HSS 460 Immune System (HIV)

Immune system

System serving as the body’s defense against living, disease-causing agents (pathogens) and nonliving agents (toxins, allergens, etc.) of disease & allergy

Pathogens

Living, disease-causing agents (e.g., viruses, bacteria, & fungi)

Innate (nonspecific) immune defenses

Parts of the immune defense that one is born with; act as the 1st line of defense against pathogens with an immediate response that DOES NOT CHANGE (non-specific) based on the agents that imitated it

• Involves the body’s physical barriers (e.g., skin, “acid mantle”, gut “flora”, mucous membranes)

• Involves a variety of WBCs, inflammation, and fever

Adaptive (specific) immune defenses

Specific responses by LYMPHOCYTES to a specific pathogen/antigen; the response takes at least a few days and is SPECIFIC to the agents that initiated it

• Involves direct cell killing & antibody production

• Leaves the body with a “memory” of the pathogen for faster defeat in the future

T lymphocytes

Lymphocytes responsible for cell-mediated immunity

Cytotoxic t cells

Aka CD8+ t cells; a type of t lymphocyte responsible for the killing of infected/cancerous cells (causes toxicity, directly killing the cell)

Helper t cells

Aka CD4+ t cells; a type of t lymphocyte responsible for recruiting and enhancing immune cells/inflammation

• The MASTER COORDINATOR — recognizes pathogen & directs immune cells in response

Antigens (Ag)

Molecules that trigger an immune response (“antibody generating”) → leads to production of antibodies

• Large, complex molecules with structures unique to the organism

• Some are “free” Ag (e.g., venom, toxins, allergens), others are part of the pathogen’s cell membrane/wall or viral “envelope”

Antibodies (Ab)

Soluble proteins (“immunoglobulins”) directed at a specific Ag — do not directly destroy a pathogen, but target it for destruction

• Found in blood plasma, tissue fluids, body secretions, and B-cell membranes

• Variations in structure give rise to 5 classes of Ab’s with unique features (IgA, IgD, IgG, IgE, & IgM)

Immunocompetence

Immune cells learn to distinguish “self” Ag from “non-self” Ag

• Process by which the immune system becomes skilled

Tolerance

Immune system “tolerates” self-Ag and does not react to them; B- and T- lymphocytes are shown antigens in the red bone marrow & thymus…

• Are the cells capable of responding to Ag? — Yes = Live; No = Die

• Do the cells respond to “self” Ag? — Yes = Die; No = Live

Hypersensitivity disorders

Represent an inappropriate, excessive immune response (allergic reactions, autoimmune diseases, isoimmune diseases [e.g., transplant rejection])

Mechanisms of hypersensitivity disorders

• Sensitization of mast cells/basophils by IgE antibodies

• Molecular mimicry

• Production of autoantibodies

Mechanisms of hypersensitivity disorders — sensitization of mast cells/basophils by IgE antibodies

Often follows exposure to an allergen → re-exposure leads to release of histamine and other inflammatory chemicals

• Ex: allergic asthma (edema, mucus, & bronchoconstriction)

• Ex: urticaria (“hives”) — an acute, inflammatory vascular response to histamine

Mechanisms of hypersensitivity disorders — molecular mimicry

Infection → Ab production → Ab’s attack “self” Ag that mimic pathogenic Ag

• Ex: Rheumatic heart disease (RHD)

Rheumatic heart disease (RHD)

The cardiac component of Rheumatic Fever; occurs 2-3 weeks after untreated Group A β-hemolytic Streptococcal (GAS) pharyngitis (“Strep Throat”)

• Antigens on the Group A Strep “mimic” antigens found in the heart, joints, and skin

• May result in valve stenosis (scarring, lack of function)

Mechanisms of hypersensitivity disorders — autoantibodies

Production of autoantibodies that mark “self” cells/tissues for destruction or dysfunction; pathogenesis thought to be multifactorial…

• “Susceptibility genes” + environmental factors → failure of “tolerance”

