Case 4: P.J. Peters Pt 1 - HIV

Lymphoid Tissue

Part of adaptive immune system + circulatory system

Primary + secondary lymphatic organs

Primary Lymphatic Organs

Lymphocyte formation + maturation locations

• Bone marrow

• Thymus

Primary Lymphatic Organs: Bone Marrow

Location: Inside long bones

Contain: Pluripotent stem cells

Function:

• B + T cell production

• B cell maturation

Primary Lymphatic Organs: Thymus

Location:

• Superior anterior mediastinum

• Retrosternal

Structure:

• Bilobar

• Surrounded by fibrous capsule

Function: T cell maturation

Thymus: Contents

Epithelial cells

Dendritic cells

Macrophages

Cortex:

• Immature T cells

• Dense

Medulla:

• Mature T cells

• Hassall corpuscles (eosinophilic cells)

Secondary Lymphatic Organs

Lymphocytes presented with antigens = Differentiate into effector cells

• Lymph nodes

• Spleen

• MALT

Secondary Lymphatic Organs: Lymph Nodes

Location: Throughout body

• Close to organs + large vessels

Function: Inflammation + Immune reaction = Paracortical hyperplasia = Lymphadenopathy

Lymph Node: Structure

Bean-shaped

Surrounded by fibrous capsule + trabeculae

• Trabecular sinus drains lymph

3 layers:

• Cortex

• Paracortex

• Medulla

Hilus

Lymph Node: Cortex

Lymphoid follicles

• B cell storage, differentiation, proliferation

• 1º: Inactive

  • Naive B cells

• 2º: Active

  • Unchallenged B cells

  • Surround germinal centre

Lymph Node: Paracortex

T-cell activation site

High-endothelial venules

• Circulating B + T cells enter/leave bloodstream

Lymph Node: Medulla

Medullary Cords: Plasma cells + lymphocytes

Medullary Sinus: Macrophages + reticular cells

• Connect to efferent lymphatic structures

Lymph Node: Hilus

Lymphatic vessels

Artery + vein branch → Capillary network → Post-capillary high endothelial venules

Secondary Lymphatic Organs: Spleen

Location:

• Under L diaphragm

• Anterolateral

Function:

• Filter old/abnormal RBCs + platelets

• Initiate humoural immune response

Spleen: Structure

Similar to lymph nodes

White Pulp: Antigen filtration + presentation

• WBCs

• B cells in lymphoid follicles

• T cells in periarteriolar lymphatic sheath

Red Pulp: Blood filtration

• Macrophages

Secondary Lymphatic Organs: MALT

Locations:

• GALT/Peyer patches: GI

• Tonsils: Naso + oropharynx, tongue base

• Bronchi: URT + LRT walls

Function:

• Defend against GI, oral, resp pathogens

• GALT M Cells:

  • Transport antigens from lumen → Lamina propria for APCs

  • B cells in germinal centre detect antigens + differentiate into plasma cells = Secrete IgA

MALT: Structure

Same as lymph nodes

Follicle-associated epithelium

• Humoural defence mechanism

• GALT: M cells

Human Immunodeficiency Virus (HIV) Infection: Description

Chronic viral disease caused by HIV

• Progress to AIDS

Type of 2º immunodeficiency

HIV Infection: Epidemiology

Prevalence: Mostly sub-Saharan Africa

Risk Factors:

• Marginalized groups

  • Black ethnicity

  • Men who have sex with men (MSM)

  • Transgender

• IV drug users

• Sex workers

HIV Infection: Etiology

Enveloped retrovirus

Capsid

Types:

• HIV-1: Most common

• HIV-2: Mostly in West Africa

Transmission:

• Sexual (80%)

  • Genital mucosal damage

• Parenteral

• Vertical

HIV Infection: Initial Infection Pathophysiology

1. HIV enters body through lesion = Attach to CD4 receptors on…

• CD4+ T cells

• Macrophages

• Monocytes

• Dendritic cells

2. Viral envelope fuse with host cell = Capsid enter cell

3. Virion RNA transcribed → dsDNA → Integrate into host DNA

• Viral reverse transcriptase

• Viral integrase

4. Viral DNA replicated + virion assembly

5. Virion exocytosis = Cell death

HIV Infection: Chronic Immunodeficiency Pathophysiology

1. Infected CD4+ lymphocytes spread infection to immune cells in lymphoid tissue = Dissemination

• Window Period: HIV abs detected 7-21 days post-infection

• Peak in weeks

2. Viral load decreases after 6-12 months + Remains stable for 8-10 years (clinical latency)

• HIV replicated in lymph nodes

3. Continued CD4+ cell depletion = Immunosuppression

• CD4+ T cells < 0.5 × 10⁹/L or 500/mm³

• Increase opportunistic infections + malignancies

4. No treatment = Progress to AIDS

• CD4+ T cells < 0.2 × 10⁹/L or 200/mm³

• AIDS-defining conditions

HIV Infection: Clinical Presentation

Usually asymptomatic

Timeline:

