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

The Establishment of HIV in the Body

HIV becomes established in the body because the immune system is initially compromised. This immunosuppression results from a combination of physical and psychological stress, substance abuse, and the actions of several viral proteins—VPR, TAT, NEF, p24/17, and gp160/120—as well as the immune hormones TGF-beta and IL-10. Collectively, these factors increase viral infectivity, promote viral replication, inhibit T cell development in the thymus, and accelerate CD4 T cell turnover. However, these effects alone do not necessarily lead to the development of clinical AIDS.

For clinical AIDS to develop, a progressive reduction in glucosteroid receptor sensitivity must occur across both lymphatic and non-lymphatic tissues. Once glucosteroid binding resistance sets in, even normal or elevated levels of hydrocortisone fail to suppress inflammation. This shift leads to the unregulated release of pro-inflammatory hormones, including TNF-alpha, IL-1, and IL-6. As a result, widespread programmed cell death occurs in the thymus and lymph nodes, viral replication increases, and physical symptoms—such as fever, night sweats, wasting, tissue necrosis, Kaposi’s sarcoma, B cell malignancies, and neurological issues like dementia—begin to appear. These clinical manifestations stem from the combined effects of viral proteins and the unrestrained activity of pro-inflammatory cytokines.

Five Overlapping Phases of HIV Infectivity

Grouppe Kurosawa divides the course of HIV infection into five overlapping phases. The accompanying chart uses plus (+) or minus (–) values to denote the importance—not quantity—of specific immune hormones or viral proteins during each stage. For instance, p24 levels may be high in late-stage AIDS, but its immunosuppressive role is more critical in earlier stages. A negative value (e.g., -4) indicates that the absence of a factor is highly significant in that phase.

The Asymptomatic Phase

This phase is marked by early control of viral replication, followed by a shift toward immunosuppression and immunological tolerance. Suppression is initially mediated by hydrocortisone and is reversible. In contrast, tolerance—driven by IL-10 and TGF-beta—is a more persistent form of immune inactivation, similar to oral tolerance in the gut.

Period One: CD4 count 1200–800/µL

Characterized by strong immune control over viral replication.
TH1 immune response predominates.
Cytokines like IL-2, IL-12, and IFN-gamma are elevated.
Hydrocortisone sensitivity remains intact.
Apoptotic mechanisms, including Fas and anti-gp160 immune complexes, are minimal.

Period Two: CD4 count 1200–700/µL

Immune control begins to decline.
IL-10 and TGF-beta levels increase, indicating growing immunosuppression.
TH2 cytokines like IL-4 and IL-6 begin to rise.
The immune system begins to tolerate viral antigens.
Apoptosis and autoimmunity triggered by anti-gp160 antibodies increase moderately.

Period Three: CD4 count 700–500/µL

Immunosuppression deepens; tolerance becomes more established.
TH2 cytokines dominate.
Viral proteins such as VPR and TAT have increased in importance.
Apoptotic processes are more active.
Hydrocortisone sensitivity starts to diminish.

The Symptomatic Phase

During this stage of infection, the immune system shifts from suppression and tolerance to heightened inflammatory activity. The regulatory “brakes” that maintained the asymptomatic phase are released, allowing both the virus and immune dysregulation to accelerate. A variety of external stressors—such as psychological strain, substance abuse, and chronic infections—can significantly shorten the time between initial seroconversion and the onset of symptoms.

Period Four: CD4 count 500–200/µL

A transitional phase with mixed immune suppression and hyperactivity.
Both TH1 and TH2 cytokines are elevated.
Increased activity of NF-kB and pro-inflammatory cytokines.
Viral proteins contribute more directly to immune cell death.
Anti-gp160 antibody-mediated damage intensifies.

Period Five: CD4 count 200–0/µL

Full-blown AIDS.
The immune system becomes hyperactive but ineffective.
Pro-inflammatory cytokines reach peak levels.
Fas-mediated apoptosis and anti-gp160 immune complex-induced autoimmunity become dominant CD4 T cell depletion mechanisms.
Glucosteroid sensitivity is largely abolished.

This model emphasizes that immune dysregulation—not merely viral replication—is central to HIV disease progression. It also highlights the immune system’s dual role as both protector and contributor to disease, depending on the phase of infection.