Retrospectacle: A Neuroscience Blog

One reason that treatments for the human immunodeficiency virus (HIV) are particularly difficult to develop is that HIV is quite good at adapting resistance to drugs. Many of the virus' surface proteins--natural targets for inhibitory drugs--have a high turnover rate and are easily changed. There are a few exceptions; a few well-conserved surface proteins that are integral to HIV's function. One of these is the protein gp41 (below), which is required for HIV to attach onto a host cell, and infect it.

However, a recent paper in Cell describes a naturally-occurring blood molecule called VIRIP (virus inhibitory peptide) which can bind to gp41, preventing the HIV virus from ever infecting cells. Furthermore, they've found a way to modify VIRIP to be 100x more potent.

(Continued below the fold...)

HIV is tiny (it 1/60 the size of a red blood cell) and has a unique composition. Within an cellular envelope (capsid) are 2 copies of single-stand RNA which code the viruses nine (yes, just nine) genes. Also within the capsid are proteins and enzymes needed for the survival and propagation of the virus. At the surface are many "Env complexes" which consist of gp41 molecules (green) and gp120 molecules (purple). These complexes are what gives the HIV virus the ability to attach to and infect human cells, dumping the capsid into the host cell and forcing it to make more HIV virus (see diagram below.)

Keeping that in mind, Munch et al. discovered that an endogenous human blood molecule called VIRIP binds to gp41 which prevents the virus from being able to attach to a host's cells. This precludes infection and viral replication, and therefore looks to be a innovative and promising therapy. This also helps to explain why some people are naturally more resistant to HIV infection. VIRIP levels in people are variable, however VIRIP levels in humans and infective risk has not yet been investigated. This therapy is promising in another regard in that gp41 molecules are required for viral function. While HIV may be wily at adapting to drugs and hosts, this is a protein that must stay put, making it a prime therapeutic target.

However, the group noticed that while regular VIRIP worked pretty well, a slight modification in VIRIP's structure (changed three amino acids) rendered it 100 times more effective at binding to and inactivating gp41. Changing the structure in another way made VIRIP inactive, which indicated the binding site (ie, don't mess with that.) The modified VIRIP inhibited every variant of HIV-1 (most common human type) that they tested, but did not change the infectivity of HIV-2 or SIV or Ebola, etc.

Trivia: The authors initially isolated endogenous VIRIP from over 10,000 liters of blood! After that, they made artificial VIRIP.

Source: Munch et al. 2007. 129. Cell.
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