From the ISIP thread tonight.
New Theory On Response To HIV Therapy
NEW YORK (Reuters) -- Dutch researchers offer a new explanation for the reappearance of CD4+ T cells, which are used to assess immune system function, in HIV-infected patients on antiretroviral therapy.
The results of a mathematical model indicate that after new highly active antiretroviral therapy (HAART), CD4+ cells are primarily redistributed, rather than newly produced, as previously suggested. But based on their findings, the researchers believe that the restoration of CD4+ cells can indeed occur in HIV-positive patients who respond to treatment, but only at a very slow rate.
Dr. Frank Miedema of the Central Laboratory of the Netherlands Red Cross Blood Transfusion Service in Plesmanlaan and colleagues evaluated the factors related to immune restoration in 33 HIV-1-positive adults following HAART. Recent studies have provided evidence for a high turnover of CD4+ T cells driven by the large amounts of virus that are produced daily, suggesting physical exhaustion of CD4+ T-cell renewal as a cause of CD4+ T-cell depletion, Miedema's group explains. However, the results of a mathematical model, which appear in the February issue of Nature Medicine, provide evidence for another explanation.
As soon as patients are started on HAART, the CD4+ cell counts in the blood rise very quickly in the first few months,. Miedema told Reuters. This has been interpreted, in a model proposed by Dr. David Ho and others, as an increase in newly produced CD4+ cells -- reflecting an immune system working very hard to produce these cells because of their depletion by the virus, he continued. And, according to that theory, the production of CD4+ cells by the immune system after a time would ultimately be exhausted.
The current findings indicate that the CD4+ cells that appear shortly after HAART are, in fact, memory CD4+ cells, that have existed before in the lymphoid tissues, rather than ''naive'' newly produced cells, he continued. ''Naive CD4+ cells are also reappearing in the blood, but very, very slowly -- 10 times slower than... the memory cells,'' Miedema continued. ''And we argue that is the real reconstitution of the immune system.'' Although we have not proven that these are CD4+ memory cells, we believe that this is the most likely explanation, he continued.
''There are two clinical implications,'' Miedema said. ''The first is... that it seems that the repopulation of the immune system may be much slower than we anticipated.'' This type of much slower, but continuous process ''...is also seen in patients after bone marrow transplantation and in patients who have undergone chemotherapy,'' he added. ''It takes a long while to recuperate.'' And he estimates that it will take several years to replenish CD4+ cell levels.
The second clinical implication is that, contrary to the original model, which proposed that the immune system would be exhausted, they believe this is not the case. ''Our interpretation is that the system... can only produce a given number of (CD4+) cells per day and that there is a slower outpour of cells.... But in most people, we expect that the system will not be exhausted.'' Miedema suggests that even in patients with low CD4+ cell counts, there's a good chance the immune system will be able to regenerate CD4+ cell levels. However, he also points out that factors such as patient age, duration of HIV infection, and type of virus will probably influence whether the CD4+ cells will be replenished.
In a second paper, a French team studied the T cell antigen receptor repertoire, the subtype profile of cells involved in immune response, in HIV-1-infected patients before and after HAART. Dr. Guy Gorochov of the Hopital Pitie-Salpetriere in Paris and colleagues observed ''normalization of the CD4+ repertoire'' after HAART in 8 out of 10 patients who had significant CD4+ T-cell repertoire perturbations prior to treatment.
The issue is whether or not the new treatments really result in improvements in the immune system, Gorochov told Reuters. The question is, does HAART just cause a rise of the absolute cell counts, but without any improvements in the structure, diversity and function of the immune system, he continued.
Gorochov concludes that ''...there is an impact of the antiviral treatments on the diversity of the T cell repertoire -- there are qualitative modifications.'' We found that ''...after six months of treatment ...at the levels of resolution used... there was no difference (in CD4+ repertoire) between uninfected people and HIV-positive treated patients.''
The new findings contradict those reported by researchers a few months back, he explained. It was proposed that there are ''so-called holes'' in the repertoire -- people assumed that AIDS patients are losing specificities in their T cell repertoire... and that this is not improved by antiviral treatment.''
Although it is premature to draw any conclusions regarding immune system restoration based on these findings, he points out that the defects in T cell repertoire are not as extensive as previously reported, and there are improvements following HAART. ''Like in mononucleosis or influenza, when you remove the virus the immune repertoire goes back to a resting state.''
These two papers ''...provide the final nail in the coffin for models of T cell dynamics in which a major reason for changes in T cell numbers is the death of HIV-infected cells,'' Dr. Mario Roederer of Stanford University in California comments.
The findings illustrate three key points, Roederer continued. The first is that ''...the blood is an imperfect reflection of the immune system.'' The second is the importance of understanding the dynamics of all subsets of immune cells during disease and therapy -- these cells need to be measured in as much detail as possible.
Finally, Roederer believes that strategies designed to restore the immune system of HIV-infected patients must be targeted at mechanisms of T cell production and balance. ''A combination of HAART, to block viral replication, with a therapy that promotes active production of naive T cells... will be critical for restoring long-term health in HIV-infected individuals,'' he concluded.
SOURCE: Nature Medicine (1998;4:145-146, 208-214, 215-221)
Reut18:51 01-29-98
(29 Jan 1998 18:50 EST)
SORRY - I meant to post this on HIV thread, not LGND, and cannot take it back. But, it's interesting anyhoo. |
