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HIV Structure, Life Cycle, and Replication (1) Dr. Matthew D. Marsden, Ph.D.

http://www.ck12.org/concept/HIV/. HIV Structure, Life Cycle, and Replication (1) Dr. Matthew D. Marsden, Ph.D. UCLA, Department of Medicine mmarsden@ucla.edu. HIV Structure, Lifecycle and Replication (1) Background: Basic Virology and Pathogenesis

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HIV Structure, Life Cycle, and Replication (1) Dr. Matthew D. Marsden, Ph.D.

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  1. http://www.ck12.org/concept/HIV/ HIV Structure, Life Cycle, and Replication (1) Dr. Matthew D. Marsden, Ph.D. UCLA, Department of Medicine mmarsden@ucla.edu

  2. HIV Structure, Lifecycle and Replication (1) Background: Basic Virology and Pathogenesis Structure: Virion structure, genomic structure, and accessory molecules Lifecycle: Infection and Expression

  3. A new disease… On http://aids.gov/hiv-aids-basics/hiv-aids-101/aids-timeline/

  4. A new disease… • By the end of 1981, there was a cumulative total of 270 reported cases of severe immune deficiency among gay men, and 121 of those individuals had died. • In 1983, Luc Montagnier and Françoise Barré-Sinoussi reported the discovery of a new virus (later called HIV) that is the cause of AIDS. • The first commercial blood test for HIV was licensed in 1985, allowing screening of the U.S. blood supply. • In 1987 the first anti-HIV drug (AZT) was approved by the U.S. Food and Drug Administration. • The first potent combination of anti-HIV drugs became available in 1995. On http://aids.gov/hiv-aids-basics/hiv-aids-101/aids-timeline/

  5. (I) Identification of AIDS Pneumocystis pneumonia—Los Angeles. Gottlieb M S, Schanker H M, Fan P T, Saxon A, Weisman J D & Polzalski “In the period October 1980-May 1981, 5 young men, all active homosexuals, were treated for biopsy confirmed Pneumocystis carinii pneumonia at 3 different hospitals in Los Angeles, California. Two of the patients died. All 5 patients had laboratoryconfirmed previous or current cytomegalovirus (CMV) infection and candidal mucosal infection”. Morbid. Mortal, Weekly Rep. 30:250-2. 1981. Pneumocystis carinii Pneumonia and Mucosal Candidiasis in Previously Healthy Homosexual Men — Evidence of a New Acquired Cellular Immunodeficiency Michael S. Gottlieb, M.D., Robert Schroff, Ph.D., Howard M. Schanker, M.D., Joel D. Weisman, D.O., Peng Thim Fan, M.D., Robert A. Wolf, M.D., and Andrew Saxon, M.D. N Engl J Med 1981; 305:1425-1431December 10, 1981 (II) Isolation of the virus Isolation of a T-Lymphotropic Retrovirus from a Patient at Risk for Acquired Immune Deficiency Syndrome (AIDS) F. Barré-Sinoussi; J. C. Chermann; F. Rey; M. T. Nugeyre; S. Chamaret; J. Gruest; C. Dauguet; C. Axler-Blin; F. Vézinet-Brun; C. Rouzioux; W. Rozenbaum; L. Montagnier. (May 20, 1983) Science, New Series, Vol. 220, No. 4599., pp. 868-871 Detection, isolation, and continuous production of cytopathic retroviruses (HTLV-III) from patients with AIDS and pre-AIDS Frequent detection and isolation of cytopathic retroviruses (HTLV-III) from patients with AIDS and at risk for AIDS Serological analysis of a subgroup of human T-lymphotropic retroviruses (HTLV-III) associated with AIDS Antibodies reactive with human T-lymphotropic retroviruses (HTLV-III) in the serum of patients with AIDS Gallo RC. et al. (May 1984) Science 224 (4648): 497–508 (III) Link Virus-AIDS