• Excessive “Helper T-cell” & “Cytotoxic T-cell” responses + inadequate “Suppressor T-cell” response

**80% of autoimmune disorders occur in women

Immunodeficiency disorders

Represent an inappropriate, inadequate immune response (primary/genetic or secondary/acquired); deficiency in a component of the immune system leaves someone vulnerable to infections related to the missing/abnormal component

• May be primary or secondary

Primary immunodeficiency

Immunodeficiency with a genetic cause — congenital or inherited and manifesting early in life

• Early detection critical to preventing life-threatening infections

• Affects B-cells, T-cells, or both

Secondary (acquired) immunodeficiency

Immunodeficiency that is NOT genetic; acquired because of exposure to…

• Malnutrition

• Cancers

• Immunosuppressive treatment (e.g., chemo, radiation, transplant rejection meds)

• Infection of the immune cells (especially with HIV)

Etiology — acquired immunodeficiency syndrome

Infection with human immunodeficiency virus (HIV), a “retrovirus” that primarily targets the CD4+ helper T-lymphocytes — coordinators of innate & adaptive immune responses

Transmission — acquired immunodeficiency syndrome

Exchange of blood/bodily fluids containing virus or infected cells; major routes of transmission are…

• Sexual intercourse

• Needle sharing/puncture

• Passage from infected mother/breastmilk to fetus/baby

Primary/acute phase of HIV infection

Seroconversion illness immediately after transfer, lasting a few days to several weeks; sharp increase in viral load and decrease in CD4+ T-lymphocytes

• Seroconversion: appearance of Ab to HIV in blood, determines being HIV+, not phases of infection; can take weeks to months

• Manifestations: sore throat, fever, fatigue, lymphadenopathy, rash, myalgia, malaise, oral/esophageal sores

• HIV blood tests: assess for presence of antibodies, viral RNA, or both

Chronic/latency phase of HIV infection

Often asymptomatic, can last years to decades & is extended with modern ART treatment regimes; CD4+ T-lymphocyte counts slowly decrease until they reach a count of 200 cells/µL, marking AIDS

Symptomatic/late stage phase of HIV infection (AIDS)

Defined by T-cell count below 200 cells/µL; immunodeficiency allows for opportunistic, “AIDS-defining” illness

PLWH

“People living with HIV”

Human immunodeficiency virus (AIDS) pathophysiology

HIV is a retrovirus that contains RNA and directly infects T helper cells; the enzyme reverse transcriptase converts viral RNA into DNA which is carried into the effected cell’s nucleus and inserted into the chromosome by the enzyme integrase; this mutated DNA allows HIV to replicate itself and assemble more HIV via protease

Antiretroviral therapy (ART) regimens

Used to treat HIV → 7 drug classes categorized by their function in limiting viral infection of host cells & viral replication; antiviral approaches inhibit:

• Binding & fusion of HIV with host cells

• Reverse transcriptase (viral RNA → DNA)

• Integrase (integration of DNA into host)

• Protease (late-stage assembly of HIV)

Effect of ART regimens on the chronic/latency phase of HIV

ART decreases mortality & morbidity; for many people living with HIV (PLWH), HIV infection has become more of a chronic condition that is managed over decades

Complications of ART regimens

• Lipodystrophy

• Weight gain

• Impaired glucose metabolism

• Insulin resistance

• Hyperlipidemia

• Osteonecrosis or avascular necrosis

• Diarrhea, nausea, and other gastrointestinal tract disorders

• Increased risk of cardiovascular disease & type 2 diabetes

HIV manifestations

• Body composition alterations

• Metabolic complications

• Opportunistic infections

• Malignant neoplasms

Body composition alterations as a manifestation of HIV

• Wasting (over 5% weight loss unintentionally) & cachexia

• Lipodystrophy — redistribution of peripheral fat (arm, legs, face) to central (visceral fat)

Metabolic complications as a manifestation of HIV

Most common problems associated with ART and HIV infection → decreased insulin sensitivity; dislipidemia (decreased HDL, increased triglycerides); increase risk of cardiovascular disease (CVD) similar to metabolic syndrome

