ĐĎॹá>ţ˙ lnţ˙˙˙k˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙ěĽÁ` řżbWbjbjć‡ć‡ 7X„í„íb#˙˙˙˙˙˙¤„;„;„;„;,°;LœGj<<<<<<<<FFFFFFF$IhnKrĽFą<<<<<ĽF<<VGNCNCNC<â<<FNC<FNCNCŒCÇcF<ü; đšěŠNűĹ„;@úSFFlG0œG[FŕKú@JŕKcFŕKcF<<NC<<<<<ĽFĽFDC <<<œG<<<<D` $` ˙˙˙˙ HIV & AIDS HYPERLINK "http://www.unaids.org/"http://www.unaids.org Chapter 19 HISTORY of HIV/AIDS 1981: CDC - large number of cases of PCP (Pneumocystis carinii pneumonia) Kaposi’s sarcoma & other opportunistic infections as well Decreased T cell numbers Young homosexual men 1983: Causative agent = virus Discovered by Luc Montagnier at the Pasteur Institute Called HIV-1: Human immunodeficiency virus type 1 HIV-2 was discovered in 1985 Causes severe immune deficiency leading to susceptibility to opportunistic infections and neoplasms Transmitted by three major pathways: Perinatal Parenteral Sexually (70% of all transmissions) Global summary of the HIV and AIDS epidemic, December 2005 Global estimates for adults and children end 2005 People living with HIV ------------ 40.3million (36.7 – 45.3) New HIV infections in 2005 ----- 4.9 million (4.3 - 6.6) Deaths due to AIDS in 2005 ---- 3.1 million ( 2.8 – 3.6) End-2005 global HIV and AIDS estimates Children (<15 years) Children living with HIV ----- 2.2 million (2.0 – 2.6 million) New HIV infections in 2004 -- 640,000 (570,000-750,000) Deaths due to AIDS in 2004-- 510,000 (460,000-600,000) About 14,000 new HIV infections a day in 2005 More than 95% are in developing countries 2,000 are in children under 15 years of age About 12,000 are in persons aged 15 to 49 years, of whom: almost 50% are women about 50% are 15–24 year olds Women are the largest group of newly infected individuals HIV STRUCTURE #1 HIV-1 and HIV-2 are enveloped retroviruses belonging to the genus Lentiviridae ENVELOPE: Derived from host cell plasma membrane has one type of peplomer Some host membrane bound proteins will be included PEPLOMERS: 72 identical surface glycoproteins gp120 non-covalently associated with gp 41 Gp160 is the precursor to gp120 and gp41 GENOME: 2 identical pieces of ssRNA (diploid) Each RNA strand ~9200 nucleotides bases long Codes for 9 genes HIV STRUCTURE #2 CAPSID: icosahedral-like that encloses the 2 ssRNA segments + 3 enzymes ENZYMES: packaged with genomic ssRNA in mature virion Reverse transcriptase (RT): copies RNA ( complementary DNA (cDNA) Protease: cleaves viral polyproteins Integrase: inserts cDNA into host cell’s DNA CELL SURFACE RECEPTORS and CO-RECEPTORS for HIV CD4: 4 extracellular Ig-like domains Expressed on cells surface of T-cell subset, MFđ and bone marrow derived dendritic cells CCR5: receptor for chemokines RANTES, MIP-1ađ and MIP-1bđ Expressed on T-cells, MFđ and Dendritic cells CXCR4: receptor for chemokine SDF-1 (stromal derived factor-1) Expressed on