Thursday, August 13, 2015

HIV-1 Vaccine Development

It has been over thirty years since the discovery of HIV-1 as the virus responsible for AIDS.  It has been a long-standing goal to produce a vaccine able to induce cross-reactive antibodies that are capable of neutralizing the infectious capability of the HIV-1 virus in all its variant forms.  Progress in this direction has been impeded due to the complexity of the surface envelope glycoprotein (ENV) – a glycoprotein is a class of proteins containing carbohydrate moieties.  ENV is responsible for the process that allows the entry of the HIV-1 virus into its host cell (CD4+ T Helper cells).

ENV is trimer consisting of three glycoproteins with a molecular weight of 160K.  This trimer is split into a 120K surface component and a 41K membrane component.  Together they constitute a moiety that facilitates the entry of the virus into the host cell called the viral spike.  Although the components of the viral spike have long been considered candidates for a vaccine, it has been elusive.  In addition, the viral genes for these components have been discovered and used in vaccine production; this approach has also been shown to be unsatisfactory.  The reason for this failure seems to reside in the fact that many of the regions of the molecular structure of the ENV subunits that are candidates for eliciting a significant immune response lie buried in areas that are effectively hidden from immune-surveillance.

As a consequence, investigators have proposed using the entire ENV trimer as an immunogen – a substance capable of stimulating the immune system to produce humoral antibodies against it.  Unfortunately, the stability of ENV outside the environment of the viral membrane rapidly degrades.  However, this intrinsic difficult has been effectively sidestepped by R.W Sanders and associates (Science 349, aac4223(2015)).  They overcame this obstacle by engineering a molecule with covalent disulfide bonds that held the subunits together.  They subsequently used this modified ENV to immunize rabbits and monkeys.  Although it worked effectively against the same strain of virus from which the ENV was obtained, it was ineffective against heterologous strains of the deadly virus.

Although the problem of creating an effective vaccine against HIV-1 remains intractable, future efforts and innovative approaches similar to ones reported here may finally yield a viable solution.  Progress in science necessarily depends on all the work that has gone on before and the collaborative effort and energy of many.