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Replication capacities of chimeric NL4-3 encoding gag-protease f rom recent HIV-1 isolates are significantly reduced compared to those derived from isolates in early days of epidemic in Japan .

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Backgrounds

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  1. Replication capacities of chimeric NL4-3 encodinggag-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

  2. 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

  3. 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

  4. plasma virus RT-PCR Methods Generation of chimeric viruses by homologous recombination gag-pro gag-pro ⊿gag-pro pNL4-3 Sequencing and subtyping infection Slope of GFP expression Measure % of GFP expression LTR-driven GFP reporter T cell line

  5. No correlation between pVL, CD4+ T cell count and first visit year pVL CD4 r=0.040 p=0.70 r=0.035 p=0.33

  6. Correlation between VRC and first visit year within a cluster in the phylogenetic tree CD4 T cell counts > 200 /ml, n = 145 stratified by CD4+ T cell count r = -0.0069 p = 0.00028** CD4 >300/μl CD4 >500/μl N = 55 NL4-3 JP US (n=22) (n=101) <Multivariate analysis> CN r p value year -0.0066 0.0012** CD4 -2.0e-5 0.72 log pVL 0.026 0.0097**

  7. 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

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