T-cells HIV REPLICATION #1 ADSORPTION gp120 binds to CD4 on host cell surface (T-cells, MFđ,đ DCs) gp120 - CD4 interaction causes a change in gp120 shape gp120 now interacts with a chemokine receptor CCR5 (early in infection) or CXCR4 PENETRATION gp120 - CCR5 (CXCR4) interaction causes a further change in gp120 shape gp41 now binds with host cell surface protein allowing virus to fuse with host cell plasma membrane & uncoats Viral genome + enzymes enter host cell HIV REPLICATION #2 BIOSYNTHESIS (active infection) RT copies RNA ( cDNA which is dsDNA cDNA enters nucleus of host cell & recombines (integrates) with host cell DNA with the help of the INTEGRASE VIRUS now is a PROVIRUS Provirus is transcribed by host cell’s DNA dependent RNA polymerase (RNA pol) ( viral mRNA Viral mRNA translated ( viral polyproteins Viral mRNA can be alternatively spliced to give rise to different proteins Capsid/core proteins, viral enzymes, peplomer proteins HIV REPLICATION #3 MATURATION Peplomer proteins (gp120 & gp41) are expressed on host cell plasma membrane Capsid assembles around viral mRNA (genome) + enzymes at membrane site containing peplomer proteins RELEASE Virus buds out of cell with an envelope derived from host cell’s plasma membrane HIV REPLICATION #3 LATENT INFECTION Is it truly latent? “CLINICAL LATENCY” - New estimates = 1 - 10 billion viral particles are produced daily! (~2 billion T-cells infected/day) ACTIVATION - of host cell (CD4+ cells) ( “reactivates” provirus stimulating biosynthesis of new virions T-cells respond to Ag ( proliferate & release cytokines Activation of NFkđB leads to low level viral transcription Activated T-cells & memory cells are produced If T-cell contains a provirus ( provirus is in the genome of the new T-cells HIV PATHOGENESIS DIRECT VIRAL CYTOPATHIC EFFECTS Massive production of viruses (host cell lysis Syncytia formation – formation of multinucleated giant cells Released gp120 ( binds CD4 & leads to death of the cell Apoptosis = programmed cell death Toxic accumulation of viral RNA, DNA or proteins IMMUNE RESPONSE LEADS TO ACTIVATION of T CELLS Ultimately resulting in death of infected cells Activated CD8+ T cells (CTLs) ( kill infected CD4+ T cells Activated CD4+ T-cells/B-cells: Anti-peplomer Abs ( bind & activate complement system ( lysis of infected cell BIOLOGY of HIV INFECTION T cells = major target but also .... Macrophages/Monocytes B lymphocytes *Dendritic cells (bone marrow derived and FDCs) HIV infects but does not necessarily replicate in….. Hematopoetic stem cells Brain - microglia, astrocytes, others Endothelial cells Epithelial cells – skin, gastrointestinal Myocardium, prostate gland, testes, some liver cells HIV-infected person = person who is infected BUT may not have detectable Abs to HIV HIV INFECTION vs AIDS