AEGiS-15IAC: Differential effects of TNF on HIV-1 expression: R5 inhibition and implications for viral evolution.

15th International AIDS Conference

Bangkok, Thailand - July 11-16, 2004

Differential effects of TNF on HIV-1 expression: R5 inhibition and implications for viral evolution.

Int Conf AIDS 2004 Jul 11-16; 15:(abstract no. MoOrA1048)

Pavlakis GN, Valentin A, Morrow M, Yarchoan R
National Cancer Institute at Frederick, Frederick, United States

BACKGROUND: Tumor necrosis factor-alpha (TNF-α) induces nuclear translocation of the transcriptional factor NFkB leading to increased activity from the HIV-1 LTR promoter. High levels of TNF-α have been found in plasma samples from some HIV-1 infected individuals.

METHODS: The effects of TNF-α on viral propagation, beta-chemokine production, and CCR5 expression were monitored in HIV-infected PBMC in vitro. Blood samples from HIV-1 infected individuals (n=63) and healthy controls (n=30) were assayed for plasma TNF-α, and for frequency of TNF-producing cells by intracellular staining and flow cytometry.

RESULTS: TNF-α treatment of HIV-1 infected lymphocytes results in inhibition of R5 HIV-1 strain propagation with no obvious effects on the levels of X4 viral strains. TNFa stimulates the production of beta-chemokines and therefore indirectly downregulates surface levels of CCR5 in primary cells. The lack of effect on the expression of X4 HIV-1 variants by exogenous TNF is due to endogenous TNF production and/or increased NF-kB activity. Experiments performed with lymphocytes from patients with H-IgM syndrome due to defective NFkB signaling resulted in stimulation of X4 viral expression upon addition of exogenous TNF-α. Analysis of a group of HIV-1 patients with high levels of plasma TNF-α demonstrated that there is no increase in the number of TNF+ circulating lymphocytes in HIV infection. In contrast, we identified several patients characterized by a reduction in the number of TNF-positive cells with a high concentration of circulating TNF in plasma.

DISCUSSION: These results identify TNF as an important regulator of HIV-1 evolution in vivo, and demonstrate that measurements of intracellular cytokine production in blood cells do not necessarily represent cytokine levels in tissues. TNF-α production has the potential to promote propagation of X4 viruses and inhibit X5, due to CCR5 downregulation.

Keywords: AEGIS, HIV-1, Tumor Necrosis Factor-alpha, Receptors, CCR5, HIV Infections, HIV Long Terminal Repeat, Acquired Immunodeficiency Syndrome, Chemokines, CC, HIV, HIV-1 Reverse Transcriptase, NF-kappa B, Cytokines, Evolution, In Vitro, Humans, virology, genetics

040711
MoOrA1048