Grouppe Kurosawa: HIV - The Initial Viral Infection and Lack of a Vigorous Pro-Inflammatory Response Against the Virus (print)

The Initial Viral Infection and Lack of a Vigorous Pro-Inflammatory Response Against the Virus

It is known that many individuals exposed to the HIV virus are not infected. This list of people includes prostitutes, children of HIV-infected mothers and individuals who routinely engage in risky sexual practices. If the HIV virus can be cleared from the body, why doesn't this routinely occur?

An increasing amount of research confirms that cytotoxic CD8 T cells, sensitized to the HIV virus, control the rate of CD4 T cell decline. Patients with the slowest rates of CD4 decline have the highest levels of cytotoxic CD8 cells in their blood. Although direct killing is one method by which CD8 T cells control the spread of virus, the secretion of suppressor factors, which inhibit the ability of CD4 T cells to make, or to be infected by virus, is now known to be yet another method by which the body attempts to limit the spread of the HIV virus. When 25 non-infected individuals with histories of high risk sexual exposures were studied, their CD4 T cells were less susceptible to infection by primary isolates of the HIV virus than was a control group of individuals never exposed to the virus. The CD8 T cells of the test subjects secreted the pro-inflammatory hormones RANTES, MIP-1 a, and MIP-1 b. In addition to the secretion of the aforementioned chemokines, CD8 cells also secrete an immune hormone called IL-16. This protein hormone represses HIV infection in lymphocytes, monocytes and dendritic cells at the transcriptional level; it is active against both laboratory and naturally acquired viral isolates. IL-16 is considered a major factor in controlling the spread of the HIV virus, since serum IL-16 levels decrease as disease symptoms appear. Most importantly, IL-16 stimulates the expression of CD25, the IL-2 receptor on naïve CD4 cells and primes them to respond to IL-2. IL-16 and IL-2 selectively expand the population of CD4 cells in a culture dish. IL-2 and IL-16 are considered prime drug candidates for promoting the reconstitution of the immune system in HIV infected persons. The neurotransmitter serotonin (it has a much broader biological role than neurotransmission) stimulates the synthesis and release of IL-16 from CD8 T cells, thereby explaining one method by which serotonin activates cell-mediated immunity.

In order for a sensitized CD8 cell to kill a virally-infected cell, it must first locate the site of the infection. Attracting immunized cells to the sites of infection is the biological role of inflammation. Pro-inflammatory hormones such as MIP-la, released from tissue macrophages and T cells at the sites of infection (e.g. the lung for influenza virus and the anal and vaginal mucosa for HIV), attract additional cytotoxic T cells to the infected tissue in an effort to eliminate the virus. This is an inflammatory response and by definition it is intended to be localized. When mice genetically deficient in MIP-1 are exposed to influenza virus, they have substantially less inflammation in their lungs and a reduced ability to eliminate the virus. Infected tissues can't efficiently recruit immunocompetent T cells to the lung in the absence of MIP-1 a. The question that begs asking is 'What happened to the inflammatory response to the HIV virus in the anal and vaginal mucosa?' We know that the virus can be cleared from the body, because these cases have been documented. If inflammation at the site of viral entry can routinely clear an infection, why is this so rare in HIV infections?

Glucosteroids, such as hydrocortisone, inhibit the synthesis of the chemokines RANTES, MIP-1 a/b, MIP-2, and IL-8 and prevent the migration of sensitized T cells, monocytes, eosinophils and neutrophils to sites of local infection. Perhaps the presence of stress, with its accompanying high levels of hydrocortisone in the blood, is responsible for determining whether the HIV virus is cleared from the body, or is allowed to establish a chronic infection. In addition to an increased release of hydrocortisone during stress, immunosuppression may additionally be induced by the viral VPR, TAT, NEF and gp120 proteins. VPR proteins are present in every viral particle whether infectious or not. VPR binds a normal cellular protein that, in turn, directly binds and activates the glucosteroid receptor. The VPR-glucocorticoid receptor complex migrates into the nucleus where it activates the expression of some genes while deactivating others. Anti-glucosteroid drugs, such as RU-486 (The Abortion Pill that blocks the activation of both progesterone and hydrocortisone receptors), inhibit the biological effects of VPR. Hydrocortisone, in elevated concentrations, complements viral VPR mutants. The effects of stress, VPR, TGFb (the synthesis of which can be stimulated by hydrocortisone, TAT, gp120 and possibly VPR), TAT and gp120 may act synergistically to induce a powerful immunosuppression, especially in the thymus and lymph nodes, organs that harbor large amounts of virus, and are particularly sensitive to the immunosuppressive effects of hydrocortisone and TGFb. This immunosuppression, whether pre-existing due to stress or drug abuse, or induced by viral proteins, may impair the establishment of a localized inflammation and subsequent clearance of the HIV virus.

It is now established that the amount of virus present in blood is predictive of progression to AIDS. The viral load is a better predictor of disease progression than reduced CD4 T cell counts. Since over 99% of secreted viral particles have been shown to be non-infectious (in an in-vivo study of 65 HIV infected people with different degrees of disease, only 1 in 60,000 viral particles on average was found o be infectious), it is difficult to reconcile a correlation between viral titers and progression to AIDS without taking other factors into consideration. There are hundreds (and perhaps up to 1000) VPR proteins present in each viral particle. If these proteins can induce an enhanced glucosteroid sensitivity in normal and infected cells regardless of the amount of hydrocortisone present in the blood, it is reasonable to speculate that HIV viral particles, whether infectious or not, may have an intrinsic ability to induce a localized and systemic immunosuppression which permits additional viral synthesis and ultimately progression to AIDS.

Copyright © 2002, Stephen Martin, Ph.D
Chief Scientist, Grouppe Kurosawa
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