HIV/AIDS

Organs of the Human Immune System

• The organs of the human immune system are distributed throughout the body and are primarily concerned with the development, growth, and dissemination of lymphocytes, or white cells.

• These organs are generally referred to as lymphoid organs. They include:  - Tonsils and Adenoids  - Bone Marrow  - Appendix  - Thymus  - Spleen  - Peyer's Patches: These are clumps of lymphoid tissue specifically located in the small intestine.  - Lymph Nodes  - Lymphatic Vessels

• Transport: Lymphocytes are transported to and from all immune system organs via blood and lymphatic fluids.

Overview of Immunity and Components

• The immune system is structured into three distinct components:  - First Component: Innate immunity, consisting of physical barriers.  - Second Component: The inflammatory response.  - Third Component: Adaptive immunity.

• Adaptive immunity initiates when the first and second components of the immune system have been compromised.

• Characteristics of Adaptive Immunity:  - It develops more slowly than innate immunity.  - It involves the production of lymphocytes and antibodies in response to an infection or other abnormal molecules.  - It is extremely specific to the offending organism.  - it possesses long-term memory.

• Cooperation: Both innate and adaptive immunities work in conjunction to protect the body against invaders.

• Transformation: Lymphocytes are transformed into T lymphocytes ($T$ cells) and B lymphocytes ($B$ cells).

Antigens and Molecules

• Antigens: Foreign substances that can bind with antibodies or with antigen receptors on $B$ or $T$ cells.

• Immunogen: A foreign substance that will bind and produce a formal immune response.

• Hapten: A small molecule that must be combined with a protein carrier to produce an immune response.  - Examples: Poison ivy (causes a $T$ cell response and resultant rash) and some drugs like PCN (Penicillin).

Antibodies and Immunoglobulins (IGs)

• Antibody and Immunoglobulin are interchangeable terms.

• Humoral immunity is the part of adaptive immunity associated with the antibody response in the body.

• $B$ cells are the specific lymphocytes that produce antibodies.

• Chief Function: Immunoglobulins specifically bind an antigen to protect the body against infection.

• Classes of Immunoglobulins:  - IgA: Present in body secretions and on exposed surfaces in the respiratory and GI tracts.  - IgD: Levels are elevated during chronic infection.  - IgE: Activates mast cells; located on the surface of basophils, mast cells, and mucosal surfaces. Levels increase during parasite infections.  - IgG: The most prevalent immunoglobulin class. It is the only one that crosses the placenta. It is high during the secondary response, activates complement, and is present in $B$ cells. It contains anti-viral, toxin, and bacterial antibodies.  - IgM: The first antibody formed in response to an antigen. It activates complement and forms ABO blood antibodies.

Immune Responses: Primary and Secondary

• Primary Response: occurs after the first exposure to an antigen. IgM is initially produced, followed by IgG.

• Secondary Response: triggered by subsequent exposure to the same antigen. IgM is produced transiently, while larger amounts of IgG are produced over a longer duration.

Characteristics of T and B Cells

• Cell Surface Proteins: Both cell types have proteins on their surfaces that identify them as $B$ or $T$ cells.

• Receptor Specificity: Both have surface antigen receptors that recognize only ONE specific antigen. One lymphocyte recognizes only ONE antigen.

• Immunocompetence: Both are immunocompetent, meaning they are able to respond to antigens.

• Cell-Mediated Immunity: This is a function of $T$ cells and is a part of adaptive immunity.

• Interaction: Immune responses involve cognate interaction between immunogens (antigens), macrophages, and lymphocytes.

Human Immunodeficiency Virus (HIV) Characteristics

• Replication Rate: HIV replicates rapidly, creating approximately $10$ billion copies per day.

• Replicating Imperfection: The replication is imperfect, leading to high rates of error which allow the virus to develop resistance and escape immune surveillance.

• Dormancy: The virus can lay dormant for $2$ to $10$ years.

• Viral Types:  - Type 1: The most common type of HIV.  - Type 2: Rarer and progresses more slowly.

• Found in: Blood, semen, saliva, breast milk, tears, urine, vaginal/cervical secretions, and Cerebrospinal Fluid (CSF).

• Host Dependency: HIV cannot replicate without a host cell.

