KITSO AIDS Training Program KITSO AIDS Training Program Lecture 2: HIV Pathophysiology and Epidemiology delivered by Dr. Daniel J. Baxter, ACHAP HIV Pathophysiology and Epidemiology

KITSO AIDS Training Program Learning Objectives Lifecycle of HIV-1. CD4 cell and host defense system. Natural history of HIV-1 disease. Immune responses to HIV-1 and mechanisms of immune evasion by HIV. HIV Pathophysiology and Epidemiology

KITSO AIDS Training Program Worldwide Distribution of HIV-1 Viral Subtypes B B C Northern America: Western Europe: Eastern Europe & Central Asia: 920,000 540,000 700,000 C,E Eastern Asia & the Northern Africa & Pacific: 640,000 Caribbean: Middle East: 390,000 400,000 Southern & Southeastern C Asia: Latin America: 7 million 1.4 million Sub - Saharan Africa: B 25.3 million Australia & New Zealand: : 15,000 B Source: WHO/UNAIDS (data as of December, 2000) HIV Pathophysiology and Epidemiology

KITSO AIDS Training Program Viruses A virus is the simplest, most primitive life form on earth. A virus is unable to replicate (reproduce) on its own and must first infect a living cell in order to replicate. HIV is a retrovirus. A retrovirus is an RNA virus which uses DNA as an intermediary for its replication. HIV Pathophysiology and Epidemiology

Human Immunodeficiency Virus KITSO AIDS Training Program Human Immunodeficiency Virus HIV Pathophysiology and Epidemiology

KITSO AIDS Training Program HIV-1 Particle HIV Pathophysiology and Epidemiology

KITSO AIDS Training Program HIV Life Cycle HIV Pathophysiology and Epidemiology

KITSO AIDS Training Program HIV Life Cycle RNA Reverse Transcriptase Protease HIV RNA RNA RNA CD4 RNA RNA RNA DNA RNA RNA Proviral DNA CD4 T -Lymphocyte HIV Pathophysiology and Epidemiology

KITSO AIDS Training Program HIV Variability HIV Pathophysiology and Epidemiology

KITSO AIDS Training Program HIV Variability HIV has enormous potential for change (mutations) The HIV copies in an infected person are not all identical but are rather like a swarm of closely related viruses. Reverse Transcriptase is a very error-prone enzyme. HIV Pathophysiology and Epidemiology

Effects of HIV Mutations KITSO AIDS Training Program Effects of HIV Mutations Mostly of no consequence. Viral fitness increased or decreased. Viral infectivity/pathogenicity increased or decreased. Escape from immune control. ARV drug resistance. HIV Pathophysiology and Epidemiology

KITSO AIDS Training Program Immunology HIV Pathophysiology and Epidemiology

KITSO AIDS Training Program Host Defense System Self versus Non-Self (antigen) Innate Immunity Adaptive Immunity B-Lymphocytes T-Lymphocytes -Skin, mucosa -Cells White blood cells Macrophages -Complement CD4 cells CD8 cells Plasma cells High Specificity/ Memory Cells HIV Pathophysiology and Epidemiology

Helper Function of CD4 Cells KITSO AIDS Training Program Helper Function of CD4 Cells Macrophage T helper cell (CD4) B Lymphocyte Cytotoxic T Lymphocyte (CD8) Infected cell Antibody secreting (plasma) cell Killed HIV Pathophysiology and Epidemiology

White Blood Cell Distribution KITSO AIDS Training Program White Blood Cell Distribution Absolute/Total cells/uL Percent Neutrophils 4000 55% WBC Lymphocytes CD4 CD8 1000 500 30% Lymphocytes Basophils Eosinophils Monocytes HIV Pathophysiology and Epidemiology

KITSO AIDS Training Program CD4 Counts in Botswana Uninfected: 750 cells/uL (IQR: 560-900) Asymptomatic HIV-1 positive: 350 cells/uL (IQR: 268-574) Patients with AIDS: 121 cells/uL (IQR: 50-250) HIV Pathophysiology and Epidemiology

Surrogate Markers of HIV Disease KITSO AIDS Training Program Surrogate Markers of HIV Disease CD4 is an indicator of the strength of the immune system. Viral Load is an indicator of the amount of viral replication. HIV Pathophysiology and Epidemiology

Natural History of HIV Infection KITSO AIDS Training Program Natural History of HIV Infection HIV Pathophysiology and Epidemiology

Natural History of HIV-1 Infection KITSO AIDS Training Program Natural History of HIV-1 Infection Acute Retroviral Syndrome Clinical Latency AIDS Viral Load CD4 count 1-2 years 1-12 weeks 6-10 years HIV Pathophysiology and Epidemiology

Acute Retroviral Syndrome KITSO AIDS Training Program Acute Retroviral Syndrome Viral Load CD4 count 1-12 weeks 8-10 years 1-2 years HIV Pathophysiology and Epidemiology

