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Replication capacities of chimeric NL4-3 encoding gag-protease from recent HIV-1
isolates are significantly reduced compared to those derived from isolates
in early days of epidemic in Japan
Shigeru Nomura, Noriaki Hosoya, Tadashi Kikuchi, Michiko Koga, Hitomi Nakamura, Tomohiko
Koibuchi, Takeshi Fujii, Ai Kawana-Tachikawa, Aikichi Iwamoto, Toshiyuki Miura
The Institute of Medical Science The University of Tokyo
Backgrounds• HIV-1 evolves rapidly, escaping from host selection
pressures like CTL response• Some CTL escape variants with reduced replication
capacities could transmit from one person to another• Escape variants accumulate in a population and could
replace previously dominant forms• Recent isolates may have distinct replication capacity
from those from early days of HIV epidemic
Objectives
• To investigate if HIV-1 replication capacity has been changed over the epidemic in Japan
Studied Population
• 158 treatment naïve Japanese with
asymptomatic chronic HIV-1 infection
• Research Hospital of the University of Tokyo
from 1994 to 2009
• Sexual Intercourse (85% were MSM)
• Plasma from near first visit
• Limited to cladeB infection
Generation of chimeric viruses by homologous recombination
RT-PCR
plasma virus
Slope of GFP expression
gag-pro
LTR-driven GFP reporter T cell line
⊿gag-pro pNL4-3
gag-pro
infection
Measure % of GFP expression
Methods
Sequencing and subtyping
No correlation between pVL, CD4+ T cell count and first visit year
r=0.035p=0.33
r=0.040p=0.70
pVL CD4
JPUSCN
NL4-3
N = 55
within a cluster in the phylogenetic tree
r p valueyear -0.0066 0.0012**CD4 -2.0e-5 0.72log pVL 0.026 0.0097**
<Multivariate analysis>
r = -0.0069p = 0.00028**
CD4 T cell counts > 200 /ml, n = 145
(n=22)
CD4 >500/μlCD4 >300/μl
(n=101)
stratified by CD4+ T cell count
Correlation between VRC and first visit year
Conclusions and Limitations
• Recent HIV-1 circulating in Japan may have reduced In vitro replication capacity
• Investigation was limited to Gag-protease
• Backbone of chimeric viruses: – NL4-3 is an early laboratory strain
• 15 years may be too short