Grouppe Kurosawa: HIV - Periods of Immune Control, Immune Dysfunction, Viral Propagation, and Transition to Clinical AIDSl (print)

Periods of Immune Control, Immune Dysfunction, Viral Propagation, and Transition to Clinical AIDS

HIV virus becomes established in the body because the immune system of infected persons is initially immunosuppressed by a combination of physical and psychological stress, drug abuse, the viral VPR, TAT, NEF, p24/17, gp160/120 proteins, and the immune hormones TGF-beta/IL-10. Although these factors can increase the infectivity of the virus, promote viral synthesis, decrease the development of T cells in the thymus, and increase the turnover of CD4 T cells, they do not necessarily lead to the development of clinical AIDS. In order for clinical AIDS to develop, glucosteroid binding sensitivity must be increasingly abolished or reduced in lymphatic and non-lymphatic tissues alike. The induction of glucosteroid binding insensitivity or resistance, even in the presence of normal or elevated amounts of hydrocortisone in the blood, will inevitability be followed by an unrestrained release of pro-inflammatory hormones, such as TNFa, IL-1 and IL-6. The release of these highly reactive pro-inflammatory hormones will result in massive programmed cell death in the thymus/lymph nodes, increased viral production, and the appearance of chronic physical symptoms such as fever, night sweats, wasting, tissue necrosis, Kaposi's sarcoma, B cell malignancies, and neurological disorders such as dementia. These physical symptoms can be attributed to the aforementioned unrestrained release of pro-inflammatory hormones and the viral TAT, NEF, VPR, gp160/120 and p24/p17 proteins.

For the sake of illustration, Grouppe Kurosawa has divided HIV infectivity into five overlapping periods. In the following diagram, plus or minus numbers refer to the IMPORTANCE of the presence or absence of a specific immune hormone or viral protein in each phase. The numbers do not refer to the overall amount or concentration of the respective protein or molecule in the blood at any particular time. For example, p24 concentrations are very high in the final period, actual AIDS, but its importance as an agent of immunosuppression is more important in the earlier periods of HIV infection. A negative value does not mean the immune hormone or viral protein is not important in a respective period. To the contrary, a minus number of 4-, for example, means the absence of this hormone in this period is VERY significant.

The Asymptomatic Phase of Infection

This phase of HIV viral replication is characterized by immune control of viral propagation, followed by mmunosuppression and immunological tolerance. Immunological suppression is best exemplified by the effect of the anti-inflammatory hormone hydrocortisone (cortisol) on the immune system. The immunosuppression induced by hydrocortisone is freely reversible when the concentration of hydrocortisone in the blood decreases. Immunological tolerance is a long-lived biochemical reaction in which the immune system is "taught" to not react to certain proteins, peptides, and other molecules. The immune hormones IL-10 and TGF-beta are intrinsically involved in inducing tolerance. The most well known form of tolerance occurs in the gastrointestinal tract in reaction to compounds found in foods. In the absence of oral tolerance, organisms could and would be killed by gastrointestinal inflammatory reactions to food antigens.

There are three overlapping periods of anti-viral activity in the Asymptomatic Phase of infection.

Period One-CD4 cell counts and CD4/CD8 ratio relatively normal.
A period of complete immunological control of viral synthesis.

IL-16-6+
Serotonin-6+
VPR-4-
TAT-4-
IL-10-4-
TGFb-4-
P24-4-
P17-4-
PGE2-4-
Cyclic Amp-4-
Interferon gamma-4+
IL-12-4+
IL-1-2+
TNFa-2+
NF-kappaB-2+
IL-2-6+
IL-4-2+
IL-6-2+
Chemokines-4+

TH1 Immune response predominates-4+
Hydrocortisone-mediated apoptosis-6-
Anti-gp160 immune complex-mediated apoptosis-6-
Fas-mediated apoptosis-6-
Autoimmunity induced by anti-gp160 antibodies-6-
Tissue sensitivity to hydrocortisone-6+

Period Two-CD4 cell counts of 1200-700 per microliter.
A period when immunological control begins to falter leading to increased immunosuppression and the beginning phases of tolerance.

