Oral Abstract Session 01 - Global HIV Vaccine Enterprise

Oral Abstract Session 10: HIV Transmission / Diversity
OA10.01
Impact of Transmitted CTL Escape Mutations on
Replicative Capacity and HIV Pathogenesis in Early
Infection
J. Prince 1 , D. Claiborne 1 , D. Heckerman 2 , J. Carlson 2 , H. Prentice 3 ,
M. Schaefer 1 , L. Yue 1 , J. Mulenga 4 , J. Tang 3 , P. Goepfert 3 ,
P. Farmer 1 , R. Kaslow 3 , S. Allen 1 , E. Hunter 1
1 Emory University, Atlanta, GA, USA; 2 Microsoft Research,
Los Angeles, CA, USA; 3 University of Alabama Birmingham,
Birmingham, AL, USA; 4 Zambia Emory HIV Research Project
(ZHERP), Lusaka, Zambia
Background: Multiple HLA class I alleles have been shown to
influence both HIV-1 transmission and viral load. In transmission
pairs, viral loads of acutely infected partners correlate with viral
loads (VL) of their chronically infected donors. This correlation
becomes highly significant after adjustment for host factors
known to modulate viral load. In addition, we have previously
demonstrated that transmission of a virus containing multiple
HLA-I associated polymorphisms resulted in a lower set point
VL in Zambian linked recipients. These studies imply that
transmitted viral characteristics play a role in defining early HIV-1
pathogenesis, and it will be important for vaccine development
to understand which viral characteristics are responsible for this.
Methods: We investigated the role that the in vitro replicative
capacity (RC) of the transmitted Gag plays in defining HIV-1
clinical parameters, by cloning gag genes from the founder
virus in newly infected partners of 149 epidemiologically linked
transmission pairs into the subtype C, R5 tropic MJ4 provirus.
Results: We observed a statistically significant positive correlation
between the RC of Gag-MJ4 chimeras and set point VL in
seroconverters (P=0.013). The RC of the transmitted Gag also
correlated (P=0.025) to the viral load in the chronically infected
donor, pointing to RC as the major viral characteristic responsible
for the link between donor and linked recipient viral loads. The
long term clinical benefit associated with the transmission of
attenuated viruses was investigated by performing a Kaplan
Meier analysis of time to CD4+ count less than 350. Individuals
infected with attenuated gag sequences (RC< 1) were delayed in
their progression to CD4+ counts < 350 compared to high (RC >2)
replicating viruses (P = 0.034).
Conclusion: Interestingly, this phenomenon seemed to be
independent of viral load perhaps highlighting the role that early
viral replication may play in defining HIV-1 pathogenesis.
Oral Abstract Sessions
OA10.02
A Deeper View of Transmitted/Founder Viruses
Using 454 Whole Genome Deep Sequencing
D.C. Tully 1 , K.A. Power 1 , H. Bedard 1 , C.L. Boutwell 1 , P. Charlebois 2 ,
E.M. Ryan 2 , N.J. Lennon 2 , M. Altfeld 1 , M.R. Henn 2 , T.M. Allen 1
1 Ragon Institute of MGH, MIT and Harvard, Boston, MA, USA;
2 Broad Institute of MIT & Harvard, Cambridge, MA, USA
Background: Understanding the composition of transmitted/
founder viruses that represent the primary target for vaccineelicited
responses is highly relevant to the design of an effective
HIV-1 vaccine. The identification of transmitted and early founder
viruses in primary infection has remained remarkably opaque,
but recent advances in sequencing technologies have enabled a
more comprehensive and sensitive assessment of the properties
of transmitted/founder viruses.
Methods: We applied full-length HIV-1 genome 454 deep
sequencing of plasma virus to 22 clade B subjects from a cohort
of men who have sex with men (MSM) identified during the
earliest phase of acute HIV-1 infection (Fiebig stage II to III).
Using novel assembly and variant detection algorithms coupled
with a mathematical model we were able to comprehensively
evaluate the viral diversity of transmitted/founder viruses in
these individuals.
Results: Using intra-host codon diversity frequencies, coupled
with a mathematical model of random virus evolution during
acute HIV-1 infection, we were able to unambiguously identify
that 30% of subjects exhibited convincing evidence for multiple
transmitted/founder viruses in line with prior reports on MSM
transmission. Surprisingly, deep sequencing outside of the Env
region identified additional low frequency variants possibly
reflective of evidence of multiple transmitted/founder viruses in
an additional 20% of subjects.
Conclusion: Our study reveals that, in line with prior reports,
approximately 30% of MSM subjects exhibit multiple transmitted/
founder viruses, with deep sequencing possibly identifying
additional cases of multiple founder viruses which will require
further validation. In summary, this data highlights the potential
that whole deep sequencing has to uncover additional footprints
originating from multiple transmitted/founder viruses. These
findings, coupled with the knowledge that dual infections are
associated with accelerated disease progression, demonstrate
that the higher risk of virus acquisition in MSM could be a greater
barrier for vaccine control which may have to contend with
multiple transmitted variants.
AIDS Vaccine 2012
83
ORAL ABSTRACT SESSIONS