  6. Human immunodeficiency virus (HIV) is a retrovirus that causes acquired immunodeficiency syndrome (AIDS). Since the epidemic was identified in 1981, more than 60 million people have contracted HIV and nearly 30 million have died of HIV-related causes. At the end of 2011, an estimated 34 million people, an estimated 0.8% of adults aged 15-49 years worldwide, are living with HIV. 2.5 million new infections in 2011; 330,000 were children. 7,000 people contract HIV everyday, nearly 300 every hour. In 2011 alone, AIDS claimed an estimated 1.7 million lives, of which 230,000 were children. HIV primarily infects vital cells in the human immune system such as helper T cells (CD4+ T cells), macrophages and dendritic cells. HIV infection leads to low levels of CD4+ T cells. http://www.unaids.org/en/

  7. Clinton Health Access Initiative (CHAI) $25 billion total needed to achieve all targets in low and middle-income countries (2009) On average it cost $380 to keep a patient on the medication for a year in Global Fund countries

  8. HIV is responsible for a catastrophic pandemic:

  9. http://aids.gov

  10. http://aids.gov ESTIMATES OF NEW HIV INFECTIONS IN THE U.S., 2009, BY TRANSMISSION CATEGORY MSM = Men who have sex with men IDU = Intravenous drug users

  11. http://aidsvu.org/map/

  12. http://aidsvu.org/map/

  13. What is HIV?

  14. What is HIV? To understand what HIV and AIDS are, let’s break it down: Causative agent: H – Human – This particular virus can only infect human beings. I – Immunodeficiency – HIV weakens your immune system by destroying important cells that fight disease and infection. A "deficient" immune system can't protect you. V – Virus – A virus can only reproduce itself by taking over a cell in the body of its host. http://aids.gov/hiv-aids-basics/hiv-aids-101/what-is-hiv-aids/

  15. What is HIV? To understand what HIV and AIDS are, let’s break it down: Causative agent: H – Human – This particular virus can only infect human beings. I – Immunodeficiency – HIV weakens your immune system by destroying important cells that fight disease and infection. A "deficient" immune system can't protect you. V – Virus – A virus can only reproduce itself by taking over a cell in the body of its host. Disease: A – Acquired – AIDS is not something you inherit from your parents. You acquire AIDS after birth. I– Immuno – Your body's immune system includes all the organs and cells that work to fight off infection or disease. D – Deficiency – You get AIDS when your immune system is "deficient," or isn't working the way it should. S – Syndrome – A syndrome is a collection of symptoms and signs of disease. AIDS is a syndrome, rather than a single disease. It is a complex illness with a wide range of symptoms. http://aids.gov/hiv-aids-basics/hiv-aids-101/what-is-hiv-aids/

  16. What is HIV? • Human immunodeficiency virus or HIV is a type of virus • (from the Latin “virus” referring to poison). • Viruses are: • Small • Generally too small to see with a regular light microscope (20 - 300 nm diameter) • If a cell was a football stadium then a small virus would be around the size of a football.

  17. What is HIV? • Human immunodeficiency virus or HIV is a type of virus • (from the Latin “virus” referring to poison). • Viruses are: • Small • Generally too small to see with a regular light microscope (20 - 300 nm diameter) • If a cell was a football stadium then a small virus would be around the size of a football. • Can only replicate in living cells • - Some can survive for long periods of time outside cells, but cannot replicate that way.

  18. What is HIV? • Human immunodeficiency virus or HIV is a type of virus • (from the Latin “virus” referring to poison). • Viruses are: • Small • Generally too small to see with a regular light microscope (20 - 300 nm diameter) • If a cell was a football stadium then a small virus would be around the size of a football. • Can only replicate in living cells • - Some can survive for long periods of time outside cells, but cannot replicate that way. • Made up of Nucleic acids (DNA/RNA) and proteins • -different from protein-only “prions” or nucleic acid-only “viroids”. • Thousands of very different types of virus exist and HIV is a particular type termed a “retrovirus”.

  19. Viruses Microscopic infectious agents that can infect the cells of a biological organism. Viruses can only replicate themselves by infecting a host cell and are incapable of reproducing on their own. A complete viral particle, known as a virion consists of nucleic acid surrounded by a protective coat of protein called a capsid.

