Retrovi ruses

1. Retroviruses Dongli Pan Department of Medical Microbiology and Parasitology Zhejiang University School of Medicine pandongli@zju.edu.cn

2. RNA viruses DNA viruses Baltimore classification Fields Virology, 6th edition

3. Retroviridae HIVHuman Immunodeficiency Virus AIDS Acquired ImmunoDeficiency Syndromes

4. People estimated to be living with HIV (2014)

5. History • In 1980-1981, 5 young men, all active homosexuals, were treated for Pneumocystis carinii pneumonia (PCP) in LA, CA. The symptoms suggest the possibility of cellular-immune dysfunction. • Clusters of PCP and Kaposi’s sarcoma observed in other hospitals. • 1982 disease was called AIDS. • Found transmitted at birth and heterosexually. • Virus was first isolated in 1983 from the lymph node of a patient with lymphadenopathy in Paris. • 1984 Electron microscopy and sequence analysis revealed HIV to be a lentivirus, known group of retroviruses.

7. 1. Biological properties 1) Structure • Nucleocapsid – +ssRNA 2copies – reverse transcriptase (RT, an RNA dependent DNA polymerase) – P24 • Envelope – P17 – lipid bilayer membrame --gp120 --gp41 (P24) Diameter: ~ 100 nm

8. HIV under electron microscope

9. 2) Genome • 2 copies of 1 RNA (~ 10 kb), 9 genes • long terminal repeat, LTR (5’, 3’- end) • 3 structural genes – gag → P55 → P24, P17, P6, P7 – pol → RT, integrase, RNase H and protease – env → glycoprotein (gp120 and gp41) • 6 regulator genes • tat, rev and nef are most important

10. Entry of HIV: receptor and coreceptor Receptor: CD4 Coreceptor: CCR5/CXCR4 Infect CD4+ T cells, monocytes, macrophages, dendritic cells, microglial cells

11. Replication provirus Watch video: http://www.hhmi.org/biointeractive/hiv-life-cycle

12. 4) Genetic variability • HIV reverse transcriptase has no proof-reading function. • Hard to develop antiviral drugs and vaccines against HIV. • Multiple subtypes: • Type 1: HIV-1 (more common and pathogenic) • Subtypes: A, B, C, D, F, G, H, J, K and CRFs (circulating recombinant forms) • Type 2: HIV-2 • Subtypes: A to H, only A and B epidemic

13. HIV types and subtypes HIV types: HIV-1 and HIV-2 HIV-1 subtypes: www.wikidoc.org

14. 2. Transmission Source: HIV carriers and AIDS patients • HIV is transmitted by certain body fluids such as blood, semen, vaginal fluids and breast milk. • HIV is NOT transmitted by saliva.

15. China’s National Health and Family Planning Commission

16. 3. Clinical manifestation: 3 stages • Acute infection: fever, rash, night sweats, muscle aches, sore throat, fatigue, swollen lymph nodes, etc. 2-4 weeks. • Clinical latency: no symptoms; serum positive for HIV antibodies. 3-20 years (8 years in average) • AIDS: Systematic symptoms: prolonged fever, night sweats, fatigue, swollen lymph nodes, diarrhea. Infection of the CNS: Memory loss, depression, and other neurological disorders Cancer (as a result of immune system dysregulation and replication of oncogenic viruses) Opportunistic infections

17. Opportunistic infections Bacterial infections mycobacterium avium complex Mycobacterium tuberculosis Viral infections Herpes simplex virus Cytomeglovirus Varicella-zoster virus Koposi’s sarcoma herpes virus Fungal infection Candida Coccidioides Histoplasma pneumocystis Cryptococcus Protozoan parasites Cryptosporidium Toxoplasma Cancer Koposi’s sarcoma Lymphoma Cervical cancer

18. 4. Pathogenesis • Damage monocytes and macrophages at early stages. • Damage CD4+ T cells. As infection progresses HIV mainly infects CD4+ T cells and causes depletion of CD4+ T cells by • 1) HIV-induced cell lysis, • 2) killing of infected cells by cytotoxic T cells and • 3) Inhibition of their production. • Lower activity of other immune cells: B cells and NK cells. • The damaged immune system (especially with very low CD4 T cell levels) cannot control opportunistic infections and cancer, resulting in AIDS.

20. Immune response to HIV infection • Cellular immune response: CTL and NK cells • Humoral immune response: HIV antibodies • However immunity cannot eliminate HIV • Lymphocytes and macrophages are damaged • CD4 helper T cells are damaged • Antigenic drift of gp120 protein • Latent infection

21. 5. Diagnosis • 1. Serology tests: • Screening tests: • ELISA. Can distinguish HIV-1 and HIV-2. Can have false positives. • b) Confirmation tests: • Western blot • c) Rapid antibody tests: • Takes 20 min. Less acurate • 2. qRT-PCR

22. 6. Treatment Difficulties in treating HIV • Fast mutation rate: drug resistant virus constantly emerge. • Infecting the immune system: the immune system cannot help eliminate the virus. • Integration into the host genome: once integrated, it is hard to remove.

23. Inhibitors of HIV replication block various steps

24. Azido-deoxythymidine (AZT) A nucleoside analog that inhibits RT.

25. Non-nucleoside RT inhibitors (NNRTI)

26. Combination therapy Highly active antiretroviral therapy=HAART • HAART is a combination of at least 3 antiviral drugs, usually 1 protease inhibitor and 2 RT inhibitors. • Efficient>80% of those who receive a therapy.Reduction of viral replication < 100 copies/mL • Reduction in the number of AIDS-affectedpersons and AIDS-deaths in USA and Western Europe • But, • There is as yet no cure! • AIDS therapy is expensive. • Can’t stop taking the drugs. • There is no vaccine.

27. Hope

28. Retroviridae HTLV Human T-Lymphotropic Virus-1

29. Human T-lymphotropic virus -1 (HTLV-1) Biological features and transmission are similar to HIV Associated diseases Malignances • Adult T cell leukemia • Inflammatory diseases • Spastic paraparesis • Arthropathy