Abstract
CD8+ T cells play a major role in controlling HIV-1 infection through the release of soluble lytic and non-lytic antiviral factors. Their decrease or defective function contributes to the HIV-1 disease progression. HIV-1 disease progression has been associated with a remarkable increase of CD38 expression on CD8+ T-cells. It has been also documented that a significant distribution of HIV-specific CD8+T-cells resides in the CD8+CD38+ T-cell sub-population. The failure of HIV-specific CD8+CD38+ T-cells to control HIV-1 infection has been attributed to several mechanisms including apoptosis. However, the relationship between the CD38 expression and molecular events involved in CD8+ T-cell apoptosis is not well understood. Using four-color flow cytometric analysis, the present cross-sectional study we evaluated the expression of four membrane-associated apoptosis-related molecules (TNFR-1, Annexin-V, CXCR4, and CD95) and two cytoplasm-associated apoptosis-related molecules (Bcl-2 and the active form caspase-3) in 41 HIV-1 positive patients and 15 HIV-1 negative individuals. Flow cytometric analysis made on freshly isolated PBMC showed that HIV-1 infection alters the level of expression of CD38, CD95, CXCR4, Bcl-2 and active caspase-3. No significant change in the expression of Annexin V or TNFR-1 was found. A positive correlation was established between CD95, CXCR4, and active caspase-3 expression with low CD4 count and high plasma viremia and CD38 expression. Data suggest that the majority of activated CD8+CD38+ T-cells were apoptotic because they expressed active caspase-3 and the rest of these cells were highly susceptible to become apoptotic since they co-expressed CD95 and CXCR4. Results also suggest that one of the most likely HIV-mediated apoptosis mechanisms is via CD95 and CXCR4 induction through the caspase cascade despite the expression of Bcl-2. All these observations may provide an additional explanation of why HIV-1 infection is not fully contained by HIV-specific CD8+CD38+ T-cells leading to HIV-1 disease progression.
Highlights
Several studies have revealed that most of HIVspecific CD8+ T-cells express CD38 [4]
A cross-sectional study was conducted in which the level of expression of apoptosis-related molecules on activated CD8+CD38+ T lymphocytes in 15 HIVnegative individuals and 41 HIV-positive patients at different stages of infection based on their CD4+ T-cell count and plasma viremia were analyzed (Table 1)
The assessment was performed by four-color flow cytometric analysis, using monoclonal antibodies against CXCR4, CD95, tumor necrosis factor receptors-1 (TNFR-1), Annexin V, Bcl-2 and the active form of caspase-3 on freshly isolated peripheral blood mononuclear cells (PBMC)
Summary
Several studies have revealed that most of HIVspecific CD8+ T-cells express CD38 [4]. T-cells during HIV-1 infection and this has been well accepted as a prognostic activation marker for HIV-1 disease progression in infected individuals who do not control viral replication [1, 2]. Apoptosis has been considered to be a central mechanism of HIV-specific CD8+ T-cell loss and a contributor of HIV-1 disease progression. Based on these previous studies, a comprehensive analysis of HIV-mediated CD8+CD38+ T-cell apoptosis during HIV-1 infection was needed. A correlation was established between the levels of expression of apoptosis-related molecules in these cells with well-accepted progression markers such as CD4 count and viral load.
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