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Why Fighting HIV/AIDS Is So Challenging

When I began work on this month’s project, I contacted a clinician, a case manager, and a scientist to get their perspectives on how we’re making progress fighting HIV and AIDS. I’ve introduced you to the clinician and the case manager, but not the scientist.

Dave Wessner doesn’t actually study AIDS, but he’s written a textbook supplement on HIV and AIDS and teaches a course at Davidson College on the subject. His students have even set up a blog discussing the history and science of HIV and AIDS. He also regularly lectures on the topic. I’ll be attending one of his talks tonight.

I asked Dave to point me to good research about the HIV virus and he showed me a 2003 review written by Stephen Goff and published in Cell. It’s a fascinating article, showing how a “seemingly minor” protein encoded in the HIV genome is actually responsible for a critical defense the virus uses against the human immune system.

As I mentioned last week, the HIV virus hijacks the apparatus of one type of cell in our immune system in order to reproduce. It’s a multi-step process, and anti-HIV drugs typically work by disrupting one or more steps in the process. Goff’s article explains how the tiny protein Vif actually stops the immune system itself from disarming the HIV virus. Humans have a protein called APOBEC3G that normally attaches itself to the virus as it’s budding off the human producer cell:

When the virus tries to convert its RNA into DNA using reverse transcriptase (RT in the diagram), APOBEC3G converts a portion of one element of the DNA produced, Cytosine, into another, Uracil. It’s like changing a small percentage of the dots in a Morse-code message into dashes. The DNA — the instructions for creating a new virus — becomes so hopelessly mangled that it’s worthless for producing copies of the HIV virus.

Vif stops APOBEC3G before it starts, allowing the virus to replicate worry-free. When researchers remove the Vif from an HIV virion, it can no longer reproduce. This represents an opportunity for pharmaceutical research: If a drug can be found that binds to Vif or deactivates it, then the HIV won’t be able to reproduce, and that will spell doom for the virus. However, as I pointed out in my column in Seed a few weeks back, it’s still possible that HIV could mutate to avoid this problem.

Indeed, this is the key issue with nearly all antiretroviral drugs. They attack one portion of the HIV replication process, but a mutation of the virus can still circumvent the problem. When are mutations most likely to occur? When patients miss doses of their medication. Why? Mutations can only occur when the virus is replicating: they are essentially errors in either the reverse-transcription process or the replication of the DNA. If millions of viruses are replicating, one of those “errors” could wind up producing a strain of HIV that resists the medication. If viral replication is stopped entirely, then there’s no opportunity to mutate.

That’s one reason why Charles has to take so many different pills to fight AIDS: Since each drug attacks a different part of the HIV replication process, then if one drug is defeated by a viral mutation, another drug can finish the virus off. But the more drugs in a treatment regimen, the more expensive treatment becomes. While new research is promising, it still costs a lot of money, which means the next generation of drugs will be just as expensive.

For the near-term, Wessner isn’t optimistic about another approach of treating HIV. A clinical trial of an HIV vaccine was completed in Thailand last year, and while there was some success, it was quite modest, and did not rise to statistical significance. It also had no beneficial effects for people who did end up getting infected with HIV.

Ultimately, if no vaccine is produced, the battle against HIV is going to be long and expensive. As I mentioned in my second post on the subject, at least 50,000 Americans are infected with HIV each year, and the rate of infection isn’t decreasing.

Goff SP (2003). Death by deamination: a novel host restriction system for HIV-1. Cell, 114 (3), 281-3 PMID: 12914693

Rerks-Ngarm S, Pitisuttithum P, Nitayaphan S, Kaewkungwal J, Chiu J, Paris R, Premsri N, Namwat C, de Souza M, Adams E, Benenson M, Gurunathan S, Tartaglia J, McNeil JG, Francis DP, Stablein D, Birx DL, Chunsuttiwat S, Khamboonruang C, Thongcharoen P, Robb ML, Michael NL, Kunasol P, Kim JH, & MOPH-TAVEG Investigators (2009). Vaccination with ALVAC and AIDSVAX to prevent HIV-1 infection in Thailand. The New England journal of medicine, 361 (23), 2209-20 PMID: 19843557

*This blog post was originally published at The Daily Monthly*


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