Factors Leading to CD4 T-cell Depletion in Omani HIV-Infected Patients Who Are Immunologically Non-Responding to Treatment

Infection with the Human Immunodeficiency Virus (HIV), the cause of the Acquired Immunodeficiency Syndrome (AIDS), is a worldwide challenging health problem. In Oman, 1300 individuals are living with HIV/AIDS. Although Highly Active Antiretroviral Therapy (HAART) represents a success in inhibiting HIV replication, some patients are not able to eliminate the damage caused to their immune system, despite having an undetectable viral load. These patients are classified as immunological non-responders (INR), and they are characterized by having undetectable viral load (andlt;50 copies/ml) and a CD4 count that is below 200 cells/andmicro;l after 3 years of HAART and viral suppression. It is now largely admitted that, in non-treated (with detectable viral load, i.e., viremic) HIV-infected individuals, microbial products translocate from the gut to the blood. This is due to the depletion of CD4 T-cells of the Gut-Associated Lymphoid Tissue (GALT), and it is a reason for hyper immune activation, which is a hallmark of HIV infection. The hyper activation of CD4 T-cells will eventually lead to the programed death (apoptosis) of these cells. While microbial translocation is decreased in patients responding to HAART on the virological and immunological levels, patients that are INR have high levels of microbial products in their blood. We have shown that, in viremic patients, microbial translocation is associated with the activation of monocytes and with increased levels of inflammatory cytokines in the blood, which is linked to CD4 T-cells dysfunction. Our hypothesis is that, in immunological non-responders, the increased levels of microbial products (lipopolysaccharide (LPS)), and markers of translocation from the gut (Intestinal Fatty Acid-binding Protein (I-FABP)and soluble CD14 (sCD14)) in the blood are associated with increased levels of CD4 T-cells hyper activation and apoptosis, the levels of inflammatory chemokines (CXCl9 and CXCL10) and the migration potential of CD4 T-cells (characterised by the ex pression of the receptor of these chomokines, namely CXCR3). It is very likely that the high levels of these microbial molecules and chemokines in the blood and the hyper activation of CD4 T-cells are associated with the depletion of these cells from the blood as they can cause their apoptosis or migration to the lymph nodes. Thus, we aim to: 1. Investigate the levels of apoptotic CD4 T-cells in the blood of Immunological non-responders and immunological responders. 2. Explore and compare the hyper activation profile of CD4 T-cells in the Immunological non-responders and Immunological responders. 3. Assess the differences in the frequency of CXCR3 + CD4 T-cells in the blood of Immunological non-responders and immunological responders. 4. Compare the levels of CXCL-9 and CXCL-10 in the blood of Immunological non-responders and immunological responders. 5. Investigate the correlation between the levels of molecules associated with the microbial translocation (LPS, I-FABP and sCD14) with the parameters stated above. This study will allow us to understand the conditions that are associated with the failure of the reconstitution of a potent immune system in HAART-treated HIV-infected patients. Hence, we might be able to suggest therapies which lead to an increase of CD4 count by decreasing the inflammatory molecules levels in the blood. In return this will help to optimize the best personalized treatment for Omani patients by covering the immunological aspects that the HAART is not able to restore.