Dr Michael Seah

Clinical posts from members and guests of the Australasian Society for HIV, Viral Hepatitis and Sexual Health Medicine (ASHM) from various international medical and scientific conferences on HIV, AIDS, viral hepatitis, and sexual health.

CROI Day 1: Bernard Fields Lecture

Posted by on in HIV Cure, eradication of HIV
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Attending my first CROI in Boston, I am amazed by two things. Firstly, how cold it is during the day. I'm sure my eyeballs were going to freeze walking to the conference venue. More of that to come - it's only reaching a maximum of 0 degrees Celsius all week. At least the locals are warm and friendly.

Secondly, the scale of CROI is enormous. Over 4000 delegates this year and the main auditorium is imposing for any speaker. Thankfully there are large screens and excellent amplification. You can still sit way down the back and still see/hear what's going on.

This evening, Dr Paul D. Bieniasz from the Aaron Diamond AIDS Research Center presented the Bernard Fields Lecture on "Making and Breaking Barriers to Cross-Species HIV-1 Transmission". 

The lecture centred on the role of intrinsic host cell factors that directly inhibit viral replication. They work through a diverse mechanism of actions on invariant or genetically fragile viral features. For HIV these defences are called restriction factors. A number of restriction factors have been studied as potential inhibitors of HIV replication. Tetherin was used as an example - the expression of which causes retention of mature, fully formed infectious HIV-1 on surface of infected cells. Tetherin works by inserting its c-terminal anchor into viral envelope, trapping nascent HIV-1 virions by a direct tethering mechanism, leading to endocytosis and signalling.

The Research Center had created an artificial tetherin that was structurally similar but not the same protein sequence as the human protein. Remarkably, this artificial tetherin had action (not as good as real tetherin) to trap virions on the cell surface, preventing release of the virus and further viral replication.

However, viruses have evolved defence mechanisms to counteract these restriction factors. HIV has the Vpu protein that binds tetherin to overcome the cell's defence mechanism. The HIV-1 Vpu protein specifically evolved to work against human tetherin.

These defences are largely species specific, making it difficult to use animal models to study the actual HIV-1 virus. Many Simian immunodeficiency viruses (SIVs) do not encode a Vpu protein, and evolved a different mechanism - the Nef protein which interacts with simian tetherin via the protein's cytoplasmic tail.

Another HIV-1 restriction factor discussed was APOBEC3. APOBEC3 is antagonised by HIV-1 Vif proteins, which also has species specific action like Vpu. The researchers developed an HIV-1 strain with SIV Vif inserted that allowed the virus to replicate in pig-tailed macaque lymphocytes. Infecting successive groups of macaques, the researchers generated a terminal AIDS defining illness in phase 4 animals, when they artificially caused CD8 depletion at the time of infection using anti-CD8 antibodies. The phase 4 macaques developed a B cell lymphoma which showed marked CD4 depletion.

Interestingly, the HIV-1 Vpu in this modified strain adapted to antagonise the pig-tailed macaque tetherin, at the expense of the ability to antagonise human tetherin, providing an insight into viral mutation and cross-species infectivity.

Although Dr Bieniasz was hopeful on the ability to develop more realistic animal models for HIV-1, he cautioned against the use of such models for more advanced research such as vaccine development. While this adapted HIV-1 strain can cause AIDS in a non-hominid species, the adaptation is incomplete. Notably, in this experiment the researches needed to induce CD8 depletion at the time of infection, as the animal quickly adapted and post-infection depletion of CD8 was ineffective at inducing an AIDS defining illness.

 

Tagged in: CROI2014 IAS2013
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