Lecture 3 Retroviruses HIV (AIDS)

Urogenital System Microbiology… Lecture 3 Retroviruses HIV (AIDS ) 1 _First: retroviruses: I. II. General features - Enveloped, single stranded, positive sense RNA viruses - Encode an enzyme: Reverse Transcriptase • This enzyme converts RNA Genome to double stranded DNA • These viruses called (retro) because of having this enzyme - Have 2 groups: • Oncoretroviruses: leads to tumors as HTLV • Lentiviruses (Lenti= slow) : growing slowly as HIV - Transmitted by bodily fluid, blood & products Families: - Human T-Lymphotropic Virus (HTLV): • HTLV-1: Causes adult T-cell leukemia (ATLL) & lymphoma • HTLV-2: causes T-cell malignancies, Hairy cell leukemia - Human Immunodeficiency Virus (HIV)- 1 & 2 causes AIDS • HIV-1 is the major cause world wide • HIV-2 is it slower and milder which appears in West Africa _Second: HIV: _ maybe watching this video from sketchy before reading the topic makes things easier https://t.me/SketchyMic/111 I. The structure: - Size: 100 nm in diameter - Diploid: with Two copies of RNA genome - Has a lipid envelope, in which are embedded the trimeric transmembrane glycoprotein (TM) gp41 to which the surface glycoprotein (SU) gp120 is attached - Beneath the envelope, is the membrane-associated matrix protein(MA) p17, the core/capsid proteins (CA) p24 and the nucleocapsid protein p7 (bound to the RNA) - With 3 enzymes for viral replication: • Reverse Transcriptase (RT), Protease (PR) & Integrase (IN) • If these enzymes were be attacked the virus will be destroyed - Other proteins with various regulatory or immuno-modulatory functions : • T-Lymphotropic (X4): attached to receptors on T-lymphocytes mainly • Macrophage Tropic (R5): attached to receptors on macrophages & monocytes • both X4/R5 (Dual Tropic): attached to both types 2 II. III. Life cycle: - Viral entry : • SU gp 120 attached to CD4+ cells • X4 & R5 attached to chemokine Co-receptor CCR5 and CXCR4 ( CCR5 higher on microphages & monocytes, CXCR4 higher on T cells) • In early stages the virus will be macrophage tropic (R5-virus), then in advanced disease the virus will be T-lymphotropic (X4-virus) - Viral post-entry: • Partial uncoating (removal of envelope) will occur • HIV reverse transcriptase start to reverse RNA and transcribe it into complementary DNA (cDNA), then dsDNA • New DNA will integrate into the host chromosomes and replicates within the cell as a provirus Pathogenesis: - HIV reverse transcriptase is error-: • The enzyme generates viral quasispecies (different mutants)… every three generation there is a new mutation! • That’s leading to, failure of immune response, increased virulence power and failure to develop an effective vaccine - HIV attacks and destroys CD4+ cells (CD4 presenting cells) ( as T-cells, macrophages, Langerhans, microglial cells and others), the steps: • First, infects Initial target cells (CD4+ /CCR5) most likely macrophages and Langerhans cells • Then, T cells CD4+/CXCR4 are infected (more efficiently than first step) • After that, infect non-CD4+ cells for example CNS cells - Ten billion viral particles produced each day! With only One billion CD4+ cells produced per day….the immune system is overwhelmed!! - Immune deficiency: reduction in numbers and effectiveness of CD4+ lymphocytes in comparison to CD8+ cells. (CD8+ not affected directly by HIV but without CD4+ cells they will not be able to do their functions so they lose their effectiveness), and that’s due to: • Killing of CD4 cells by HIV • Bystander apoptosis of uninfected T cells • Antibody dependent cytotoxicity (ADCC) via GP 120 • Reduction in cytokine production and function which leads to reduction in macrophages and CTL functions 3 • Generalized failure of cell mediated immunity(CMI) and polyclonal B cells stimulation malignancy, leading to opportunistic viral, fungal and bacterial infections _ polyclonal B cell stimulation occurs because of CD4+ cells reduction (24 sales regulates and control B cells functions)… B cells will active in an exaggerated manner but effectiveless) IV. - From the fig. • Violet line shows viremia at first days ,then the virus enters the latent phase for many years (up to 10 years)then the viremia appears again. • red line shows that CD4+ t cells will drop during the peak of Viremia. Then CD4+ cells well drop fastly after reactivation of the virus. • Cytotoxic T cells (CTL) functions decreases - as shown by the green line -(Because CTL depends on CD4+ t cells to initiate their response). • The blue line shows neutralizing bodies increasing in number at the latent phase then they will drop down after reactivation of the virus. • The end result: decreasing in immune complexs and increasing in virus number Epidemiology (of AIDS): - Recognized in homosexuals, hemophilic, and Drug abuser - Transmission: Sexual and infective fluid - Perinatal transmission in 30% of pregnancy cases: • Transplacental • Intrapartum (via birth canal) • postpartum (via Breast milk) • Using of HAART during pregnancy reduces the risk of Vertical transmission • Testing blood supply reduces risk of Transmission (eg. by Needle sticks in health workers)… u can give Prophylaxis 4 _ Third: Clinical Features: I. Initial HIV infection: - Flue or mononucleosis-like illness: • Appears after 2 - 4 weeks after being infected, lasts for 2 - 6 weeks. • with: fever, malaise, lymphadenopathy, hepatosplenomegaly, arthralgia & rash.. Aseptic meningitis may occur. - Then the patient enters asymptomatic period. Which may continuous for years (up to 10 years or more than that): • can be isolated from a blood, , body fluids and tissues which means the infected person is able to spread the infection • 60% developed disease AIDS • Highly active ART or HAART (we will talk about it) can delay the progression of the disease. II. Progression to AIDS: - AIDS patients are HIV antibody positive and have CD4+ lymphocytes counts lower than 200 cells/mm3 or less than 14% of Total T lymphocytes. - AIDS severity dependent on absolute number of CD4+ for Cells: Overt AIDS in cases with less than 200 cells/mm3 (the normal is 800-1200) - Opportunistic infections may occur when CD4+ cells numbers are less than 500cells/mm3 : • Bacterial Infections: (Mycobacterium) ▪ M. avium intracellularae, when CD4+ cells 50-100 cells/mm3 ▪ M. Tuberculosis, tuberculous pneumonia, 200-500 cells/mm3 • Viral infections : ▪ Mucocutaneous H. simplex, H. zoster ▪ CMV chorioretinitis or disseminated, 50-100 cells/mm3 • Fungal infections: ▪ C. albicans (oral thrush, esophagitis) • Protozoal infections: ▪ Cryptococcus meningitis • Neurotropic (HIV in CSF in 50-70% of patients), can lead to Dementia when CD4+ < 200 cells/mm3 • Commonly pneumocystosis (PCP 50%), When CD4+ cells < 200 cells/mm3 5 III. Diagnosis: - Antibody test ( to virus or viral components): • ELISA for screening (Sensitive, but could be False positive) • Rapid HIV antibody test (strip) • ELISA Confirm by western blot analysis (WBA) ELISA + WBA = High specificity , if both are +ive, the virus is diagnosed - HIV antibody found in: Blood, urine or saliva • Antibodies detected at 6 -12 wks post-infection • “ Window Period”: Before 6 -12 wks , an Infectious period, So Must be diagnosed to prevent spreading by : ▪ RT-PCR for HIV RNA (6-10 days +) or HIV DNA ▪ Branched-chain DNA (bDNA) Assay _ fourth: Treatment: Highly Active Antiretroviral Therapy (HAART) - Six classes of antiretroviral (HAART) agents: 1) 2) 3) 4) 5) 6) Nucleoside analog reverse transcriptase Inhibitors (NRTIs) Non-Nucleoside analog reverse Transcriptase inhibitors (NNRTIs) Protease Inhibitors (PIs) gp41 fusion inhibitor CCR5 antagonist Integrase inhibitors - Basis of the HAAT Treatment • Use 3 inhibitors from 2 different classes (ART): 2 backbone NRTIs + a base of either NNRTIs or PI: _Fifth: Immune Reconstitution Inflammatory Syndrome (IRIS)/ Immune Recovery - inflammatory response mediated by Reconstituted CD4+ lymphocytes after Successful suppression of HIV by ART which Makes the symptoms of infection worse, e.g.: • Tuberculosis & nontuberculous mycobacteria Infections • CMV retinitis • Cryptococcal meningitis • Hepatitis B and Hepatitis C 6 _ past years’ questions: - CD4+ cells in overt AIDS are less than: Answer: 200 - No true Regarding CMV infection: Answer: AIDS patients usually have Anti-HIV Antibodies (-) test - Not true about HIV: Answer: CD8 infection - One is false about AIDS : Answer: Ab of HIV is protective - Attachment between HIV and infected T cell may involve the following antigens/receptors except: a. CCR5. B. CD8 c. gp 41. D. gp 120. E. CXCR4 Answer: b. CD8 7