The Bay Area Reporter - August 4, 1998
Jeff Gustavson, ACT UP/Golden Gate Writers Pool

Levy recalled the inability to isolate HIV directly without the removal of CD8+ cells from the media in which they were cultured, suggesting a non-Major Histo-Compatibility Complex restricted, or in other words a non-specific immune mechanism was responsible for the immune suppressive activity.

Longterm non-progressors

Levy then went on to talk of his studies of asymptomatic Long Term Non Progressors saying that in cells taken from those persons and cultured, there was a notable decrease in viral messenger RNA as compared to progressors, however, the frequency of latently HIV infected cells was the same, suggesting that the block occurs at the level of transcription and is not coreceptor (CCR5, CXCR4) restricted.

In other words, he has shown CAF to be distinct from the chemokines (MIP-1-alpha, MIP-1 beta, and RANTES) that Dr.Robert Gallo from the Institute for Human Virology so eloquently showed in December 1995 as being capable of blocking HIV entry into CD4 cells. When this writer asked Levy to speculate on the mechanism underlying this transcriptional block, he said it may inhibit NF-Kappa-B, a transcription factor that binds the Long Terminal Repeat (LTR), the functioning enhancer region for the proviral genome.

HIV-specific CD4

Dr. Bruce Walker, from Harvard, showed his data on the absence of anti-HIV specific CD4 cells in progressors to symptomatic AIDS and his successful efforts to preserve them in people with early infection by treating with antiretroviral drugs and suppressing viral burden.

The French Connection

Dr. Brigitte Autran, from France, presented her work on how the V-beta repertoire becomes skewed as a result of HIV infection. The V-beta repertoire is a measure of the depth of the number of different antigens to which a person's T-cells can respond, and in fact refers to the portion of the T-cell receptor responsible for variability or diversity.

Autran showed that a trend towards normalization occurs following successful treatment with potent protease inhibitor containing regimens and correlates nicely with the second phase rise in T cells, as well as with the percentage of cells that are naive - that is are brand new and have yet to be called into action. She then extrapolated outward and predicted that it would take approximately seven years of a highly suppressive regimen for a near complete normalization of the CD4 cell repertoire.

Reconstitutional amendment

Autran's work points to the controversy of the origin of these naive cells. Traditional dogma holds that adults no longer have a functioning thymus. T cells are however capable of maturing outside of the thymus, but are generally thought to have a much narrower range of specificity.

Recently, Dr. Mike McCune, from the Gladstone Institute here in San Francisco, published his work in the Journal of Clinical Investigation, showing an index of thymic mass by CT scan (a computerized X-ray) in adult males with HIV infection correlates with a high percentage of naive cells as measured by the surface markers CD45RA and CD 62L.

Lips like sugar

In collaboration with Dr. Marc Hellerstein, McCune has also shown that incorporation of deuterated glucose (glucose that has a non-radioactive isotope or alternate form of hydrogen and can be detected by mass spectrometry) into the sugar backbone of the DNA of naive T cells, which again points to new generation. They did this by infusing HIV-infected volunteers with this special blood sugar, and then taking blood samples and analyzing them.

The circle game

Dr. Rafick Senkaly, from the University of Montreal, also in collaboration with McCune, explained his work with excision circles. These loops of DNA are made when the T cell rearranges its V,D, and J genes which code for the variablr portion of the T cell receptor. These circular byproducts are only present in brand new T cells, their progeny will lack these circles.

Currently, they are determining what is the normal range for the frequency of these cells in HIV negative adults. They will then look for them in HIV positive people and hope to find a greater number of them, thereby taken in sum total with all of the work above, will show almost absolutely that adults are capable of immune recovery.

Certainly, they are trying to sort out if it is possible to stimulate this function, sort of jump start it in people who are HIV infected, because ultimately if the immune system can gain the upper hand, it ought top be able to control or at least minimize HIV infection. One of the take home messages from the conference was the irologists have taken the problem as far as they can for those whom they have been successfully able to treat,but ultimately, HIV/AIDS is an immune disorder that must have an immunologic solution, both in terms of a vaccine as well as treatment. Great strides are being made in the basic science arena that are bringing us incrementally closer to these goals.
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