Protease inhibitor based HAART and lymphoid regeneration

Active HIV infection is known to produce profound changes in both the function and structure of lymphoid tissue throughout the body.

Follicular hyperplasia and the formation of germinal centres occur; these being normal reactions intended to facilitate trapping and processing of viral particles. Later in the course of infection follicular dendritic cell (FDC) involution takes place and the architecture of lymphoid tissue degenerates. In untreated infection an increase in viral load and disease progression seem to correlate directly with the collapse of lymphoid tissue.

This current research by Macias and colleagues in Spain evaluated the effect of a quadruple antiretroviral regimen after 48 weeks on the tonsil lymphoid tissue architecture of HIV-infected patients with CD4 T cell counts above 500 cells/mm3. All patients received a dual protease inhibitor (PI) based combination of indinavir plus saquinavir together with either stavudine (d4T)/lamivudine (3TC) or zidovudine (ZDV)/lamivudine (3TC). A total of 11 patients were evaluable for the study and most of these patients achieved maximal viral suppression and a rise in CD4 T cell counts.

An unexpected range of moderate to severe lymphoid tissue lesions were found at baseline in these subjects despite the mild degree of immunosuppression (median CD4 count at baseline was 658 (431-1178) cells/mm3. This lymphoid tissue damage was partly restored after 48 weeks of PI based HAART. Restoration included both FDC network regeneration and repopulation of lymphoid tissue, particularly with naïve cells. Global cellularity increased and well-developed germinal centres were observed. An increase of lymphoid associated CD4 cells and naïve cells was documented, whereas CD8 cells diminished.

The investigators conclude that even early in the course of HIV-infection, disease may not just be a matter of effects on peripheral CD4 T cell counts. Indeed, duration of HIV-infection might have an impact on lymphoid tissue not predicted by peripheral estimations. The study also confirmed that serious lymphoid tissue lesions can be recovered by effective protease inhibitor based HAART.

Comment

We have yet to be provided with any evidence that lymhoid structure recovers under NNRTI or 3NA therapy. The Atlantic Study did, however, suggest that such recovery was not seen with triple nucleoside analogue therapy in this trial. Further studies are needed to determine if this recovery is indeed a protease inhibitor specific effect.