HIV-infected ( no detectable Abs SEROCONVERSION Time when an HIV-infected individual begins to have measurable levels of Abs in the blood to HIV 6-18 weeks or within 3 months for 95% of people within 6 months for 99% of people People have flu-like or mononucleosis-like symptoms with swollen l.n. ASYMPTOMATIC: No major symptoms (usually 1-8 years) SYMPTOMATIC: Persistent or opportunistic infections ~8 years after infection until death AIDS: Person usually dies within 2 years CD4+ T cells/ mđl : healthy = 1000 AIDS = 200 or less TRANSMISSION Virus is found in body fluids, secretions, and blood. Saliva, semen, vaginal discharge, tears, urine. Sexual intercourse:homosexual and heterosexual, anal, vaginal, and oral Blood: transfusions and blood products Contaminated needles, IV drug abuse, accidental exposure Mother to child, across placenta, breast feeding Organ transplant CDC CLASSIFICATION of HIV INFECTION GROUP 1 Time frame: 1-12 months Viremia, no HIV Abs present until 1 – 18 weeks ~1000 CD4+ T-cells/mđl Acute infection of T cells, followed by a decrease in viral number Asymptomatic or persistent lymphadenopathy (swollen l.n.) (2-4 weeks) Mononucleosis-like symptoms CDC CLASSIFICATION of HIV INFECTION GROUP 2 Time frame: 1  8 years Asymptomatic infection  no apparent disease ~500 CD4+ T-cells/mđl CDC CLASSIFICATION of HIV INFECTION GROUP 3 Time frame: Begins during asymptomatic phase Up to 15 years Divided into Early and Advanced HIV-related symptoms Persistent generalized lymphadenopathy Night swea  ./0EFRfk¤°  7 ź E  Ş ­ š ş Î Ď â ë ě ¨ ůîůŕîŘîůÍż´Ś´ůż´ů´ůÍů›Ž‚v‚j`L&h’“h’“5CJOJQJ\^JaJh’“h’“6]h’“h’“9CJ#aJ#h’“h’“9CJaJh’“h’“9CJaJh’“h’“OJQJ^Jh’“h’“CJaJh’“h’“6CJ]aJh’“h’“CJaJh’“h’“5CJ\aJh’“h’“CJaJh’“h’“>*jh’“h’“Ujh’“h’“U h’“h’“ GRf°ę  7 m Ÿ ź E O Z ~ ş ě + i § ¨ úňňúęâââęââÚęęâââúúŇŇŇÍgd’“ & Fgd’“ & Fgd’“ & Fgd’“ & Fgd’“$a$gd’“gd’“bWý¨ Î Ď Ř ă ĺ # $ ™ Č X Z Ę Ë *,5Ş´-4Ť˛óű)DPQktőîăŇÇłžłî”†”‚îxî”î”î”î”î”îj_Q_j jŕđh’“h’“CJaJh’“h’“CJaJh’“h’“5CJ\aJh’“h’“6]h’“h’“h’“5CJ\aJh’“h’“5\)h’“h’“5CJH*OJQJ\^JaJ&h’“h’“5CJOJQJ\^JaJh’“h’“CJaJ h’“h’“CJOJQJ^JaJh’“h’“CJaJ h’“h’“h’“h’“CJ#aJ#¨ ĺ $ ^ ˜ ™ Č ň  X o  Ę Ë Ü ,vŞŘ-[ˆšúňňňíúĺĺĺÝŐŐúúĺĺÍĺÍÍĺÍÍ & Fgd’“ & Fgd’“ & Fgd’“ & Fgd’“gd’“ & Fgd’“gd’“šŤó)k˝žđTÄœĆězčFŒ¤ˆŻúňňęęęĺúňÝňÝňÝúňŐŐŐÝňŐŐŐ & Fgd’“ & Fgd’“gd’“ & Fgd’“ & Fgd’“gd’“tš˝đôT^ŞŹŔÄňô,ějnxzFŒ¤ŻÂĎâđńŮÚüý“ŚąaiťÎßmwz‹őçőŕÖŕÉŕÖŕÉŕÉŕÉŕÖŕÖž­ž­žŕÖžŕÖྟžŸžŸž”ŕÖžÖžŕ־ֆžh’“h’“5CJ\aJh’“h’“CJaJ jŕđh’“h’“CJaJ h’“h’“CJOJQJ^JaJh’“h’“CJaJh’“h’“OJQJ^Jh’“h’“5\ h’“h’“h’“h’“5CJ\aJh’“h’“CJaJ1ŻÂâs‹ć\“ŚąýaişťÎßómŐ T°JúňęęęęęââúňęęňęÝúňęęňęâęęgd’“ & Fgd’“ & Fgd’“ & Fgd’“gd’“‹Œ”•ëě TěîJlŞŹčęQRÍü9:JK]^tu™š˝ž˘!¸!Ĺ!Ć!Ů!ç!é!đ"#J#o#w#—#$óčÚčÚčĎžĎčÚ衭Ÿˇ•ˇ•ˇ­ˇˇ•ˇˇˇ•ˇ•ˇ‚čÚčˇčˇčˇ‚ˇčˇh’“h’“CJaJh’“h’“H* jŕđh’“h’“h’“h’“5CJ \aJ h’“h’“5\ h’“h’“ h’“h’“CJOJQJ^JaJh’“h’“CJaJ jŕđh’“h’“CJaJh’“h’“CJaJh’“h’“CJH*aJ/JlŹBzœÍü,gÖđ + 9 i ž ś Ü î !M!