HIV Transmission and Risk Factors

• Transmission Routes:  - Blood, blood products, or organ transplants.  - Sexual contact (vaginal, anal, or oral).  - Maternal transmission (perinatal); the rate decreases with the perinatal use of antiretrovirals.  - Breast milk.

• Risk Populations:  - Men having sex with men (MSM).  - IVDU (Intravenous Drug Users) via needle sharing.  - Infants born to infected mothers.  - Healthcare personnel.  - Individuals with STDs, as they increase the risk of HIV infection.

Viral Action and Pathophysiology

• Receptor Target: HIV attacks any cell with a CD4 receptor.

• Cellular Depletion: T helper cells (CD4) are depleted, and monocytes/macrophages are used by the virus.

• Normal CD4 Functions (Impaired by HIV):  - Recognizing and helping activate antibody-producing $B$ cells.  - Orchestrating cytotoxic $T$ cells (CD8) and natural killer (NK) cells.

• Pathogenic Process:  - The virus infects and destroys CD4 $T$ helper cells, which are required to create plasma cells and cytotoxic $T$ cells.  - The virus suppresses the immune response against itself and creates a generalized immune deficiency.

• HIV-1 Pathophysiology (Retrovirus):  - HIV carries genetic material in RNA.  - It binds to CD4 and chemokine receptors.  - The HIV membrane fuses with the host cell membrane, and the viral genome enters the cytoplasm.  - Reverse Transcriptase copies viral RNA to make a mirror-image, double-stranded DNA.  - The virus enters the nucleus and joins the DNA of the host cell by inserting HIV DNA into the host's DNA.  - It reprograms the CD4 $T$ cell to produce viral RNA and messenger RNA, forming new viruses.  - New viruses are expelled by lysis, killing the original host cell.

Impact on Cell Types

• T4 (CD4) Importance: These cells are essential for fighting Mycobacterium, Fungi, Parasites (such as P. jiroveci/carinii and Giardia), and Viruses (like Herpes).

• T4 Interference: Alcohol (ETOH) also interferes with T4 production.

• Monocytes: Can leave the bloodstream and enter tissues such as the brain, various organs, and skin cells.

• Macrophages: These cells also have CD4 receptors, making them functionally impaired by HIV infection.

• Hallmark of HIV: A decrease in the absolute number of CD4 $T$ helper lymphocytes.

Laboratory Data and Diagnostics

• Viral Load:  - Measures the number of circulating HIV particles per ml in peripheral blood.  - Reflects the level of viral reproduction in lymph tissue (though it cannot measure reservoirs in lymph nodes, brain, or GU tract).  - Levels should drop after therapy begins and become undetectable by $6$ months.

• ELISA (Enzyme Linked Immunosorbent Assay):  - Detects antibodies produced against HIV.  - Quicker and less expensive but prone to high false positives due to non-specific reactions.

• CD4 Count:  - Normal cell count: $800$ to $1000$ cells/mm^3.

• Seroconversion:  - Antibodies typically appear in $1$ to $3$ months, but can take up to $6$ months.  - The Window Period: The time between infection and detectable antibodies where a person tests negative but can still transmit the virus (infectiousness can begin within $2$ weeks).

• Other Lab Findings:  - Increase in T8 cells (possible body compensation).  - T4 cell count drops but may remain above $400$ cells/uL in earlier stages.  - Hypergammaglobulinemia (Great increase in antibody production, specifically IgG and IgA).  - Lymphocytopenia (<1000 cells/cc^3).  - Thrombocytopenia.  - Increased ESR (Erythrocyte Sedimentation Rate).

Factors Accelerating HIV Production

• Certain factors "turn on" T4 cells, stimulating HIV acceleration:  - Stress.  - Multiple infections.  - Malnutrition.  - Herpes virus.  - Continued exposure to foreign substances (such as drugs).

Phases of HIV Infection

• Primary Phase:  - Occurs at seroconversion; early-stage disease.  - Symptoms: Flu-like (fever, chills, headache, N/V, fatigue, rash, sore throat, irritability, myalgia, night sweats, GI problems, lymphadenopathy, and macular-papular rash).  - Duration: Symptoms usually disappear after $1$ to $6$ weeks.  - Status: High viral loads and decreased CD4 for $2$ to $4$ weeks after exposure as the virus proliferates in lymph nodes.

