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Basic Training

January/February 2005


This article is part of The Body PRO's archive. Because it contains information that may no longer be accurate, this article should only be considered a historical document.

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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.

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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 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 copies 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.




This article was provided by Gay Men's Health Crisis. It is a part of the publication GMHC Treatment Issues. Visit GMHC's website to find out more about their activities, publications and services.
 

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