• Early

• Latent

• AIDS

HIV Infection: Early Clinical Presentation

Incubation period: 2-4 weeks

Flu-like symptoms

• Fever

• Fatigue

• Myalgia

• Headache

Generalized non-tender lymphadenopathy + rash

GI symptoms

Oropharyngeal symptoms

HIV Infection: Latent Clinical Presentation

Non-AIDS-defining conditions

Chronic subfebrile temp

Generalized lymphadenopathy

Chronic diarrhea

Opportunistic infections

• Oral candidiasis

• Vaginal infections

Oral hairy leukoplakia: Lesions from EBV

HPV carcinoma

Skin manifestations

• Warts

• Psoriasis

• Shingles

HIV Infection: AIDS Clinical Presentation

AIDS-defining conditions

Esophageal/bronchial candidiasis

Pneumocystis pneumonia

Wasting syndrome

Kaposi’s sarcoma: Endothelial soft tissue cancer from herpes

HIV: Investigations

Screening

Serology

Virlogical testing

CBC

HIV Investigations: Screening

Antigen/antibody immunoassay

• 1 time in adolescents + adults

• 1 time in early pregnancy

• Pt request

HIV Investigations: Serology

Detect HIV antigen, antibody, both

• 14 days post-transmission

Indications: Initial confirmation in adults + children

HIV Investigations: Virological Testing

Detect HIV RNA/DNA

• 10 days post-transmission

Transmission Threshold: 200 copies/mL

• Undetectable = Untransmissable

Indications:

• Infant

• Confirmation in adults + children

HIV Investigations: CBC

T cell counts

CD4+: < 500 cells/mm³

• Normal > 500 cells/mm³

CD8+: Elevated

• Normal 150-1000 cells/mm³

CD4/CD8 ratio: Low

• Normal 1-4

HIV Infection: Treatment/Management

Pharmacological

Infection prophylaxis

Immunizations

HIV Infection Treatment: Pharmacological

Antiretroviral therapy (ART)

Regimens:

• 2 NRTIs + 1 NNRTI

• 2 NRTIs + 1 PI

• 2 NRTIs + 1 INI

• Golutegravir + Iamivudine

HIV Infection Treatment: ART Classes

Nucleoside reverse transcriptase inhibitors (NRTIs)

Nonnucleoside reverse transcriptase inhibitors (NNRTIs)

Protease inhibitors (PIs)

Integrase inhibitors (INIs)

Entry inhibitors

ART: NRTIs

MOA: Nucleoside analog = Inhibit reverse transcriptase function

Ex:

• -ine

  • Didanosine

  • Lamivudine

  • Stavudine

• Abacavir

• Tenofovir

Adverse Effects:

• Mitochondrial toxicity

• Lipodystrophy: Abnormal fat distribution

  • Accumulate in liver, muscles, abdomen, breast, neck, back

  • Glucose intolerance

  • Hyperlipoproteinemia

ART: NNRTIs

MOA: Inhibit reverse transcriptase

Ex:

• Delaviridine

• Doravirine

• Rilpivirine

Adverse Effects:

• Hypersensitivity

  • Rash

  • Stevens-Johnson syndrome

• Hepatotoxicity

ART: PIs

MOA: Inhibit HIV-1 protease = Inhibit virion production

Ex: -navir

• Atazanavir

• Lopinavir

• Ritonavir

Adverse Effects:

• GI upset

• Nephrolithiasis + hematuria

• Metabolic

  • Hyperglycemia

  • Dyslipidemia

  • Lipodystrophy

• Bleeding risk

• Hair thinning

• Thrombocytopenia

ART: INIs

MOA: Inhibit viral integrase = Inhibit viral replication

Ex: -gravir

• Dolutegravir

• Raltegravir

• Bictegravir

Adverse Effects:

• Hypersensitivity

  • Rash

  • Steven-Johnson syndrome

ART: Entry Inhibitors

MOA: Inhibit HIV virion binding/fusion with host cell

Ex:

• Enfuvirtide

• Maraviroc

Adverse Effects:

• Enfuviritide

  • Skin irritation at injection site

• Maraviroc:

  • Cough

  • URT infection

  • Fever

  • Hepatotoxicity

ART: Continuous Monitoring

Viral load

• < 200 copies/mL

CD4+ cell counts

• Increase to 200-500 cells/mm³

BMP

LFTs

Lipid profile

Glucose

Urinalysis

HIV Treatment: Infection Prophylaxis

Indication: CD4+ < 200 cells/mm³

Antimicrobials:

• Fluconazole

• Fluconazole OR Itraconazole

• TMP/SMX

• Azithromycin OR Clarithromycin

HIV Infection Prophylaxis: Fluconazole

Infection: Coccidioidomycosis

• Fungus

HIV Infection Prophylaxis: Fluconazole OR Itraconazole

Infection:

• Histoplasmosis

  • Fungus

• Talaromycosis

  • Fungus

HIV Infection Prophylaxis: TMP/SMX

Infection:

• Pneumocystis pneumonia

  • Fungus

• Cystoisopsoriasis

  • Parasite

• Toxoplasma gondii

  • Parasite

HIV Infection Prophylaxis: Azithromycin OR Clarithromycin

Infection: Mycobacterium avium complex

• Bacteria

HIV Management: Immunizations

NOT live-attenuated

HIV Prevention

ARTs given for…

• PrEP: HIV-negative at-risk populations

• PEP: High-risk HIV exposure

HIV: Complications

Mortality similar to noninfected on ART

Opportunistic infections

Increase risk of chronic comorbidities

• CVD

• DM

• Cancer

Immune reconstitution inflammatory syndrome (IRIS)

HIV Complications: IRIS

Description: Inflammatory syndrome at ART initiation

• New condition

• Worsen preexisting condition

Pathophysiology: Restore immune system = Respond to antigen

Management:

• Supportive care

• Continue treatment

• Severe: Corticosteroids

Prevention: Do not start if…

• Tb meningitis

• Cryptococcal disease

• CMV retinitis