Grouppe Kurosawa: HIV - The Relative Absence of Tumor Necrosis Factor During the Primary Immune Response Against the Virus (print)

The Relative Absence of Tumor Necrosis Factor During the Primary Immune Response Against the Virus

In 1991, a Japanese scientific group posed the question, 'Is AIDS a tumor necrosis factor disease?' This is a compelling question, and the answer is complicated. Certainly TNFa/b contributes to the serum markers associated with AIDS, such as increased concentrations of beta-2 microglobulin, neopterin, and IL-2 receptors in the blood. Clinical symptoms associated with both TNF and AIDS include fever, headache, wasting, fatigue and nausea. TNF is also an extremely pro-inflammatory hormone, and chronic inflammation is characteristic of clinical AIDS.

Nevertheless, at specific periods during an immune response, too little TNF is as deleterious to an optimal immune response as too much. The immune system has a multitude of feedback mechanisms for controlling inflammatory responses to pathogens. These feedback responses are designed to be activated by and follow a vigorous primary immune response. In the case of HV, we believe the virus is directly and indirectly activating the feedback response or loop before a vigorous primary immune response can be mounted. As a consequence, the virus is never completely cleared from the infected tissues. Over time, as the viral titer builds and pro-inflammatory hormone-inducing opportunistic infections become more common, the immunosuppression finally collapses, thereby allowing the transition to clinical AIDS.

Although increased concentrations of TNFa have routinely been reported in clinical AIDS, very little is known about the activity of TNFa during the early period of infection. In FIV or feline immunodeficiency virus infected cats, a cat population studied over three years remained asymptomatic and showed depressed TNFa production in a number of cell types. IL-6 production was not impaired. The authors concluded that deficiencies in TNFa production were an intrinsic characteristic of the asymptomatic FIV infection. The infection of adherent human PBMC by HIV virus induces the release of high concentrations of IL-1 a/b and IL-6, but not TNFa. Long term in vitro studies {1 month) showed no changes in the secretion of TNFa or IL-1 /IL-6. In other studies, HIV infected macrophages exposed to Pneumocystis carinii did not produce TNFa or IL-1 b and therefore could not destroy the pathogen. The reduction in TNFa was confirmed at the mRNA level. There are numerous interpretations for these data. First, NEF, TAT and gp120 stimulate IL-6 production and IL-6 specifically induces the release of TGFb, an inhibitor of B cell hyperactivity, among other immune functions. Second, TAT specifically activates the gene for TGFb, and TGFb and TNFa are antagonistic immune hormones. Third, VPR and other viral proteins may inhibit calcineurin. The activation of calcineurin is necessary for TNFa gene transcription. Fourth, VPR activates the glucosteroid-receptor axis, and glucosteroids activate TGFb gene expression in T lymphocytes. Glucosteroids also inhibit the activity of transcription factors, such as NF-kB, which additionally regulates TNFa gene transcription. There is very little hard evidence that TNF secretion is impaired early in HIV infections. It is a difficult question to study. Nevertheless, TNFa plays an important role n activating the immune response against viruses and other pathogens so it is a logical place to look for HIV-induced changes in immune responsiveness.

TNFa inhibits the entry of HIV-1 into primary human macrophages, an important early target of virus infection and a reservoir for virus production. Pretreatment of macrophages with TNFa for as little as 2 hours inhibits 75% of viral entry into the cells. This inhibition is mediated by the TNFa 75kD receptor. When a TAT gene is transfected into uninfected cell lines, the expressed TAT protein down-modulates the very same TNFa receptor from the membrane. Down-modulating the TNFa receptor from the membrane of infected cells may actually protect the cells from the known cytotoxic effects of TNFa. Chronically HIV infected T cell lines are killed by TNFa doses as low as 10ng/ml, white non-infected cells are resistant to exposure to TNFa at concentrations up to 1000 ng/ml. In uninfected cells, TAT would be expected to impair the ability of TNFa to activate the various leukocyte subtypes involved in initiating the primary immune response against the virus

Dendritic cells acquire soluble antigen in peripheral tissues and transport it to lymph nodes where they effectively activate resting or naive T cells. The increased release of dendritic (Langerhans) cells into lymph is TNFa-dependent. TNFa activates dendritic cells in part by inducing the expression of cell adhesion molecules, such as ICAM-1. TNFa also regulates the dendritic cell-mediated primary mixed leukocyte reactions, and induces T cell proliferation by increasing the expression of histocompatibility class II antigens and IL-2 receptors. TNFa is constituitively synthesized in the thymus where it regulates thymocyte proliferation and/or selection. IL-2 induces the release of TNFa and this may account for the toxicity associated with IL-2 infusion therapies. TNFa is also an autocrine growth factor for normal human B cells. In addition to activating and inducing the migration of dendritic cells, TNFa regulates neutrophil migration and activates superoxide production. Activated neutrophils are viricidal against the HIV virus. TNFa further activates superoxide production in monocytes, which contributes to host protection against AIDS associated opportunistic pathogens such as Pneumocystis carinii and Toxoplasma gondii. In the absence of TNFa, the primary immune response against soluble antigen, viruses, and parasites is severely impaired. An inability to process soluble antigen is one of the earliest defects in a primary HIV infection.

TNFa is known to be very toxic so its biological effects are tightly regulated by inhibitors such as glucosteroids and TGFb. TGFb is released along with TNFa from IL-2 stimulated T cells and monocytes. TGFb serves to limit an inflammatory response to localized areas by antagonizing the ability of TNFa to excessively stimulate cells. If an inflammation is severe, the stress response is activated (by TNFa, IL-6and IL-1 b acting directly on the hypothalamus), and hydrocortisone is released to further inhibit the synthesis and activity of pro-inflammatory hormones.