Background:  The gut-associated lymphoid tissue (GALT) is the largest lymphoid organ in the body and plays an important role as an early site for HIV-1 replication and severe depletion of CD4⁺ T cells. However, the success of HAART is currently measured by increases in peripheral blood CD4⁺ T cells and the reduction of plasma viral loads. Our recent studies suggest that to accurately assess the efficacy of HAART, pathogenic processes occurring in mucosal tissues must also be monitored, in addition to the peripheral blood. Current guidelines recommend initiation of HAART when CD4⁺ T cell counts fall below 350 cells/mm³. However, the clinical benefits of initiating HAART during primary HIV-1 infection vs chronic HIV-1 infection on the restoration of mucosal CD4⁺ T cells and immune function remains largely under investigated.

Methods:  Longitudinal jejunal biopsies and peripheral blood samples from HIV-1-infected patients initiating HAART during primary or chronic HIV-1 infection were evaluated for CD4⁺ T cell restoration and function and HIV-1-specific CD8⁺ T cell responses utilizing flow cytometry and gene expression profiling. 

Results:  A delayed and biphasic restoration of CD4⁺ T cell levels in GALT was observed in primary HIV-1 infection patients following HAART, despite normal CD4⁺ T-cell numbers in the peripheral blood. The rate of CD4⁺ T cell restoration in GALT of primary HIV-1 infection patients was significantly higher than that observed in chronic HIV-1 infection patients (p = 0.012). Microarray analysis indicated substantially reduced inflammatory responses and increased expression of growth factors and cell adhesion molecules in GALT of primary HIV-1 infection patients, as compared with chronic HIV-1 infection patients, in response to HAART. Immunophenotypic analysis also suggested higher levels of CD4⁺ T cells expressing CD11a, αEβ7, CCR5, and CXCR4 in GALT of primary than chronic HIV-1 infection patients. Finally, primary HIV-1 infection patients displayed stronger HIV-1-specific CD8⁺ T cell responses in both GALT and peripheral blood as compared with chronic HIV-1 infection patients.

Conclusions:  Our findings indicate that initiation of HAART during primary HIV-1 infection was more effective in restoring or maintaining mucosal CD4⁺ T cells and suppressing viral loads than initiation during chronic HIV-1 infection. Furthermore, these data emphasize the importance of monitoring clinical disease progression in lymphoid tissues as well as peripheral blood for a more accurate assessment of the efficacy of HAART.