Abstract
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-naive 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 naive 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.
Highlights
Human Immunodeficiency virus, HIV-1 initiates infection via viral envelope (Env) glycoprotein gp120 interacting with cell surface CD4, followed by its association with a co-receptor that triggers the fusion of viral and host-cell membranes
HIV-1 infected patients confirmed by the blood sample being reactive by three rapid tests, as per National AIDS Control Organization (NACO) guidelines were enrolled from the Integrated Counselling and Testing Centre (ICTC) in the Department of Immunopathology, Postgraduate Institute of Medical Education and Research (PGIMER), and Chandigarh, India
pulmonary tuberculosis (PTB) and HIV-PTB patients confirmed positive for Mycobacterium tuberculosis by chest x-ray, sputum smear positivity and TB-PCR were recruited from DOTS centre, in our hospital.The study was approved by the Institutional Ethics Committee (IEC) of Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India and peripheral blood was obtained from enrolled subjects after an informed consent
Summary
Human Immunodeficiency virus, HIV-1 initiates infection via viral envelope (Env) glycoprotein gp120 interacting with cell surface CD4, followed by its association with a co-receptor that triggers the fusion of viral and host-cell membranes. All HIV-1 strains are classified phenotypically as R5 (Macrophage tropic), X4 (T-cell tropic), or R5X4 (dual tropic i.e. both M-tropic and T-tropic) depending on whether they preferentially utilize cysteinecysteine receptor 5 (CCR5) or cysteine-X-cysteine receptor 4 (CXCR4) or mixed [1] This inter-conversion of tropism requires only a small number of changes in the Env V3 region. Why there is selective advantage of CCR5 tropic viruses in establishing HIV-1 infection, switching over to CXCR4 utilization in the advanced stage of disease, is not clearly understood yet This tropism switch has been associated with rapid disease progression and poor clinical prognosis [7,8,9]. 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
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