Important note: Information in this article was accurate in January 2005. The state of the art may have changed since the publication date.
Treatment Issues: Newsletter of Current Issues in HIV/AIDS - Volume 19, Number 1 & 2, January / February 2005
Bob Huff
The Conference on Retroviruses and Opportunistic Infections (CROI) is the most important AIDS science meeting of the year. The conference organizers run a tight ship with attendance limited to working scientists and a sprinkling of community members involved with treatment advocacy and education. It is not a trade show and there are no pharmaceutical company pavilions, free pens or slick sales pitches at CROI.
Yet as exclusive at CROI is, it is also the most accessible HIV meeting of the year owing to a commitment to webcast nearly every important session on the Internet. This year, over 32 hours of plenary talks, symposiums and special sessions are available for free viewing at www.retroconference.com. The webcasts offer audio and synchronized slides for those with slow Web connections and streaming video plus slides on speedier hookups. If you want a glimpse into the state of the art of HIV research, these webcasts let you see and hear the people and ideas that represent the latest understanding on nearly every aspect of the virus and the immune system. You may not understand everything you hear, but if you are truly curious about what makes HIV tick, then many of these sessions will be fascinating and informative.
Here are some highlights of CROI 2005 on the Web:
Daniel Douek: Making Sense of HIV Disease Pathogenesis
Friday, 9:00 am
Douek blows the lid of what we thought about early HIV disease progression. A stunning picture of how HIV ravages lymphoid tissue in the gut within days of a new infection.
Bernard M Branson: Symposium: Rolling Out Rapid HIV Tests in the United States
Wednesday, 4:00 pm
There is growing pressure to change how HIV is diagnosed in the U.S. Branson traces the long and winding path to rapid testing.
Kasia Malinowska-Sempruch: Symposium: The HIV/AIDS Epidemic in Eastern Europe
Wednesday, 4:00 pm
Injection drug use is driving the explosive spread of HIV in Russia. So why are inflexible national drug policies standing in the way of arresting this epidemic? No science jargon here, just the hard reality.
Grant Colfax: Symposium: The Epidemiology of Substance Use and Sexual Risk Behavior among Men Who Have Sex with Men: Implications for HIV Prevention Interventions
Wednesday, 4:00 pm
Substance use — including crystal meth — is a key factor in the continuing transmission of HIV among gay men in the U.S. But what interventions have been shown to decrease substance use and cut the risk? Jargon free!
Bob Grant: Research Overview: Pre-Exposure Prophylaxis (PrEP)
Friday, 12:15 pm
Since a protective vaccine may be years away, the idea of using tenofovir (Viread) in people with high risk behaviors is being studied. It worked in monkeys (for a while). It may be safe. But can it put a dent in runaway infection rates in the developing world?
James McIntyre: Plenary: Controversies in the Use of Nevirapine for the Prevention of Mother-to-Child Transmission
Wednesday, 9:00 am
For an update on the never ending nevirapine story and current controversies in preventing mother-to-child transmission of HIV, this webcast is must viewing.
Julie Overbaugh: Plenary: The Biology of HIV-1 Transmission and Re-Infection
Thursday, 9:00 am
Some people still don't believe in "superinfection." That's the medical term for acquiring a new HIV infection on top of an existing HIV infection. But HIV superinfection is a real possibility and may occur as frequently as first infections do. Barebackers take note!
Special Symposium on the "Super Bug"
Thursday, 6:00 pm
A special session was called to address the press frenzy over an announcement that a new, potentially virulent and drug-resistant strain of HIV had been found. Overall, this was a remarkably dull take on a hot topic, but these two presentations are worth a look:
David Ho: Case Report of Recent Infection by a Multi-Drug Resistant, Dual-Tropic HIV-1 in Association with Rapid Progression to AIDS
Significant finding or headline-hogging scare tactic? David Ho lays out the facts about the New Yorker with multi-drug-resistant virus and a fast-moving case of AIDS.
Harold Jaffe: Public Health Aspects of the NYC Case
The former CDC head takes a common sense look at the real prevention issues behind the hype.
These sessions might be tough going for the uninitiated, but it's surprising how quickly one starts to pick up the key concepts after hearing them a few times. Of course, plenty of people don't want to hear about it, and that's fine too. Let's face it: there's no red carpet or paparazzi at CROI — just several thousand very smart people working hard to end this epidemic. Give them a play.
