Lessons Learned from Transient
Remission Cases:
Clues to Biomarkers of HIV Rebound
Katherine Luzuriaga, MD
University of Massachusetts Medical School
Worcester, MA
USA
www.ias2015.org
Global Eradication of Pediatric HIV-1 Infection
• New pediatric infections (MTCT) cut by
50% between 2001 and 2012: 900,000 new
infections prevented since 2009
• 3.2 million children < 15 yrs living with HIV
• 1.5 million HIV-1+ women give birth each
year; only ~68% receive ART for PMTCT
• 240, 000 children acquire HIV-1: one new
infection every 2 minutes
UNAIDS, 2014
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Rationale for Early cART
• Rapid tempo of disease progression in HIV infected
infants
• Median viral loads > 105 copies/ml over first 2 years
of life
• High rates of viral production
• Less robust adaptive HIV-specific immunity
• Ready identification of infants at risk and ability
to make early nucleic acid-based rapid diagnosis
• Early cART reduces HIV-related morbidity and
mortality (Violari et al, NEJM, 2008)
• Early HIV diagnosis and cART are globally
recommended as standard of care
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Early cART restricts the latent reservoir
Restricted latent reservoir if
treated < 6 wk (red circles) vs.
> 6 wk (blue circles)
Reservoir decays over the
first 2 yrs in early-treated
infants (half-life 11 months
[95% CI: 6 to 30 months]
Remains detectable in most
(60%) at two years of age
Persaud et al. AIDS, 2012
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Lower PBMC DNA Levels In Children
With Younger Age at Virologic Control
2-LTR DNA circles
detectable in 20% of
youth:
Proviral DNA copy
number higher in those
with detectable (median
= 191) than in those
with undetectable
(median = 23)
2-LTR circles
Median
4.2
19
71
Persaud et al, JAMA Pediatr, 2014
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Clearance of HIV-specific Antibodies is a
Hallmark of Early Effective cART in Infants
EIA negative at 15 months:
A.
Durable HIV RNA suppression
to < 400:
11 (73%) of 15 infants
B. Early tx, incomplete /transient
suppression:
None (0%) of 5
C. HIV-uninfected infants born to
HIV-infected women:
5 (100%) of 5
D. HIV- infected infants first
treated > 12 mo:
None (0%) of 4
Luzuriaga et al, J Virol, 2000
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Low Proviral DNA Loads in Children with
HIV-1 Negative or Indeterminate Wb
Persaud et al, JAMA Pediatr, 2014.
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Early and Very Early Therapy Restrict the Size
and Modify the Persistence of HIV-1 Reservoirs
Contribution to the
proviral reservoir:
TTM > TCM, EM
Luzuriaga, CROI, 2014; Persaud, CROI, 2015; Luzuriaga,
JID, 2014; Persaud, JAMA Peds, 2014; Ananworanich,
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AIDS, 2014; van Zyl, JID, 2015; Bitnun, CID, 2014
HIV Remission Following Very Early cART
 ARV administered 31 hours - 18 months
 Remission 28 months off cART
•
•
•
•
No detectable HIV-1 in routine or scRNA assay
No replication-competent virus recovered
No detectable HIV-1 specific antibodies or CD4/CD8+ T cells
Absence of host factors associated with elite control
 Viral Rebound at age 46 months
SC RNA: 9 copies/ml
AZT/
3TC/
NVP
AZT/
3TC/
LPV/r
AZT/
3TC/ +RAL
EFV
Persaud et al, NEJM, 2013; Luzuriaga, NEJM, 2015
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HIV-1 rebound despite limited proviral
and latent reservoirs
MS Baby
Canadian
Milan 1
Milan 2
Timing of
infection
Time to rebound
IU
IU
IU
IU
27 mo
< 1 mo
1 mo
< 1 mo
Pre-ART RNA
19,812
808
15,300
152, 560
Time to RNA< 400
Time on ART
Cell-associated
DNA
Viral outgrowth
< 1 mo
18 mo
6 mo
3 yr
1 mo
2 yr
3 mo
3 yr
+/-
-
-
-
-
-
ND
- culture
HIV Ab
HIV-sp T cells
No T cell
activation
-
+
+
+ T cell
activation
Other
+ CAR
Bitnun, CID, 2014; Giacomet, PIDJ, 2014; Persaud, NEJM,
2014; Luzuriaga, NEJM, 2015; Vigano, J Peds, 2006
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Summary: Early/Very Early cART Alters HIV1 Persistence in Children
• Limits proviral and replication competent
reservoirs
• Size correlated with the rapidity of control of
HIV replication
• Decay rapidly over first year of therapy
• Slower decay with prolonged suppression of
HIV replication
• Decay in HIV proviral reservoirs over time in
absence of HIV-specific immune responses
suggests that early cART limits infection of
long-lived cells
• Contribution to the proviral reservoir: TTM > TCM,
EM
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Markers for low-level proviral and
latent reservoirs
• Plasma RNA below detection
limits of single copy assays
• Lack of detectable 2 LTR DNA
circles
• Absence of T cell activation
• Lack of HIV-specific antibodies,
and CD4 and CD8+ T cell
responses
Luzuriaga et al, J Virol, 2000;
Persaud et al, JAMA Peds, 2014;
Ananworanich et al, AIDS, 2014
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Pathways to Remission:
Post-Treatment Controllers
 Adults: 5-15% treated during PHI
• On cART 12-192 mo (median 36 mo)
• Remission off cART: 48-115 mo (median 89 mo)
• Low level T cell activation and HIV-specific T
cell responses
• Low circulating HIV-1 DNA levels (median 52
c/106 PBMC), with progressive decline over
time in some
 Pediatric case
• Infected despite infant ARV prophylaxis
• Received cART ~3 mo – 6 years
• Plasma HIV-1 RNA < 50 for 12 years, except for
blips at 1, 2, 11, and 14 years; now < 4-9 c/ml
• HIV-1 DNA 125-136 copies per million PBMC
Saez-Cirion, PLoS Pathogens, 2013
Saez-Cirion, IAS, 2015
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Current Protocols
 IMPAACT P1115: Very Early Intensive Treatment
of HIV-Infected infants to achieve HIV
remission: A proof of concept study
 IMPAACT P1107: Cord Blood Transplantation
with CCR5Δ32 Donor Cells in HIV-Infected
Subjects who Require Bone Marrow
Transplantation for any Indication and its
Observed Effects on HIV-1 Persistence
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Early/Very cART and HIV
Persistence in Children

HIV positive infants and children with
persistent suppression of HIV on cART are
excellent candidates for additional strategies
aimed at remission, particularly therapeutic
vaccines:
• Normal immune responses
• Absent HIV-specific immunity
• Limited viral diversity
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Acknowledgements
Children and Families
Hannah Gay and Deborah Persaud
Persaud Lab: Carrie Ziemniak, Ya Hui Chen
Luzuriaga Lab: Margaret McManus, Linda Lambrecht,
Joyce Pepe, Robin Brody, Keri Sanborn, Jim
Coderre, Mohan Somasundaran
Collaborators: Matthew Strain, Danielle Murray,
Douglas Richman, Tae-Wook Chun
Manuel Garber, Barbara Tabak
Funding: NIAID, NICHD,
AmFAR, JHU CFAR, UMMS
CFAR, UMass Center for
Clinical and Translational
Science
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