During the last couple of years,? observed microbiologist Zhi-Qiang Zhang, ?we have a very powerful triple-drug treatment cocktail that reduces the viral load in HIV-infected patients. And now, the question is whether the patients? damaged immune system can benefit from this effective therapy.?

He noted that ?one of the three drugs is a protease inhibitor, which breaks the cycle of viral replication, and the other two are reverse transcriptase inhibitors, which also check HIV replication.?

Zhang, a scientist at the University of Minnesota Medical School, in Minneapolis, is first author of a paper in the current Proceedings of the National Academy of Sciences (PNAS), dated April 27, 1999, which offers an answer to his question. Its title reads: ?Reversibility of the pathological changes in the follicular dendritic cell network with treatment of HIV-1 infection.?

?We were interested in seeing whether or not there was any improvement after this potent combination antiviral therapy,? Zhang told BioWorld Today. ?Our paper shows slow reconstitution and repopulation of the CD4⁺ T cells in the lymphoid tissue. And this is very important, because HIV infection mainly targets those CD4⁺ T cells. This time, we looked at another aspect of the immune system, the follicular dendritic cells (FDC).?

The lymphoid follicles are where the humoral (B-cell memory) response is generated. Follicular dendritic cells support B cell and T cell antigen interaction.

This 3-dimensional FDC network in the lymph nodes supports a repository of antigens. Those dendritic cells handle antigen collection and presentation by the immune system?s antibody-generating B cells and its foreign-cell-killing T lymphocytes.

?HIV infection,? Zhang pointed out, ?damages this network so badly that eventually, in the AIDS stage, it is destroyed, contributing to the breakdown of the immune system. Which raises that question: Whether after effective antiviral therapy, which clears much of the virus from the network, the network could be restored? We didn?t know if this was a possibility.?

Doubts Of Immune Regeneration Disproved

?No people thought this immune-system damage could be reversed,? Zhang said. ?But we were curious as to whether this was true or not. We never had a chance before to look at such an issue because we didn?t have a really potent antiviral regimen. This time we did have the chance. And we were surprised to find that the damage is reversible, even in a patient at an advanced stage of HIV infection. So, this is very encouraging. For the first time in the HIV field, I think, we offer evidence that this immune-system damage is reversible.?

To muster this evidence, Zhang and his co-authors conducted controlled clinical studies over a year and a half.

?To understand this possibility for reversibility,? he said, ?first of all we needed to know the damage inflicted by the HIV infection without therapy. So, we took biopsies of tonsil tissue from 10 HIV-infected patients, especially late-stage cases, to measure how much damage their follicular dendritic cells had sustained, and from six healthy controls.

?Then, in order to know whether this immune-system injury was reversible or not, we took lymphoid tissues from patients under potent antiviral cocktail therapy,? he added. ?Using the same quantitative image analysis method, we compared the patients? lymphoid tissue before the three-drug regimen, and six months and one year after therapy, to see if there was any quantitative change in the network.

?The answer was that the FDC increased, especially after one year of therapy, compared to the pre-treatment baseline.?

Zhang and his team then tested another cohort of 12 patients, who had been on less potent medication for one year, before cocktail therapy came on the scene. They found that after 1.5 years on the new therapy, the hallmark follicular dendritic network had slowly reversed its damage, ?and increased significantly.?

Whether HIV-infected patients face a lifetime on the triple-drug therapy to maintain their immune systems ?is another issue,? Zhang opined. ?It?s really whether you can eradicate the virus. So far we don?t have very convincing data. But if you can control replication of the HIV ? which is our precondition ? and keep the viral load at lower and lower levels, there is a hope that even in a patient at an advanced stage of infection, the immune-system damage might recover. But the extent of this recovery we don?t know. We want to observe them for a longer time, 2.5 years.

?But I think this is very encouraging news,? Zhang went on, ?because even without eradication of the viral infection, maybe the immune system can recover from its damage under such potent therapy. We?ve already measured pathological change in the lymphoid tissue. Now we?d like to know if the patients have really functional immune recovery. This will be another interesting aspect we?d like to look at.

?If you do have an effective drug in a patient with an advanced stage of infection, it is still possible to reverse, to improve, the immune system,? Zhang said, concluding: ?This is very important for the drug developers.? n