HIV suppresses adaptive immune functioning in multiple ways:
It leads to the impairment and destruction of T cells, dendritic cells and macrophages.
HIV causes B cell dysfunction and dysregulation, leading to hypergammaglobulinemia.
Disease progression unfolds as follows:
Primary infection, which occurs when the HIV viron breaches mucosal tissues; as a result, T cell destruction, viremia, and host immune response with partial containment occurs.
Chronic infection with clinical latency; during this time, HIV replicates in the lymphoid tissues, where they evade destruction by the host immune response.
HIV can progress to
AIDS, which is characterized by immunosuppression, and the opportunistic infections that can lead to death.
We show a layer of mucosal epithelium and the submucosa; specialized dendritic cells and CD4+ T-cells reside within the submucosa.
Primary Infection
The first step of primary infection is HIV infection of the mucosa.
In the submucosa, HIV destroys the T cells, and attaches to dendritic cells.
HIV can destroy T cells via multiple mechanisms, including direct killing and pyroptosis via inflammasome activation.
Dendritic cells carry the HIV virions to the lymphoid tissues, including the
lymph nodes, where they replicate, establishing infection.
From the lymph nodes, HIV enters general circulation, aka, viremia.
Additionally, levels of cytokines and chemokines also increase, with both anti- and pro-viral effects. For example, IFN-alpha and IFN-beta inhibit HIV-1 replication, but, TNF and others stimulate HIV-1 replication.
In response, the host's anti-viral immune system activates:
HIV-specific cytotoxic CD8+ T cells partially contain infection.
Anti-HIV antibodies are produced and can be detected in the blood, thus marking period of seroconversion; this occurs approximately two weeks after infection.
It is thought that the "founder" virus begins to evolve at this point.
Clinical correlation: Many individuals experience acute retroviral syndrome (aka, seroconversion illness), which is characterized by flu-like symptoms of fever, muscle and joint pains, etc.
Viral set point is established at the end of the primary infection phase; it reflects the balance between viral replication and host immune response – and it may predict the rate of HIV progression due to CD4+ T cell destruction. For example, the higher the set viral load, the more likely the disease will progress to AIDS.
Chronic infection
This period is characterized by continuous viral replication in the lymph nodes and
spleen.
Clinical latency: largely asymptomatic with continuous HIV replication outpaces the production of new CD4+ T cells; thus, chronic infection leads to significant T cell loss.
This period can last for several years.
AIDS
CD4+ T cell depletion and full immune suppression.
Thus, progression to AIDS results in fatal vulnerability to opportunistic infections, neoplasms, and neurologic diseases.
Many of these are latent infections that reactivate in the absence of a functioning immune system.
2 most common causes of death in the US:
Pneumonia (caused by Pneumocytis fungi) and
Kaposi's sarcoma (vascular neoplasm)
Viral infections: Herpes simplex, herpes zoster, cytomegalovirus, and multifocal leukoencephalopathy.
Fungal infections: Candidiasis, Crytpococcal meningitis, and histoplasmosis.
Bacterial infections: Atypical Mycobacterium avium-intracellulare and Mycobacterium tuberculosis; world-wide, tuberculosis is the leading cause of death of individuals with HIV.
Protozal infections: Toxoplasmosis and Cryptosporidiosis.
In an untreated individual:
Y-axis: Relative Levels
X-axis: 0 – 12 weeks, then, 0 – 10 years. (Interrupted)
Primary infection lasts approximately 9 weeks, followed by chronic and clinical latent infection; without treatment, disease progression to AIDS occurs approximately 10 years later.
Viral RNA
Levels of viral RNA spike upon infection, causing acute retroviral syndrome in many individuals, then gradually fall as the host immune system responds.
During the period of chronic infection, viral RNA levels steadily rise, then, during the final stage, AIDS, increase dramatically.
CD4+ T cells
CD4+ T cell counts are initially high, but decrease due to HIV destruction. Some authors state that the gut-associated lymphoid tissue (
GALT) is a major site of CD4_ T cell destruction at this time; furthermore, GALT is thought to be a key reservoir for HIV during clinical latency.
CD4+ T cell counts may rise temporarily, but, overtime, steadily decrease as HIV replicates during the chronic period; then, by definition, CD4+ T cell counts fall drastically with the onset of AIDS, thus leaving the host vulnerable to opportunistic infections and death.
The host begins producing
anti-HIV antibodies towards the end of the primary infection period; they continue to rise during the chronic period, and, despite their inability to eradicate HIV, remain elevated with the onset of AIDS.
CD4+ T cells are depleted, including both activated and memory cells.
HIV induces a shift from predominantly the Th1 subset of helper T cells to Th2, which leads to shifts in
cytokine production that favor HIV infection.
CD8+ T cells are also affected, with decreases in their cytotoxicity.
B cell activation is impaired by loss of functional T cells; paradoxically, mature B cells are over stimulated, leading to hypergammaglobulinemia, but become unable to mount effective antibody responses to new antigens. Circulating immune complexes form, and the risk of lymphomas increases.
Macrophages become dysfunctional, with decreased chemotaxis and phagocytosis and reduced ability to present antigens to T cells.
