HIV master of disguise

HIV master of disguise - N&V-nm0403.qxd 3/17/03 4:26 PM...

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NATURE MEDICINE • VOLUME 9 • NUMBER 4 • APRIL 2003 393 NEWS & VIEWS H IV-1 mutates to avoid recognition by the host immune response. This al- lows the virus to chronically replicate and to eventually wear down the body’s defenses by destroying the very cells necessary to coordinate an effective im- mune response 1 . A key feature of im- mune escape is the ability of HIV-1 to conceal itself from neutralizing anti- bodies that would otherwise bind the virus and block its entry into cells. This stealth-like property may explain why antibodies generated by candidate HIV- 1 vaccines neutralize so few strains of the virus. This has frustrated attempts to develop a vaccine because neutraliz- ing antibodies are believed to be a key component of the protective immune response. The disappointing results of the first phase 3 trial of a candidate AIDS vaccine, AIDSVAX (see page 376 ) , based on the gp120 viral envelope gly- coprotein, highlight how tough it is to generate a protective antibody response against HIV-1. In the March 20 2003 issue of Nature , Wei et al. add a new level to our under- standing of the mechanisms used by HIV-1 to resist neutralization by circu- lating antibodies 2 . Specific genetic changes in the HIV-1 envelope glyco- proteins seem to result in the acquisi- tion and rearrangement of sugar moieties (asparagine-linked glycans), forging them into an evolving protec- tive shield that prevents antibody bind- ing. Neutralization epitopes reside on the surface gp120 and transmembrane gp41 envelope glycoproteins, which are de- rived from a gp160 precursor molecule. These glycoproteins form a complex that mediates receptor and co-receptor binding and the subsequent membrane fusion events that permit virus entry 3 . HIV-1 is neutralized when antibodies bind critical regions on either glycopro- tein, thereby disrupting the entry process. During the course of infection, the virus survives by mutating to escape an- tibody recognition 4 . The viral escape variants elicit subsequent neutralizing antibody responses. Multiple rounds of neutralization-escape are thought to ex- plain, in part, how HIV-1 persistently replicates in the host. A similar phe- nomenon occurs during infection with several other animal lentiviruses 5–7 . HIV-1 neutralization escape is not al- ways a simple matter of changing the contact amino acids in the cognate epi- tope. Some epitopes, such as those that directly bind the receptor, need to be preserved to maintain viral fitness. HIV- 1 has devised several clever strategies to mask these conserved epitopes 8 . The re- ceptor binding domains are positioned in recessed pockets on the gp120 mole- cule, where access to antibody is lim- ited. Other epitopes are shielded by conformationally flexible tertiary folds on the gp120 molecule.
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HIV master of disguise - N&V-nm0403.qxd 3/17/03 4:26 PM...

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