Revista de SIDA e investigación clínica

Differential Expression of Rac-1, Cxcr4 and CCR5 on CD4 T-Cells at Different Stages of HIV-1 Disease Relate To Its Progression in Therapy Naive Individuals

Abstract

Jaideep S Toor, Aman Sharma, Sukhdev S Kamboj and Sunil K Arora

Background: HIV-1 uses different co-receptors (CCR5/CXCR4) at different stages of disease to enter target cells. Any information in understanding this mechanism has important implication on both, the rate of disease progression and our understanding of the immunopathogenesis of this disease.

Methods: This cross-sectional study involved 67 treatment-naïve HIV-1 infected individuals. The expression of CCR5 and CXCR4 on T-cell subsets was evaluated in the peripheral blood of patients at different stages of HIV disease, active pulmonary tuberculosis (PTB), HIV/PTB co-infection and healthy controls, to assess their possible role or association with change in Treg frequency during the disease progression. Furthermore, we investigated the impact of Rac1 expression in relation to functionally active CXCR4 and NF-κB expression.

Results: Significantly higher CCR5 expression on CD4+CD25high Treg cells in HIV-1 subjects in early stage of the disease correlated well with initial decrease in Treg frequency. On the contrary, higher CXCR4 expression on CD4+CD25low/negative T-cells (non-Treg cells) in advanced stage of disease explained the shift to X4 type with faster progression to AIDS. This shift is further supported by initial significant decrease in Rac1 expression in early disease followed by returning to normal expression with disease progression. Interestingly, PTB co-infection correlated significantly with increase in CCR5 expression on Treg population only, at the same time favoring increase in CXCR4 expression on CD4+CD25low/negative subset.

Conclusion: The study indicates novel inter-relationships of co-receptor expression and their regulatory genes in therapy naïve individuals and how the virus manipulates the host machinery to its advantage. The Rac-1 seems to regulate not only the functional conformation of CXCR4, but also the expression of both FoxP3 and NF-κB genes there by affecting the disease progression in HIV subjects. These findings need further attention to look at their clinical implication and disease outcome in a larger study.