IL-16-3+
Serotonin-3+
P24-1+
P17-1+
PGE2-1+
Cyclic Amp-1+
VPR-1+
IL-10-1+
TGFb-1+
IL-4-1+
IL-6-1+
Vitamin D-1+
IL-12-1-
IL-1-1-
TNFa-1-
Interferon-gamma-1-
NF-kappaB-1-
IL-2-1-
TAT-1-
Chemokines-1-

TH2 Immune response predominates-1+
Hydrocortisone-mediated apoptosis-2+
Anti-gp160 immune complex-mediated apoptosis-2+
Fas-mediated apoptosis-1-
Autoimmunity induced by anti-gp160 antibodies-1+
Tissue sensitivity to hydrocortisone-2+

Period Three-CD4 cell counts of 700-500 per microliter.
A period when immunosuppression and tolerance become increasingly more dominant, and the immune response shifts to a TH2 dominant response.

IL-16-1+
Serotonin-1+
P24-3+
P17-2+
PGE2-3+
Cyclic Amp-3+
VPR-3+
IL-10-2+
TGFb-2+
IL-4-2+
IL-6-2+
Vitamin D-2+
IL-12-3-
IL-1-3-
TNFa-3-
Interferon-gamma-3-
NF-kappaB-3-
IL-2-3-
TAT-2+
Chemokines-3-

TH2 Immune response predominates-3+
Hydrocortisone-mediated apoptosis-4+
Anti-gp160 immune complex-mediated apoptosis-3+
Fas-mediated apoptosis-3-
Autoimmunity induced by anti-gp160 antibodies-3+
Tissue sensitivity to hydrocortisone-4+

The Symptomatic Phase of Infection

This phase of HIV infectivity is characterized by the collapse of immunosuppression and immunological tolerance and a shift toward a cell-mediated immune response against viral and non-viral proteins. The immunological brake that maintained the asymptomatic phase of infection has been released and the vehicle, in this case the HIV virus, is starting to build up speed. Many outside factors, such as psychological stress, drug abuse, and chronic infections, can substantially shorten the time frame between seroconversion and the appearance of the symptomatic phase of infection.

Period Four-CD4 cell counts of 500-200 per microliter. A period of mixed immunosuppression and immunological hyperactivity.

IL-16-2-
Serotonin-2-
P24-2+
P17-2+
PGE2-2+
Cyclic Amp-2+
VPR-1+
IL-10-1+
TGFb-1+
IL-4-2+
IL-6-3+
Vitamin D-2+
IL-12-2+
IL-1-2+
TNFa-2+
Interferon-gamma-2+
NF-kappaB-2+
IL-2-2+
TAT-3+
Chemokines-2+

TH1 Immune response predominates-2+
Hydrocortisone-mediated apoptosis-2-
Anti-gp160 immune complex-mediated apoptosis-5+
Fas-mediated apoptosis-1+
Autoimmunity induced by anti-gp160 antibodies-5+
Tissue sensitivity to hydrocortisone-2-

Phase Five-CD4 cell counts of 200-0 per microliter. A period of maximal immune hyperactivity. Full Blown AIDS.

Il-16-6-
Serotonin-6-
P24-1+
P17-1+
PGE2-1+
Cyclic Amp-1+
VPR-4-
IL-10-3-
TGFb-3-
IL-4-4+
IL-6-4+
Vitamin D-1+
IL-12-2+
IL-1-4+
TNFa-4+
Interferon-gamma-4+
NF-kappaB-4+
IL-2-3+
TAT-4+
Chemokines-4+

TH1 Immune response predominates-4+
Hydrocortisone-mediated apoptosis-4-
Anti-gp160 immune complex-mediated apoptosis-7+
Fas-mediated apoptosis-3+
Autoimmunity induced by anti-gp160 antibodies-7+
Tissue sensitivity to hydrocortisone-4-