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View Webcasts CROI's webcast technology is easy to navigate. Select the day and session you want to view and the program begins to play in a separate window. Click on "Index" and you can jump to the speaker or topic that interests you. On some browsers you can even play the videos at a higher speed, which lets you move through dull stuff at a faster pace. You can also slow down the playback to take notes, which offers the added amusement of making some of the world's most prominent scientists sound like they are on quaaludes.
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Reviewed by Bob Huff
CROI Webcast
Tuesday, 9:00 am
Workshop for New Investigators
This special session was organized for young scientists to entice them into studying emerging research topics in the basic science of HIV. It provides an overview of some of the key unanswered questions about how HIV behaves in the body and how the body behaves when infected with HIV. Nearly 25 years into the age of AIDS, it is sobering to learn how much we don't know about this virus.
Molecular Virology
Ned Landau
This lecture reviews the big three of the known interdependencies between HIV and human host proteins. HIV carries a relatively small toolkit of viral proteins which adapt and hijack human cellular proteins in order to replicate. For example, there is a natural anti-viral protein in cells called APOBEC 3G that would force HIV to mutate into an increasingly mangled state if it were not deactivated by a small viral protein called Vif. One potential therapeutic strategy would be to defeat Vif and let APOBEC 3G take care of the virus. Another natural chain of events that normally acts as the "garbage collector" of the cell is somehow subverted by HIV into chaperoning newly forming virus particles as they migrate to the cell's
surface to be released into the bloodstream. A therapy that could disrupt this hijacked system would leave HIV harmlessly trapped inside the cell. Then there is TRIM5-alpha, possibly another natural antiviral factor found in monkeys and humans that is able to stop HIV before it gets started in monkeys, but is only weakly active in humans. Could a drug make man more like a monkey? There are more of these virus/host interactions known (hRIP is one) and likely many more yet to be discovered, but these three are keeping scientists busy this year.
Viral Pathogenesis
John Coffin
This talk provides an overview of how HIV causes disease, how it evades the immune system and why it is so hard to treat. HIV is unique among viruses because it preferentially infects activated memory CD4+ T cells, a type of cell that the body normally makes in abundance in response to an immune challenge. Typically, when the challenge has passed, the excess T cells cells are recycled and the immune system quiets down. But in HIV infection, this episodic response becomes a continuous state of alert, with billions of CD4 cells becoming activated, infected, and destroyed in an ongoing cycle. Activated CD4 cells typically live for only about a day, but before they go, these doomed cells make enough new virus to infect an equal number of
newcomers, thus holding the total number of infected cells — and the amount of virus they produce — relatively steady from day to day. But over time — ten years on average, but in as little as a few months or as long as never — this balance between the creation and destruction of CD4 cells slips toward depletion, resulting in a dangerous loss of immunity. Although there are many theories, we still don't know exactly how the steady state of chronic HIV infection turns into AIDS.
When a person with measurable viral load begins taking an effective antiretroviral drug, their viral load can drop until it almost seems to disappear. Although the standard for successful viral suppression is "undetectable" virus of less than 50 copes per mL of blood plasma, more sensitive tests can usually find at least 2 or 3 copies of HIV still hanging around. One theory is that these stragglers may be coming from long-lived memory cells that have been quietly warehousing HIV and only occasionally become activated to produce new virus. Yet these few cells are enough to spark a return to full-scale replication if drug therapy is removed or stops working. One reason therapy might stop working is if a random mutation allows a single virus to resume replicating despite the drugs. The persistence of archived virus is also why complete eradication of HIV is considered so unlikely.
This leaves us with a few big questions: How does HIV kill infected cells? How does HIV cause AIDS? Where in the body does HIV replicate? What is the source of that low-level persistent virus?
If you think these seem like basic questions, you are right. While there are many theories, science is still wrestling with some very fundamental problems about what HIV is doing in the body. Hopefully, a new crop of young scientists will be motivated to help find these answers.
Immunopathogenesis
Rick Koup
One of the most vexing unanswered questions in AIDS is: How does HIV escape control by the immune system? In most newly infected people, the immune system is able to provide some initial defense against HIV, but all too soon the virus begins to mutate and is soon able to escape suppression. The CD8+ T cells have much of the responsibility for recognizing and eliminating HIV, but they are never quite able to keep up with the shifty virus. There is also some evidence that HIV actually helps defeat the defenses by altering the way these immune cells work. CD8+ T cells in people with HIV often contain a different mix of signaling and cell-killing substances than in people without HIV. So, is this a result of the cells adapting to control HIV
or is HIV itself causing these cells to change? Another big question: does chronic immune activation lead to increased HIV replication or does increased replication lead to immune activation? Understanding these issues will be critical to the development of a vaccine or an immune-based therapy for HIV.
