Zhiwei CHEN

AIDS Institute and Dept of Microbiology LKS Faculty of Medicine The University of Hong Kong

(HA Convention, May 19, 2015)

F.  Barre-­‐Sinoussi  &  L.  Montagnier  

2008    

Discovery of AIDS in 1981

AIDS No  AIDS

AIDS

SIVrcm  from  RCMs  Chen  et  al.  JEM.  1997  

SIVsm  from  wild  SMs  Chen  et  al.  JV.  1996  

0.01

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Liu et al.. JAIDS. 2005

Zhuang et al. JAIDS. 2003 Su et al. AIDS. 2003. Zhang et al. J Virol. 2004.

Lu et al. Nature 455, 2008 Y Zhang et al. PLoS Med. 2006

New HIV/AIDS Infections Surged 15% in China in 2014

X  Yao,  …,  Z  Chen*.  JAIDS.  2012  

(Source:  HK  AIDS  Office,  2015)

 

Risk factors：number of partners、partners’ infection status，STDs

Johnston  et  al  AIDS  2009  

Problems: AMC does not protect women and MSMs (JAMA. 2008 Oct 8;300(14):1674-84); Lancet. 2009 Jul 18;374(9685):229-37

Quinn  et  al,  NEJM  342(13):921-­‐9,  2000.30    

•  Mucosal secretions contain a lot of viruses

RNA  Viral  Load  in  HIV+  Source  Partner    

Annu

al  Frequ

ency    

of  Transmission

 

0  5.2  

25  30.3  

38  

0  

10  

20  

30  

40  

50  

<400   400-­‐3,500   3,500-­‐  10,000  

10,000-­‐  50,000  

>50,000  

Strategy: “Seek and Treat” Challenges: low adherence, drug

toxicity, resistant mutants, aging, neuroAIDS

Rate of death in US since 1996 (US CDC)  

4X PAIC90 1X PAIC90

First  vRNA  detecPon  

Andrews et al, Science 2014

Nature  Medicine  20,  296–300  (2014)    David  BalVmore  

IY31CH23-Lanzavecchia ARI 15 February 2013 23:22

V1-V2 site:PG9, PG16,

CH01-CH04,PGT141-145

V3-tip:447-52D,HGN194

V3/V4/glycans:PGT121–123,

10–1074, PGT135-137

Glycans:2G12

CD4i:17b

Glycan-V3 β-strand:PGT125–131

CD4bs:b12, HJ16,

VRC01, VRC03,NIH45-46, 3BNC117,

3BNC60, PGV04,CH30-34, J3

MPER:2F5, 4E10,

Z13, m66, 10E8

N332

V1-V2V3

CD4i/V3:3BC176, 3BC315

N301

N156N160

PG9

PGT128

VRC01

VRC01 b12 CD4 NIH45–46 PGV04

Figure 2Model of the HIV-1 Env trimeric glycoprotein bound to broadly neutralizing antibodies. The tridimensional model of the Env trimer(Electron Microscopy Data Bank code EM-5019) with two of the three gp120 subunits highlighted in gray was positioned on amodeled lipid bilayer (64). The left panel shows the major sites targeted by broadly neutralizing antibodies. The approximatepositioning of the V1/V2 and V3 loops is shown, and the CD4 footprint on the gp120 monomer is highlighted in blue. The right panelshows the Fabs of broadly neutralizing antibodies VRC01 (3ngb), PG9 (3us2), and PGT128 (3tyg) bound to gp120. Carbohydrates(oligomannose, red spheres) were modeled on the unliganded YU2 gp120 core (3tgq) using GlyProt, with the exception of the glycansbound by PGT128 and PG9 (depicted with different colors), which were taken from the structures. The location of PG9 above thetrimeric gp120 is approximate; VRC01 and PGT128 Fabs were docked by superposition with the unliganded YU2 gp120 model. Thebottom panel shows in blue the footprints of CD4 (1gc1) and the CD4bs-specific antibodies PGV04 (3se9), NIH45-46 (3u7y), b12(3dnl), and VRC01 (3ngb). Figures were made with PyMOL.

www.annualreviews.org • Broadly Neutralizing Antiviral Antibodies 711

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SG  Hansen  et  al.  Nature  000,  1-­‐5  (2011)  doi:10.1038/nature10003  

Shan   et   al.     SPmulaPon   of   HIV-­‐specific   CTL   facilitates   eliminaPon   of   latent   viral  reservoir  aXer  virus  reacPvaPon.  Immunity.  2012.  36:491-­‐501.    Hansen  et  al.  Immune  clearance  of  highly  pathogenic  SIV  infecPon.  Nature.  2013.  (Oct)  502,  100–104.  “The  virus-­‐specific,  effector  memory  T  cells  maintained  by  a  persistent  vector  (CMV)  can  funcPonally  cure  and  possibly  eradicate  this  infecPon.”          

Tan,  Z…Chen  Z*.  Cancer  Research.  2014  

1981  AIDS  idenPfied

1983/84  HIV  idenPfied  as  the  cause  of  AIDS

1995  HAART  introduced

2009  RV144:modest  efficacy  (31.2%)

2009-­‐2013  mulPple  HIV-­‐1  bNAbs  isolated

1.  Lack  of  a  TherapeuKc  Cure        

2.  Lack  of  an  EffecKve  Vaccine    

35  million  deaths,  35  million  PLHIV  

2008    

2  million  new  infecVons/year  

Asia:  the  2nd  largest  epidemic  region  

We thank HK-RGC762209M /762712, CRF-HKU5/CRF/13G, ITS/194/13, PCFB, ATF and HKU-UDF/LKSFM Matching fund.