Background:  Studies of CD4 depletion and reconstitution in HIV infection have focused on peripheral blood, a fraction of total CD4 T cells, and have not examined preservation and restoration of the CD4 T cells in lymph nodes or gut-associated lymphoid tissue (GALT).

Methods:  We obtained inguinal lymph nodes and ileum biopsies (via colonoscopy) from 32 HIV⁺ and 11 HIV^– individuals with a second set of biopsies obtained after 6 months of HAART in 15 of the HIV⁺ individuals. Using flow cytometry and quantitative image analysis (QIA), we determined the size of the total, naïve, central and effector memory CD4 populations in peripheral blood, lymph nodes, Peyers patches, and lamina propria.

Results:  We found that all compartments were significantly depleted (p< 0.0001, 2-sample t-test) and that there were significant increases after 6 months of HAART in peripheral blood (p = 0.0003) and lymph node (p = 0.0001), but no change in lamina propria.  However, in Peyers patches, the inductive site where naive and central memory CD4⁺ T cells in GALT reside, there was a significant increase (p = 0.0076) that was restricted to only the central memory population. We compared stage of infection and entry CD4⁺ T cell count to reconstitution of CD4⁺ T cells in each compartment and found significant correlations in peripheral blood and lymph node (p = 0.008 and 0.02, respectively, F statistic from ANOVA). For HAART started in the acute/early and presymptomatic stage of infection, the mean increase in peripheral blood CD4⁺ T-cell count was 388 cells/mm³ and 176 cells/mm³, respectively. In lymphoid tissue, the corresponding values were 12.5% and 13.65% of parafollicular T-cell zone occupied by CD4⁺ T cells, respectively. There was no change in any CD4⁺ subset if HAART was begun when the patient had AIDS. We found that baseline peripheral blood CD4⁺ T-cell count was an even stronger predictor of immune reconstitution in peripheral blood and lymph node (r² = 0.38, p = 0.01 and r² = 0.71, p = 0.0002, respectively). Importantly, we found that earlier initiation of HAART was associated with greater increases in the central memory population of Peyers patches, especially if begun in the acute/early stage of infection. This is important because, in the non-human simian immunodeficiency virus (SIV) model of infection, the size of the central memory population in GALT is associated with longer survival.

Conclusions:  Lymphatic tissues do not uniformly reconstitute CD4⁺ T cells with HAART. Lymph node and Peyers patches are capable of limited reconstitution, the degree of which depends on earlier initiation of HAART than is currently recommended.  This was most striking for central memory CD4 cells in Peyers patches.