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

The Role of TNF in AIDS Pathophysiology

In 1991, a Japanese scientific group posed the question: “Is AIDS a tumor necrosis factor (TNF) disease?” This remains a compelling inquiry with a complex answer. TNF-α and TNF-β contribute to serum markers commonly associated with AIDS. These include elevated levels of beta-2 microglobulin, neopterin, and IL-2 receptors in the blood.

Moreover, clinical symptoms associated with both TNF activity and AIDS include fever, headache, wasting, fatigue, and nausea. TNF is also a highly pro-inflammatory cytokine. Consequently, chronic inflammation is a defining feature of clinical AIDS.

Immune Regulation of TNF in HIV Infection

During immune activation, both excessive and insufficient TNF can disrupt proper function. The immune system, therefore, relies on feedback mechanisms to regulate inflammation in response to pathogens. These feedback loops are intended to follow a vigorous primary immune response.

In the case of HIV infection, the virus appears to activate these feedback mechanisms prematurely. This occurs before the body can mount an effective primary immune response. As a result, the virus is not fully cleared from infected tissues. Over time, viral load increases, and opportunistic infections that stimulate inflammatory hormones become more frequent. Eventually, immunosuppression deepens, leading to the development of clinical AIDS.

TNF Activity in Early HIV Infection

Although elevated TNF-α is a well-known feature of clinical AIDS, its role during early infection is less understood. Studies in feline immunodeficiency virus (FIV) provide insight into this stage. Infected cats observed over three years remained asymptomatic and showed reduced TNF-α production. This reduction was seen across several cell types, whereas IL-6 production remained normal. These findings suggest that low TNF-α may be characteristic of asymptomatic FIV infection.

In human studies, HIV-infected adherent PBMCs released high levels of IL-1α/β and IL-6; however, TNF-α was not produced. Long-term in vitro studies conducted over one month showed no change in TNF-α or IL-1/IL-6 secretion. In another investigation, HIV-infected macrophages exposed to Pneumocystis carinii failed to produce TNF-α or IL-1β. Consequently, they could not eliminate the pathogen. This reduction in TNF-α was also confirmed at the mRNA level.

Viral Protein Effects on Cytokine Production

Several HIV proteins directly influence cytokine behavior and immune function:

1. NEF, TAT, and gp120 stimulate IL-6 production. In turn, IL-6 promotes the release of TGF-β, which inhibits B-cell hyperactivity and various immune functions.
2. TAT specifically activates the TGF-β gene. Since TNF-α and TGF-β are antagonistic cytokines, this activation further alters immune regulation.
3. VPR and other viral proteins may inhibit calcineurin, which is necessary for TNF-α gene transcription.
4. VPR also activates the glucocorticoid receptor axis. Glucocorticoids stimulate TGF-β gene expression and suppress transcription factors such as NF-κB. NF-κB plays a key role in regulating TNF-α expression.

While there is limited evidence for early TNF-α suppression in HIV infection, the question remains challenging to study. Nonetheless, because TNF-α is essential for mounting immune responses against viruses, it remains a logical focus when investigating HIV-induced immune dysregulation.

TNF-α and HIV Entry into Macrophages

TNF-α inhibits HIV-1 entry into primary human macrophages, both early infection targets and long-term viral reservoirs. Notably, pretreating macrophages with TNF-α for as little as two hours can reduce viral entry by 75%. This effect is explicitly mediated through the TNF-α 75kD receptor.

Experimental models demonstrate that transfecting uninfected cells with the TAT gene results in the downregulation of this receptor on the cell surface. This receptor down-modulation may protect infected cells from the cytotoxic effects of TNF-α. Chronically infected T cell lines are susceptible to TNF-α concentrations as low as 10 ng/ml. In contrast, non-infected cells can tolerate TNF-α concentrations up to 1000 ng/ml.

Furthermore, in uninfected cells, the TAT protein is expected to impair TNF-α’s ability to activate key leukocyte subsets, which are essential for initiating the primary immune response against HIV.

TNF-α in Dendritic Cell Activation

Dendritic cells collect soluble antigens in peripheral tissues and deliver them to lymph nodes, where they activate naive or resting T cells. The release of Langerhans (dendritic) cells into lymph is TNF-α dependent.

In addition, TNF-α activates dendritic cells by upregulating adhesion molecules such as ICAM-1. It influences primary mixed leukocyte reactions and promotes T cell proliferation. This occurs through increased expression of MHC class II antigens and IL-2 receptors.

Moreover, TNF-α is continuously synthesized in the thymus, regulating thymocyte proliferation and selection. IL-2 induces TNF-α expression, which may account for the toxicity observed during IL-2 therapy. TNF-α also serves as an autocrine growth factor for normal human B cells.

TNF-α in Neutrophil and Monocyte Function

In addition to its role in dendritic cell activity, TNF-α regulates neutrophil migration and enhances superoxide production. Activated neutrophils exhibit viricidal effects against HIV. Likewise, TNF-α promotes monocyte superoxide generation, contributing to host defense against opportunistic pathogens such as Pneumocystis carinii and Toxoplasma gondii.

Without TNF-α, immune responses to soluble antigens, viruses, and parasites are significantly impaired. One of the earliest immune defects in HIV infection is the inability to process soluble antigen effectively.

Regulation of TNF-α by TGF-β and Glucocorticoids

Because of its potent biological effects, TNF-α is tightly regulated. Glucocorticoids and TGF-β function as inhibitors and are co-released by IL–2–stimulated T cells and monocytes.

TGF-β limits inflammation by counteracting TNF-α activity at localized sites. When inflammation worsens, TNF-α, IL-6, and IL-1β act on the hypothalamus. This activates the stress response and triggers the release of hydrocortisone. Hydrocortisone then suppresses further synthesis and activity of pro-inflammatory hormones, helping restore immune balance.