HIV Vaccines and Neutralizing Antibodies
Dennis Burton
If cellular immunity is impaired by HIV, what about the other main arm of the immune system, antibodies? Most researchers think that any successful vaccine to prevent infections in a new host will need to stimulate antibodies capable of neutralizing transmitted HIV. But HIV is changeable and well-protected. Several promising antibodies have been found, but the problem is they either don't recognize a wide enough range of HIV variants or if they do, they are too weak to neutralize the virus. The dual problems of HIV's escape from antibody-based immunity and CD8+ cell-based immunity are why few foresee an effective vaccine within the next ten years. That's one reason why, with so little success in effecting immune control of the
virus, the attention of this conference inevitably turns to drugs.
Reviewed by Bob Huff
CROI Webcast
Symposium: Antiviral Drug Discovery
Dale Kempf. HIV Protease: Can Better Inhibitors be
Found? Thursday, 4:00 pm
Protease inhibitors (PIs) are potent anti-HIV drugs — their arrival in 1995 was the main reason that AIDS death rates plummeted soon after. But PIs have their problems. If they don't send you running to the bathroom, they can cause one of your blood test values to soar or your kidneys to ache. Dale Kempf, of Abbott Laboratories, and one of the architects of Kaletra, discussed some new tools drug developers are now using to screen out these unwanted side effects before a new PI candidate ever gets into a human body.
The most obvious quality for any ideal HIV drug is potency. It should be able to quickly knock down viral load levels to the point where the virus is just barely replicating. Ideally, the drug should be able to do this not only for the virus that is most commonly found in the community (wild-type) but also for HIV that has become resistant to all other available drugs. And it should continue working even if a few new resistance mutations happen to crop up. These are all aspects that can be tested in the laboratory, and these are the qualities that drug designers look for first. In the old days, that was enough. But problems with existing PIs — namely their side effects and their propensity to interact with the blood levels of other drugs — keep us searching for the perfect PI.
The most attractive feature of the protease inhibitor Reyataz is that it doesn't cause the elevated blood lipid levels (cholesterol and triglycerides) that can come from using Kaletra. Unfortunately, this newer PI has its own quirky side effect that can make the eyeballs of some of its users turn yellow due to excess bilirubin in the blood. Kempf reports that scientists have been using new lab-based tools to understand the underlying mechanisms of these side effects so they can be avoided in future drugs.
New technology allows a drug to be tested against an array of tens of thousands of human genes all at once. Genes that become activated when exposed to the drug are targeted for further investigation. This was how Abbott scientists learned that Norvir, but not Reyataz, inhibits a cellular recycling system called the proteosome, which had been implicated in the lipid problem. Knowing this, Kempf and colleagues began looking for a potent PI molecule that didn't affect these proteosome genes. After several tries they found a promising candidate and continued tweaking it until it passed a similar test that looked for effects on bilirubin production. This finalist candidate was called A-792611 (at this early stage drugs have only numbers, not names) and it looked promising, with ten times the potency of lopinavir (the active PI in Kaletra) and little likelihood of sharing either Kaletra's or Reyataz's side effects.
At this point the drug scientists began assessing the potential for "611" (the compound's nick-number) to interact with other drugs. PIs are notorious for speeding up or slowing down each other's metabolism. While Norvir was originally developed as an antiviral drug, its true talent is in slowing down the elimination of other PIs. This "boosting" effect keeps PI blood concentrations higher, longer, which has made protease inhibitor therapy much more convenient and reliable than when it was first introduced. While "611" did not speed up the removal of other drugs, it stumbled when the assay revealed that it shuts down a key avenue of drug metabolism. Since this would have caused extreme and unmanageable drug interactions in real life, that was the end of the line for "611". Fortunately, all of this was discovered quickly and efficiently, and the molecular fiddling goes on to find the ideal PI candidate to take forward into human testing. Of course, surprises will always arise once a drug starts being used in people, but these new preclinical checkpoints should help increase the chances that the next PI down the pike is as easy on your body as it is tough on HIV.
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