Retroviruses • Probably the most studied group of viruses in molecular biology!!! • Enveloped, positive-strand RNA viruses • Unique morphology and replication • Replicate through a DNA intermediate by reverse transcriptase (RT)
Retroviruses • Baltimore and Temin in 1970 • RNA-dependent DNA polymerase (reverse transcriptase ) encoded by retroviruses • Retroviruses replicate through an DNA intermediate • This DNA copy of viral genome integrates into host chromosome • This discovery earned the Nobel prize: contradicted the central dogma of molecular biology-genetic information passed from DNA to RNA and then to protein • Here: from RNA to DNA
History • Rous sarcoma virus: solid tumors in chicken • Other cancer causing retroviruses from other animal species (oncogenes) • 1981: first human retrovirus: Human T-lymphotropic virus (HTLV-1) • 1983: Human immunodeficiency virus (HIV)
Oncoviruses:immortalize or transform target cells, A,B,C,D type according to their core and capsid • Lentiviruses:slow viruses associated with neurologic and immunosuppresive disease • Spumaviruses:no disease • Endogenous viruses:transmitted vertically, 1% of human chromosome, in many animal species and humans, one detected in placental tissue which facilitates placental function
Retroviruses • Enveloped sperical virion • Two copies of positive-strand RNA genome • RT • Provirus integrates randomly into host chromosome • Transcription of the genome is regulated by the interaction of host transcription factors with promoter and enchancer elements in the long-terminal repeat portion (LTR) of the genome
Retroviruses • Simple retroviruses encode gag,pol and env genes • Complex viruses also encode accessory –regulatory genes (tat,rev,nef, vif, vpu for HIV) • Assembles and buds from the plasma membrane • Final morphogenesis requires protease cleavage of gag and gag-pol polypeptides after envelopment.
Gp120 • CD4 surface receptor protein • Initially expressed on cells of the macrophage lineage (macrophage, dendritic cells, microglial cells) (M-tropic)+ second receptor CCR5 • Later on helper T cells (T-tropic) +fusin (CXCR4)
Chemokine receptors • CCR5: binds macrophage-tropic, non-syncytium-inducing (R5) viruses mucosal and intravenous transmission of HIV infection. • CXCR4: T-cell-tropic, syncytium-inducing (X4) viruses, which are frequently found during the later stages of disease. • In up to 13% of individuals of northern European descent, a naturally occurring deletion of 32 base pairs in the CCR5 gene results in a mutant CCR5 receptor that never reaches the cell surface. Individuals homozygous for this mutation (1-2% of the Caucasian population) are almost completely resistant to HIV infection.
Transmission *Blood, semen,vaginal secretions • Sexual contact • Exposure to contaminated blood and blood products • From infected mother to her baby perinatally
HIV is not transmitted • Casual contact • Touching, hugging, kissing, coughing, sneezing, insect bites, water, food, utensils, toilets, swimming pools, public baths
Transmission • Inoculation of blood: Transfusion, needlesharing among intravenous drug abusers, needlestick, open wound, mucous membrane exposure, tattoo needles • Sexual trasmission: anal and vaginal intercourse • Perinatal transmission: Intrauterine, peripartum and breast milk
Population at high risk • Intravenous drug abusers, sexually active people with many partners (homosexual, heterosexual), prostitutes, newborns of HIV infected mothers • Blood and organ recipients and hemophiliacs: before 1985 (pre-screening programs)
Epidemiology • Late 1970s-early1980s • Young homosexual men, Haitians, heroin addicts, hemophiliacs were noted to be dying of normally benign opportunistic infections • HIV appears to have evolved since 1930s from a simian virus and then rapidly spread Africa and the world by an increasinly mobile population. • There is an expanding epidemic worldwide.
AIDS cause by HIV • Retroviridae family • Lentivirinae genus • Enveloped, positive strand RNA virus • 2 identical 9-10kb RNA
AIDS • Human immunodeficiency virus type 1 and 2 (HIV-1, HIV-2)
HIV • HIV-1: isolated in1983 • Responsible from AIDS pandemic • HIV-2: isolated in 1986 • HIV-2 less pathogenic slow progression to AIDS
HIV group and subtypes • Rapid mutation and recombination HIV-1 • Group M (major): A-J • Group O • Group N HIV-2 • A-E subtypes