Acute Retroviral Syndrome KITSO AIDS Training Program Acute Retroviral Syndrome Non-specific ‘flu-like’ symptoms; Fever Fatigue Pharyngitis Lymphadenopathy Rash HIV Pathophysiology and Epidemiology

Pathogenesis of Acute HIV-1 Infection KITSO AIDS Training Program Pathogenesis of Acute HIV-1 Infection Initial infection of CD4 cells and macrophages at site of exposure. Dissemination of infection to lymph nodes. Burst of viral replication results in intense viremia. Development of humoral immunity (HIV-specific antibodies). Development of cellular immunity (HIV-specific CD4 and CD8 cells). HIV Pathophysiology and Epidemiology

KITSO AIDS Training Program Acute HIV-1 Infection HIV-antibodies Viral Load CD4 count CD4 cell count Viral load 0 3 6 12 weeks after HIV infection HIV Pathophysiology and Epidemiology

KITSO AIDS Training Program Clinical Latency Viral Load CD4 count 1-2 years 1-12 weeks 6-10 years HIV Pathophysiology and Epidemiology

KITSO AIDS Training Program Clinical Latency At CD4 cell counts over 500 cells/uL many complications overlap with conditions found in uninfected populations (bacterial pneumonia, tuberculosis, minor skin conditions), but they may be more frequent. At CD4 counts between 200 and 500 cells/uL other conditions and opportunistic infections may begin to appear (Kaposi’s sarcoma, oral/genital candidiasis, herpes zoster, etc.). HIV Pathophysiology and Epidemiology

Pathogenesis of Chronic HIV-1 Infection KITSO AIDS Training Program Pathogenesis of Chronic HIV-1 Infection High turnover of CD4 cells. Continuous destruction and compensatory increased production of CD4 Lymphocytes. Viral load plateaus at viral set point. Non-specific, generalized, immune activation resulting in immune dysfunction. Viral reservoirs in resting infected cells. HIV Pathophysiology and Epidemiology

Relative Control of HIV-1: Viral Set Points KITSO AIDS Training Program Relative Control of HIV-1: Viral Set Points Predictor for: Disease progression Risk of transmission Viral load Year 1 HIV Pathophysiology and Epidemiology

KITSO AIDS Training Program Viral Load CD4 count 1-2 years 1-12 weeks 6-10 years HIV Pathophysiology and Epidemiology

KITSO AIDS Training Program HIV Pathophysiology and Epidemiology

KITSO AIDS Training Program Immune Evasion by HIV HIV Pathophysiology and Epidemiology

Inability to Eradicate HIV-1 Infection KITSO AIDS Training Program Inability to Eradicate HIV-1 Infection CD4 T cell decline CTL response inadequate Viral reservoir Viral infection in sanctuaries (brain and genito-urinary tract) Viral persistence in lymphoid tissue Latency – archiving in resting cells Mutational Potential of HIV-1 Escape of HIV from CD8 immune response and neutralizing antibodies HIV Pathophysiology and Epidemiology

Variability of Response to HIV Infection KITSO AIDS Training Program Variability of Response to HIV Infection Typical Progressor Viral load CD4 count Time Rapid Progressor CD4 count Viral load Time HIV Pathophysiology and Epidemiology

Immune Response in Children KITSO AIDS Training Program Immune Response in Children Viral set point is higher in children. Disease progression similar to adults. 15-20% of children develop AIDS or die within 1 year. 10% survive for a prolonged period (5-6 years). HIV Pathophysiology and Epidemiology

Immune Response in Children (2) KITSO AIDS Training Program Immune Response in Children (2) Because the infant’s immune system is immature, disease progression is expressed as CD4%. CD4% is the percent of total lymphocytes that are CD4 cells. e.g., if total lymphocytes are 4000 cells per uL and 1000 of these cells are CD4 cells, the CD4% is 25%. HIV Pathophysiology and Epidemiology

HIV Transmission and Prevention KITSO AIDS Training Program HIV Transmission and Prevention Modes of Transmission Mucosa (genital/rectal) Blood (transfusion, MTCT, needle stick injury) Breast Feeding Prevention Avoidance of infected mucosal secretions Safe blood transfusion service Post-exposure prophylaxis Prevention of Mother-to-Child Transmission Avoidance of breast feeding Universal precautions Hand washing Safe disposal of infected material HIV Pathophysiology and Epidemiology

KITSO AIDS Training Program Summary HIV life cycle involves transcription of viral RNA into DNA and integration into human genome. Mutational potential of HIV-1 results in worldwide diversity (subtypes), viral escape from immune response and development of drug resistance. Viral replication persists throughout infection. Fundamental pathology is the inability of the host immune system to eradicate HIV infection, which results in progressive destruction of the immune system. HIV Pathophysiology and Epidemiology