Background:  The objective of this study was to assess the kinetics of CD4⁺ T-cell repopulation and gain insights into the molecular mechanisms of virally induced disruptions in the gut-associated lymphoid tissue (GALT) in the presence or absence of antiretroviral therapy (ART).

Methods:  Eight healthy juvenile rhesus macaques (RM) were intravenously infected with SIVmac251 for 26 weeks. Five macaques were given antiviral therapy consisting of daily subcutaneous administrations of (R)-9-(2-phosphonylmethoxypropyl) adenine (PMPA), while the remaining 3 macaques received no antiretroviral treatment. Longitudinal peripheral blood samples were analyzed for plasma viral loads by real-time polymerase chain reaction (PCR), and for immunophenotypic changes in T-cell subsets by flow cytometry. Jejunal tissue samples were subjected to T-cell immunophenotypic analysis, immunohistochemical staining, quantitative real-time PCR assays, and DNA microarray analysis of host gene expression.

Results:  In contrast to ART-naïve simian immunodeficiency viris (SIV)-infected RM, SIV-infected animals treated with PMPA displayed significant viral suppression; restoration of intestinal and peripheral CD4⁺ T cells; a characteristic expression profile in GALT involving down-regulation of lymphocyte activation and inflammatory response-associated genes; and substantial up-regulation of genes involved in epithelial repair and regeneration. SIV-infected RM not receiving PMPA therapy increased transcription of cytotoxic response factors, as well as genes involved in lymphocyte activation and inflammatory responses.

Conclusions:  Initiation of PMPA therapy in primary SIV infection was effective at restoring mucosal CD4⁺ T-cell numbers during chronic infection and led to reduced inflammation and promotion of epithelial repair in the intestinal mucosa. Gene expression studies suggest that intestinal epithelial growth and repair pathways could provide potential molecular targets for novel therapeutic approaches to restore intestinal mucosal function during SIV and HIV infections and thereby improve clinical outcome.

Keywords: SIV; PMPA; immune restoration