Early Antiretroviral Therapy for Simian Immunodeficiency Virus Infection Leads to Mucosal CD4⁺T-Cell Restoration and Enhanced Gene Expression Regulating Mucosal Repair and Regeneration

Abstract

Simian immunodeficiency virus (SIV) and human immunodeficiency virus (HIV) infections lead to rapid depletion of CD4؉ T cells from gut-associated lymphoid tissue (GALT). Although the administration of antiretroviral therapy (ART) has been shown to increase CD4 ؉ T-cell levels in the peripheral blood in both SIV and HIV infections, its efficacy in restoring intestinal mucosal CD4؉ T cells has not been well investigated. To gain insights into the molecular mechanisms of virally induced disruptions in the mucosal immune system, we have evaluated longitudinal changes in viral burden, T-cell subsets, and mucosal gene expression profiles in SIV-infected rhesus macaques in the absence or presence of ART. Our results demonstrate a dramatic suppression of mucosal viral loads and rapid reconstitution of CD4 ؉ T cells in GALT in animals receiving ART that were not observed in untreated SIV-infected animals. DNA microarray-based gene expression profiling indicated that CD4؉ T-cell restoration in GALT was associated with up regulation of growth factors and genes involved in repair and regeneration of the mucosal epithelium. In contrast, untreated SIV-infected animals increased expression of lymphocyte activation and inflammatory response-associated genes and did not up regulate mucosal growth and repair associated transcription. In conclusion, these data indicate that initiating ART in primary SIV infection may lead to the restoration of the mucosal immune system through reduction of inflammation and promotion of epithelial repair in the intestinal mucosa.

The Influence of Age and Sex on the Cell Counts of Peripheral Blood Leukocyte Subpopulations in Chinese Rhesus Macaques

“…So there maybe exist difference in leukocyte subpopulations counts of these two animals. The baseline levels of CD4 + T cells of Indian rhesus macaques were 1369 cells/μl (median number) in Reimann et al's study (33) and 1300 cells/μl in George et al's study (34). Chinese rhesus macaques analyzed in Qiu et al's (1661 ± 777 cells/μl) and our study (1611 ± 718 cells/μl) showed a higher CD4 + T cells counts.…”

HIV infection and the gastrointestinal immune system

“…Hence HIV infection could quite reasonably be considered a disease of the GI tract. Our new understandings in this regard have pointed to new therapeutic directions: the aim would be to prevent or reduce the propagation of HIV at mucosal surfaces 35,102 and to restore the immunological and epithelial integrity of the mucosal barrier. 35 …”

“…33 Furthermore, SIV-infected macaques also manifest enteropathy, 34 which is associated with decreased expression of genes such as trefoils that are involved in mucosal repair. 35 Hence, in pathogenic SIV infection of rhesus macaques, the majority of the body's CD4 T cells are depleted within the short acute phase of the infection -a finding not reflected by analysis of peripheral blood or lymph nodes.…”

Gut mucosal T cell responses and gene expression correlate with protection against disease in long-term HIV-1-infected nonprogressors

“…4B) in intestinal mucosa that are required for normal maturation of enterocytes. In the SIV model, multiple growth factors as well as genes mediating intestinal epithelial (enterocyte) repair and regeneration have been shown to be dysregulated in GALT during primary acute and chronic stages of infection (6)(7)(8)(9)(10). Moreover, SIV-infected macaque studies have demonstrated impaired nutrient digestive and adsorptive functions during primary SIV infection (6).…”