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Gender Difference in Mucosal Integrity Impacts Response to HAART in HIV Infection
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Reported by Jules Levin
CROI 2012 March 5-8 Seattle WA
Sumathi Sankaran1, Lauren Nagy1, Monica Macal1, Michael George1, Irina Grishina1, Larissa Goulart1, Katie Coolidge 1, Mary K Miller2, Jason Flamm4, Thomas J. Prindiville3, and Satya Dandekar1
Departments of Medical Microbiology & Immunology1, and Internal Medicine3, UC Davis, CA, Kaiser Permanente Medical Group4, Sacramento, CA, 2 Student Health Services, UC Santa Barbara, CA.
DISCUSSION
· Women have higher levels of T cell activation at all stages of HIV infection and during HAART
· The factors contributing to this systemic immune activation have not been fully characterized
· These preliminary data suggest that increased microbial translocation may explain why women have sustained CD4+T-cell activation despite effective viral suppression.
· The increased microbial translocation could be the result of decreased or ineffective tight junction formation or increased disruption of the tight junctions due to a combination of infection and hormonal factors
· Studies investigating the effects of HAART in women should also focus on the maintenance of mucosal integrity and health.
ABSTRACT
Background
Human Immunodeficiency Virus (HIV) infection is one of the leading causes of death in women in Africa. HIV infection results in loss of CD4+ T-cells in Gut- Associated Lymphoid Tissue (GALT) and in compromised gut epithelial integrity. HIV disease progression correlates with immune activation, which is higher in women compared to men. Antiretroviral therapy (HAART) effectively suppresses viral replication and stimulates immune reconstitution. HIV positive women on HAART have higher levels of T-cell activation than HIV positive men on HAART. We hypothesize that the compromised mucosal integrity allows for increased microbial translocation in women on therapy, which stimulates systemic immune activation. This may increase morbidity and disease progression in women.
Methods
Peripheral blood samples and small intestinal biopsy samples were obtained from HIV+ men (n=14) and women (n=8) on long term HAART (>2years). Immunophenotypic analysis was performed using multicolor flow cytometry. Gene expression profiles in gut mucosa and isolated T cell populations were analyzed using DNA microarray technology and Real-Time PCR assays. Fluorescent IHC was used to measure tight junction protein expression. Plasma levels of 16S rRNA were quantified using Real-Time PCR assay.
Results
Despite effective viral suppression, HIV+ women on HAART had a greater proportion of activated GALT CD4+T-cells (37.4% vs 6.5%) and GALT CD8+T-cells (42.7% vs 12.52%) compared to men (p<.05, 2-tailed t-test). Gene expression profiles in the gut mucosa were reflective of the sustained T-cell activation in women on HAART as compared to men on HAART. Mucosal gene expression showed greater down regulation of epithelial regeneration pathways (Wnt Signaling) and tight junction protein ZO-1 (2-fold decrease), in women than men on HAART. Indicators of microbial translocation, such as bacterial 16S rRNA and LPS levels in plasma, were increased in women compared to men on HAART.
Conclusions
Results suggest that increased microbial translocation explains in part the gender discrepancy in T-cell activation in women compared to men, despite effective control of viral replication. The results provide evidence that gender and sex hormones are important in the maintenance of gut epithelial function, during HIV infection and HAART. Future studies in this field will be needed to investigate the molecular mechanisms involved and to provide additional therapeutic options.
Results 1: Women retain higher levels of immune activation despite effective viral suppression during HAART.
HIV negative women have 5% higher levels of HLADR+ (Activation marker) CD4+ T cells (A) and 17% higher activation levels in CD8+ T cells (B) in peripheral blood. In the gut associated lymphoid tissue there are >20% higher levels of HLADR+ CD4+ T cells (C) and >15% higher levels of HLADR+ CD8 T cells (D) in HIV - women as compared to men. These differences are further increased during HIV infection. However, following Highly Active Anti-Retroviral Therapy (HAART), despite complete viral suppression, women retain higher levels of T cell activation, especially in the GALT (30% in CD4+ T cells and 29% in CD8+ T cells). The results from peripheral blood and GALT are summarized in E. (* indicates p<.05)
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