Ą!˘!¸!úňęęęęęňęęęúňęęęňęęęęęňĺúgd’“ & Fgd’“ & Fgd’“gd’“¸!Ů!é!J"z"œ"â"#J#o#˜#V$p$<%>%Î%&G&x&‰&ś&Î&ý&(Œ(÷ďççççďďßďçÚďŐďďďďďÚďďççgd’“gd’“ & Fgd’“ & Fgd’“ & Fgd’“ & Fgd’“$$‰&ś&Ŕ&''((((P)Ş)Ŕ)Ř)Ú)D*F*X*Z*`*ş*Ň*,HŞHŹHI IHIJI’IęIJ J>JpJrJLLWLdL§M¨MNN%NCN\NŔNO1O¸OĎOíOPŁPĺPRVVbWóěá×ěĎěóěĎěá×ě×ěĎěóěá×ěÍěĎěĎěóěá×ě×ěóěáěĂěĎěĎěáľěŞľěŞá×ě×ěÍóěh’“h’“CJaJh’“h’“5CJ\aJh’“h’“6]Uh’“h’“H*h’“h’“5\h’“h’“CJaJ h’“h’“h’“h’“OJQJ^J=Œ()P)Ş)Ú)4*^*`*ş*+2+ž+ě+¤HI’IęI"J>JvJžJäJVKL4LŤLąL÷ďę÷÷ďĺę÷ďď÷ďďĺę÷÷ďďďďďďďďgd’“gd’“ & Fgd’“ & Fgd’“ts, weight loss, fatigue, mild opportunistic infections (thrush), severe diarrhea CD4+ T-cells numbers begin to decrease slowly (CD4+ T-cell count falls to 200-499/mđl) as viral titer slowly increases CDC CLASSIFICATION of HIV INFECTION GROUP 4 Time frame: months to years Clinical AIDS CD4+ count falls to <200/mđl Neurologic symptoms (AIDS dementia) Diagnostic as AIDS Slow increase in viruses, sever opportunistic infections Persistent infections appear --> shingles, Candidiases, fever, HSV infections, persistent diarrhea, others Viral concentration increases Opportunistic infections ---> CMV, Mycobacterium infections, PCP, toxoplasmosis of the brain, Kaposi’s sarcoma, others Death HIV EVASION of the IMMUNE SYSTEM Virus becomes latent Virus infects non-proliferating memory cells Antigenic changes due to rapid mutation rate Syncytia = fusion of several T cells Syncytia forming forms are rapidly more fatal Destruction of CD4+ T cells = “CENTER” of the immune system ---> susceptible in infections & cancer No help to activate B cells or CD8+ T-cells ANTI-RETROVIRAL TREATMENTS #1 Nucleoside base analogs Competitively bind to RT and inhibit the activity of RT Require phosphorylation to become activated AZT: azidothymine ddI: dideoxyinosine ddC: dideoxycytosine 3TC: lamivudine (Epivir) Non-nucleoside RT Inhibitors Bind non-competitively to the HIV RT causing a disruption in the catalytic site of the RT Do not require activation by phosphorylation Nevirapine (Viramune) ANTI-RETROVIRAL TREATMENTS #2 PROTEASE INHIBITORS Acts late in late replicative stage of HIV infection Prevents cleavage of capsid & other polyproteins 1995: Saquinavir 1996: Ritonvir & Indinavir 1997: Nelinavir COMBINATION THERAPY CHEMOKINE RECEPTOR BLOCKERS FUSION INHIBITORS VACCINE??? What epitope(s) important? Viral mutation rate is high What type of immunity required? Becomes “latent” Systemic vs mucosal immunity Whole Inactivated HIV-1 Deadly virus ąL˛LÓLčLMBMgM•MůM%NCN\N”NŔNŇNćNűNO1O‹O¸OÎOĎOíOPúőííííĺíĺőÝĺĺŐŐŐŐÝĺĺŐúőí & F gd’“ & Fgd’“ & Fgd’“ & Fgd’“gd’“gd’“P6PgPxP“PŁPˇPÓPĺPćPńP Q(QHQYQvQŽQHVšVÔV W8W^W`WbW÷÷ďďďçççâÝç÷ç÷÷ç÷ç÷÷÷÷âŰgd’“gd’“ & Fgd’“ & Fgd’“ & Fgd’“\đ inactivated or attenuated = RISKY Subunit vaccine: WHAT PART IS IMPORTANT? 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