• Latency Phase:  - Chronic and asymptomatic phase.  - Signs: No symptoms except possibly lymphadenopathy.  - Duration: $10+$ years ($8$ to $12$ range).  - Status: CD4 count decreases gradually; viral load stays down.

• Overt AIDS:  - CD4 count is <200 cells/mm^3.  - High risk and very rare conditions start appearing.  - Leads to death in $2$ to $3$ years without treatment.

AIDS: Definition and Clinical Manifestations

• Acquired Immunodeficiency Syndrome (AIDS) is the end stage of HIV infection.

• Average development time: $10$ years from initial infection without treatment.

• Characterized by: Immune dysregulation, dysfunction, deficiency, atypical/opportunistic infections, cancers, and debilitating chronic diseases (wasting, recurring fevers).

• AIDS Defining Illnesses:  - Internal candidiasis (oropharyngeal, esophageal, vaginal).  - Fungal/Viral: Coccidioidomycosis, Cryptococcosis, Cryptosporidiosis, CMV, HS, Histoplasmosis.  - Bacterial: TB, PCP (Pneumocystis jiroveci/carinii pneumonia), Salmonella.  - Cancer: Kaposi’s sarcoma, cervical cancer, lymphoma.  - Systemic: Encephalopathy, Wasting syndrome.

• Common Systemic Symptoms:  - Rapid unexplained weight loss ($10$ to $25$ lb).  - Fever, night sweats, chills, fatigue (prolonged/unexplained).  - Cough, SOB.  - Thrush, ulcers, arthralgia/myalgia.  - Chronic diarrhea (often bloody and watery), which increases as CD4 counts decrease.

Opportunistic Infections and Complications

• Occur due to severe immune compromise from organisms that normally would not cause infection.

• Specific Organisms: Cytomegalovirus (CMV), Mycobacterium (TB, avium), Candida, and Herpes (HSV).

• Toxoplasmosis: Protozoa from cats, raw meat, milk, or raw eggs. Causes encephalitis and CNS, heart, or lung infections.

• Esophagitis: Caused by Candida, CMV, or HS.

• Cryptococcus: Fungal infection that causes meningitis.

• Diarrhea Agents: Cryptosporidium, Salmonella, CMV, C. diff, E. coli, Shigella, Giardia.

• CNS Manifestations:  - AIDS Dementia Complex: A late complication including decreased concentration and cognitive ability, decreased motor speed, and apathy.  - Toxoplasmosis: Fever, headache, confusion, lethargy, seizures, and visual changes.  - Progressive Multifocal Leukoencephalopathy: Demyelination of white matter; results in weak limbs, movement difficulties, visual changes, mental status changes, and seizures.

• Cancers:  - Kaposi’s Sarcoma: Cancer of connective tissue and blood capillaries. Presents as lesions on skin, mouth, lymph nodes, or internal organs.  - Non-Hodgkin Lymphoma.  - Cervical Dysplasia.

• Wasting Syndrome: A significant systemic symptom defined by weight loss >10% related to diarrhea, weakness, and fever. It is caused by anorexia, metabolic abnormalities, and malabsorption.

Treatment and Prevention

• Treatment Goal: Slow viral multiplication and arrest disease progression.

• ART (Antiretroviral Therapy):  - Uses specific drugs from different classifications with specific timing and dosages.  - Resistance: Develops due to spontaneous genetic mutations or poor adherence.

• Other Care: Prophylaxis for PCP, vaccines, nutrition, and adequate sleep.

• Herpes Tx: Acyclovir.

• Prevention Strategies:  - Safe sex via all routes (heterosexual or MSM).  - No needle sharing.  - Use of protection during contact.  - Universal donor screening.

Immunizations and Immunity Types

• Active Immunity:  - Long-term immunity developed by the person's own body.  - Result of previous exposure to an antigen (via illness or vaccination) to generate an immune response.

• Passive Immunity:  - Short-term immunity obtained from outside the body.  - Example: Immune globulin, breastfeeding, and maternal-infant antibody transfer.

• Vaccines:  - Biologic preparations of antigens that stimulate antibody production or cellular immunity without causing life-threatening disease.  - Goal: Provide long-lasting protective immune responses under safe conditions.  - Booster Vaccines: Used to boost the immune response by increasing memory cells and maintaining antibodies or $T$ cells.

• Passive Immunotherapy: Preformed antibodies given to an individual (e.g., Hep A and Hep B immunoglobulins).