antibody (nAb) selection followed by repeated escape develop more compact, hard-to-neutralize envelopes.
• Using viruses with such impenetrable envelopes in primates may set the bar for achieving vaccine protection unrealistically high.
• Neutralization resistance is an issue for SIVmac239 and primary SIVmac251 grown in rhesus monkey PBMC.
• Essentially, nAb-based vaccines cannot be evaluated for efficacy with these challenge strains.
Vaccine Challenge Studies in Primates:
Getting Real…
• mucosal route (intrarectal, intravaginal, oral) • R5-tropic virus• repeated low-dose vs. standard high-dose
challenges• neutralization-sensitive virus• virus lacking overwhelming, acute
pathogenicity• heterologous virus (with regard to vaccine)
The chance of a human AIDS vaccine
recipient to be exposed to an HIV-1
strain that exactly matches his/her
vaccine approaches zero…
Given the many HIV-1 quasispecies and their increasing divergence with time, human AIDS vaccine recipients will not encounter viruses exactly matched to their vaccine.
Vaccine efficacy testing in primates should reflect this reality. Exactly matching vaccine and challenge virus may overestimate the potential of new vaccines and raise unjustified expectations.
Success with homologous virus challenges may also stimulate the development of vaccine strategies that yield highly protective but only narrowly focused immune responses that fail to protect against divergent viruses.
Heterologous Virus Challenge: Reflecting Viral Complexity in Real Life
SHIV Challenges: Closer to the Real Thing
• SHIV chimeras allow efficacy testing of HIV-1 Env-based vaccines.
• SHIV chimeras allow testing of neutralizing antibodies isolated from HIV-1-infected individuals.
• As such, vaccine development could be significantly accelerated because primate-tested reagents can be directly used in clinical trials.
• In contrast, SIV challenges only allow the evaluation of active or passive immunization concepts but not the actual vaccines or antibodies intended for human use.
Summary
• AIDS vaccine efficacy studies in primate models should focus on mucosal challenge with R5 strains
• SHIVs have the added advantage of directly testing anti-HIV-1 Env responses
• SHIVs allow development of passive immunization with human anti-HIV-1 Env nmAbs in primates
• Challenge viruses should encode neutralization- sensitive, primary envelopes
Summary, continued
• To reflect HIV heterogeneity, vaccine and challenge virus should not exactly match. Ideally, primate vaccine efficacy studies should employ fully hetero-logous virus, rather than one differing in env only.
• Replacing single high-dose viral challenges with
repeated low-dose mucosal exposures has shown promise.
• Ultimately, efficacy data generated in primate models
need to be compared directly to phase III clinical vaccine trials for validation.
Acknowledgements
DFCI / Harvard Medical SchoolRuijiang SongRobert RasmussenAgnès Chenine
Mila Ayash-RashkovskyLauren GoinsRicky GrissonPei-lin LiChantelle McCannSaied MirshahidiHelena OngClaudia RuprechtEla Shai-KobilerTao WangJames WhitneyW. XuL.-Y. Yeh
Beth-Israel Deaconess Medical CenterLisa CavaciniMarshall Posner
Institute of Applied Microbiology, Vienna, AustriaHermann Katinger Gabriela Stiegler
Harvard School of Public HealthJanet Andersen
Memorial Sloan-Kettering Cancer CenterTing Chao Chou
Yerkes National Primate Research Center
Harold McClure† James Else Elizabeth Strobert
Centers for Disease ControlW. Evan Secor
University of NebraskaCharles Wood H. Zhang
Univ. Teaching Hospital, Lusaka, ZambiaGanapati Bhat Chipepo Kankasa
University of WashingtonShiu-lok Hu Patricia Polacino
NIAIDHIV-RAD P01: Nancy Miller
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