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

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

Retroviridae HIV Human Immunodeficiency Virus AIDS Acquired ImmunoDeficiency Syndromes

People estimated to be living with HIV (2014)

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.

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

HIV under electron microscope

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

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

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

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

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

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.

China’s National Health and Family Planning Commission

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

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

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.

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

5. Diagnosis 1. Serology tests: 2. qRT-PCR 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

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.

Inhibitors of HIV replication block various steps

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

Non-nucleoside RT inhibitors (NNRTI)

Highly active antiretroviral therapy=HAART 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-affected persons 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.

Hope

Retroviridae HTLV Human T-Lymphotropic Virus-1

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