Human Immunodeficiency Virus and Acquired Immunodeficiency Syndromes 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

People estimated to be living with HIV (2014)

How was HIV discovered 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 started to be 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.

Where is HIV from

Structure of HIV particle • Core – +ssRNA 2copies – reverse transcriptase (RT, an RNA dependent DNA polymerase) – P24 • Envelope --gp120 --gp41 (P24) Diameter: ~ 100 nm www.wikidoc.org

HIV genome 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 长末段重复序列

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

HIV entry: one receptor, two co-receptors Receptor: CD4 Coreceptor: CCR5/CXCR4 HIV targets CD4+ cells. The major targets are CD4+ T cells. But it can also infect monocytes, macrophages, dendritic cells, etc.

HIV types and subtypes HIV’s genome is highly variable Reverse transcriptase of HIV does not have proofreading activity HIV has two types: HIV-1 and HIV-2 HIV-1 is more common, more virulent and more infectious than HIV-2 Each type has many subtypes www.wikidoc.org

Transmission of HIV Source: HIV carriers and AIDS patients HIV is transmitted by certain body fluids such as blood, semen, vaginal fluids and breast milk. HIV is usually not transmitted by saliva.

China’s National Health and Family Planning Commission

Pathogenesis of HIV 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. Damage 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.

Three stages of HIV infection

Three stages of HIV infection 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 period: Systematic symptoms: prolonged fever, night sweats, fatigue, swollen lymph nodes, diarrhea. Infection of the CNS: Memory loss, depression, and other neurological disorders Cancer Opportunistic infections

Opportunistic infections Bacterial infections mycobacterium avium complex 鸟型分支杆菌 Mycobacterium tuberculosis 结核分支杆菌 Viral infections Herpes simplex virus Cytomeglovirus Varicella-zoster virus Kaposi’s sarcoma herpes virus Fungal infection Candida 念珠菌 Coccidioides 球孢子菌 Histoplasma 组织包浆菌 Pneumocystis 肺囊虫 Cryptococcus 隐球菌（致脑膜炎） Protozoan parasites Cryptosporidium 隐孢子虫 Toxoplasma 弓形虫 Cancer Kaposi’s sarcoma Lymphoma Cervical cancer

Diagnosis of HIV 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

HIV treatment Inhibitors of HIV replication block various steps

Zidovudine （Azido-deoxythymidine) 齐多夫定 A nucleoside analog that inhibits RT.

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 But, There is as yet no cure! AIDS therapy is expensive. Drug resistant viruses appear. Can’t stop taking the drugs. There is no vaccine. Why so difficult to treat? Fast mutation rate: drug resistance Infecting the immune system: the immune system cannot help eliminate the virus. Integration into the host genome: latent reservoir persists

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.