• Are multifactorial and include age, smoking, male gender, chronic inflammation due to HIV infection, & ART regimens

Opportunistic infections as a manifestation of HIV

• Pneumocystis carinii pneumonia (PCP): caused by fungus Pneumocystis jiroveci (quickly multiplies to cause bacterial pneumonia)

• Mycobacterium avium complex: group of mycobacterial species that cause respiratory and gastrointestinal infections

  • diarrhea, nausea and wasting is common (recall the rich immune cell population in the gut)

Malignant neoplasms as a manifestation of HIV

• Non-Hodgkin Lymphomas → fever, night sweats, wasting

• Kaposi Sarcoma (KS): malignancy of endothelium → lesions on skin/mucosae

• Viral-related cancers (e.g., HPV-related cervical/anal cancer, hepatitis-related liver cancer)

Scope of HIV

• Earliest cases reported by CDC in 1982

• Over 38 million people worldwide living with HIV (~14% are unaware of the infection)

• In the US, ~1.1 million

Most common HIV symptoms related to exercise interventions

• Lipodystrophy

• Impaired glucose & lipid metabolism

• Sarcopenia

• Increased CVD risk factors

Overall exercise recommendations for PLWH

Consensus that exercise training does not negatively affect immune function or disease progression → general exercise prescription similar to general adult population

• Long-term goals: decrease morbidity & mortality, improve QoL

• Patients should receive medical clearance

• Begin at low intensity & short duration; use functional movements

• Combination of cardiovascular & resistance training most effective (targets CVD factors and sarcopenia/body composition changes)

History and physical examination for PLWH

• Changes in body weight/composition (wasting, lipodystrophy, sarcopenia)

• Symptoms of metabolic disorders

• Motor abnormalities (hyperreflexia, loss of equilibrioception)

• CV disease (arrhythmias, edema)

• Immune status

• Functional capacity & fitness

• Osteonecrosis, peripheral neuropathy, etc.

Assessment of functional status of PLWH

Disease status categorized into one of four categories for functional status and fitness testing:

1. Asymptomatic, medically stable, and physically active

2. Asymptomatic, medically stable, and physically inactive

3. Recovering from a medical or disease-related event

4. Symptomatic and suffering from acute illness

General exercise testing recommendations for PLWH

Testing considered safe & necessary — assess for functional status: GXTs if needed, but functional exercise tests recommended

• Assess for conditions that contraindicate exercise — acute infection, chronic joint pain, nausea, major CVD

Cardiorespiratory exercise testing for PLWH

Maximal tests considered safe; CRF levels in PLWH are among the lowest in comparison to other vulnerable populations

• Individuals on ART may have diminished ability to extract & use O₂ in the working skeletal musculature and exhibit a decrement in peak a-VO₂ difference values

• Recommended functional assessments: 400m walk or 6-minute walk test (HR predictor of CV endurance)

Musculoskeletal & flexibility testing for PLWH

Assessing muscular strength & flexibility in PLWH should not differ from people without HIV, but monitor for peripheral neuropathy and/or osteonecrosis

• Recommended functional assessments: hand grip dynamometry, multiple-RM (2RM -10RM), chair stand or short physical performance battery, sit-and-reach

Cardiorespiratory exercise guidelines for PLWH

• 3-5 days/wk

• 30-39% of VO₂ or HRR (decreased intensity)

• 10-20 min. per session (decreased duration)

Resistance exercise guidelines for PLWH

• 2-3 days/wk

• 40-50% of 1RM (decreased intensity)

• 1-2 sets, 10-25 reps, 6-8 exercises (slightly modified duration)

Flexibility (ROM) exercise guidelines for PLWH

Same as general population

Other considerations for exercise prescription in PLWH

• Strongly consider methods to positively affect adherence — self-efficacy, goal setting, group exercise, etc.

• Be mindful of disease transmission when working with patients — low risk of transmission, but use general good practice for sanitation