Oral Abstract Session 01 - Global HIV Vaccine Enterprise

Topic 3: B Cell Immunology and Antibody Functions
P03.13
Cross-Reactive Neutralizing Activity in HIV-1 Infected
Injecting Drug Users
Z. Euler 1 , M.J. van Gils 1 , H. Schuitemaker 1
1 Academic Medical Center, University of Amsterdam,
Amsterdam, Netherlands
Background: Vaccine elicited HIV-1 specific cross-reactive
neutralizing humoral immunity may provide protection against
acquisition of HIV-1. Several studies have focussed on a better
understanding of cross-reactive neutralizing activity (CrNA) in
natural infection, but only in homosexual and heterosexual HIV-1
transmission cases.
Methods: To analyze the prevalence and characteristics of CrNA
in HIV-1 infected individuals who reported injecting drug use as
the only risk factor, we screened serum samples from 50 male
and 35 female participants of the Amsterdam Cohort Studies
(ACS) on injecting drug users (IDU) for CrNA across a heterologous
6-viral panel. For comparison, similar data from the ACS on men
who have sex with men (MSM) were available.
Results: HIV-1 infected IDU showed significantly lower geometric
mean IC50 values and a lower proportion of individuals that
was capable of neutralizing the majority of viruses in the panel
as compared to MSM. This difference was however no longer
observed when women were excluded from the IDU group.
Interestingly, three out of 50 in the male IDU population qualified
as elite neutralizer as compared to 1 out of 299 among MSM.
Multivariate analysis with viral load at setpoint, CD4+ count at
setpoint, gender and transmission route as co-variates revealed
only CD4+ count at setpoint as independently associated with
CrNA in serum.
Conclusion: CrNA prevalence and potency in HIV-1 infected
IDU was lower than in MSM. This could be attributed to the
presence of women in the cohort, rather than the route of
exposure, which could be explained by the fact that women
had a higher CD4+ T cell count at setpoint, which was the only
independent predictor for the presence of CrNA. Our data may
implicate that the ability of an HIV-1 vaccine to elicit CrNA may
be lower in women and testing for gender dependent future
vaccine efficacy may be recommended.
P03.14
AIDS Vaccine 2012
Posters
Structural Definition for a New Modality of Broad
and Potent Antibody Neutralization at the CD4-
Binding Site on HIV-1 gp120
T. Zhou 1 , S. Moquin 1 , R. Lynch 1 , X. Wu 1 , J. Zhu 1 , Y. Yang 1 ,
B. Zhang 1 , J.R. Mascola 1 , P.D. Kwong 1
1 National Institute of Allergy and Infectious Diseases/NIH,
Bethesda, MD, USA
Background: The initial site of CD4-attachment on HIV-1 gp120
is vulnerable to neutralizing antibodies, and a number of such
antibodies have been found that target this site. One set of
antibodies, represented by VRC01, mimic CD4 in their recognition
and utilize a common V-gene origin (VH1-2*02). Another set of
antibodies, represented by the recently identified VRC13, derives
from VH1-69*01 and is able to neutralize over 90% of circulating
HIV-1 isolates, including isolates resistant to VRC01. Do the
VRC13-like antibodies also mimic CD4, or do they represent a
new modality of effective CD4-binding-site neutralization?
Methods: To define the mode of recognition used by VRC13, we
crystallized its antigen-binding fragment in complex with HIV-1
gp120, from both VRC01-sensitive and VRC01-resistant strains,
and determined these X-ray structures.
Results: The structure of VRC13 indicates a mode of recognition
rotated by 45 degrees and translated ~10 Å from that of VRC01,
although both VRC01 and VRC13 utilize similar angles of
approach. Unlike VRC01-like antibodies, which feature gp120
contacts primarily in the heavy chain 2nd complementarity
determining region (CDR H2), VRC13 utilizes a long heavy chain
CDR H3 to contact the CD4-binding site. Overall, the structural
details of VRC13 do not mimic those of CD4.
Conclusion: Broad and potent neutralization at the CD4-binding
site is not limited to the VRC01-mode of CD4 mimicry. A new
mode of effective HIV-1 neutralization, which is defined by the
VRC13-gp120 structure and utilizes CDR H3 recognition, may
serve as an additional template for the design of an effective
HIV-1 vaccine. The natural diversity of the CDR H3 – a product of
V-D-J recombination – may provide advantages in the elicitation
of VRC13-like antibodies.
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POSTERS