  20. The HIV genome is composed of 9 genes, which encode 15 proteins. http://tcf.epfl.ch/page-20833-en.html http://biology.kenyon.edu/slonc/gene-web/Lentiviral/Lentivi2.html For comparison, the E. Coli bacterium contains around 4,377 genes and the human genome encodes around 21,000 genes.

  21. How does HIV cause disease?

  22. HIV is a virus that infects and destroys cells of the immune system (CD4+ cells). http://aids.gov/hiv-aids-basics/hiv-aids-101/what-is-hiv-aids/

  23. HIV is a virus that infects and destroys cells of the immune system (CD4+ cells). http://aids.gov/hiv-aids-basics/hiv-aids-101/what-is-hiv-aids/ Approximately 8-10 years Asymptomatic period (clinical latency) Initial infection AIDS Often (not always) accompanied by severe flu like symptoms: Opportunistic infections and cancer: AIDS (acquired immunodeficiency syndrome) is the late-stage HIV disease. This occurs when immune system becomes so damaged that it cannot fight off diseases and certain types of cancer.

  24. HIV Life cycle http://preprod.www.tibotec.com/content/backgrounders/www.tibotec.com/hiv_lifecycle.html

  25. Movie of the HIV Life Cycle http://www.youtube.com/watch?v=9leO28ydyfU

  26. Viral RNA gp120 p24 RT & other virion proteins Reverse transcription Infection Fusion & Entry Binding Nuclear localization & entry Integration CD4 CXCR4

  27. Viral RNA gp120 p24 RT & other virion prteins Viral Gene Transcription Cellular Activation Assembly Post-translational processing Budding Translation Expression

  28. HIV Structure Virion Genomic Proteomic

  29. http://www.readcube.com/articles/10.1038/nrmicro2596

  30. http://upload.wikimedia.org/wikipedia/commons/0/00/HIV_Mature_and_Immature.PNGhttp://upload.wikimedia.org/wikipedia/commons/0/00/HIV_Mature_and_Immature.PNG

  31. HIV Structure SIV HIV

  32. HIV Structure Virion Genomic Proteomic

  33. Reverse transcription Referred to as: • Provirus • Proviral DNA • Integrated Provirus 2 copies of viral RNA gp120 p24 RT & other virion proteins Infection Fusion & Entry Binding Nuclear localization & entry Integration CD4 CXCR4

  34. HIV Genome R U5 U3 R R U5 U3 HIV RNA R U5 U3 Reverse transcription Integration HIV DNA Host DNA Host DNA LTR LTR

  35. HIV-1 RNA R U5 U3 R RRE Nature Reviews Microbiology 2, 461-472 (June 2004)

  36. Nature 460, 711-716 (6 August 2009)

  37. HIV-1 Integrated DNA R U5 U3 R U5 U3 CD4 & MHC downregulation Host DNA Host DNA LTR LTR Modified from : The AmFAR AIDS Handbook, D Ward, pp. 348

  38. RNA Splicing Translational Frameshift

  39. Source: The Molecular Biology of HIV/AIDS, D Ward, pp. 19 These are the major spliced RNA species, but HIV can actually produce at least 109 different spliced RNAs (Nucleic Acids Res. 2012 Nov 1;40[20])

  40. Initiation of HIV transcription is performed by cellular factors Source: Atlas of Infectious Diseases, Mandell & Mildvan (ed.), pp. 3.13

  41. Dr. Isabelle BOUALLAGA Institut Pasteur. http://www.123bio.net/

  42. Source: Atlas of Infectious Diseases, Mandell & Mildvan (ed.), pp. 3.13

  43. HIV Structure Virion Genomic Proteomic

  44. HIV Proteins Structural Proteins Gag: Matrix, Capsid, NC, p6 Pol: Protease, Reverse Transcriptase, Integrase Env: gp120, gp41 Regulatory Proteins Tat Rev Nef Accessory proteins Vif Vpr Vpu

  45. Structural protein expression and function CD4 & MHC downregulation

  46. Gag and Gag-Pol Source: The Molecular Biology of HIV/AIDS, D Ward, pp. 19

  47. Gag and Gag-Pol Source: BioAfrica Bioinformatics for HIV Research. http://bioafrica.mrc.ac.za/

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