Retroviruses (chapter 65)

1. Retroviruses (chapter 65) • Positive strand RNA viruses (5000-12000 bp) • Enveloped • Contain reverse transcriptase enzyme • Copies RNA into DNA • Cause chronic disease long after infection • Due to integration of viral DNA into host chromosome

3. Figure 65-1 Morphologic distinction of retrovirions. The morphology and position of the nucleocapsid core are used to classify the viruses. A-type particles are immature intracytoplasmic forms that bud through the plasma membrane into mature B-type, C-type, and D-type particles.

4. Figure 65-2 Electron micrographs of two retroviruses. A, Human immunodeficiency virus. Note the cone-shaped nucleocapsid in several of the virions. B, Human T-leukemia virus. Note the C-type morphology characterized by a central symmetrical nucleocapsid. (From Belshe RB, editor: Textbook of human virology, ed 2, St Louis, 1991, Mosby.)

5. Figure 65-2 Electron micrographs of two retroviruses. A, Human immunodeficiency virus. Note the cone-shaped nucleocapsid in several of the virions. B, Human T-leukemia virus. Note the C-type morphology characterized by a central symmetrical nucleocapsid. (From Belshe RB, editor: Textbook of human virology, ed 2, St Louis, 1991, Mosby.)

6. Figure 65-4 Genomic structure of human retroviruses. A, Human T-lymphotropic virus (HTLV-1). B, Human immunodeficiency virus (HIV-1). The genes are defined in Table 65-2 and Figure 65-7. Unlike the other genes of these viruses, production of the messenger RNA for tax and rex (HTLV-1) and tat and rev (HIV) requires excision of two intron units. HIV-2 has a similar genome map. The vpu for HIV-2 is termed vpx. LTR, Long-terminal repeat. Protein nomenclature for HIV: ca, capsid protein; in, integrase; ma, matrix protein; nc, nucleocapsid protein; pr, protease; rt, reverse transcriptasesu, surface glycoprotein component; tm, transmembrane glycoprotein component. (Redrawn from Belshe RB, editor: Textbook of human virology, ed 2, St Louis, 1991, Mosby.)

7. Figure 65-5 The life cycle of human immunodeficiency virus (HIV). HIV binds to CD4 and chemokine co-receptors and enters by fusion. The genome is reverse transcribed into DNA in the cytoplasm and integrated into the nuclear DNA. Transcription and translation of the genome occur in a fashion similar to that of human T-lymphotropic virus (HTLV-1) (see Figure 65-7). The virus assembles at the plasma membrane and matures after budding from the cell. cDNA, complementary DNA. (Redrawn from Fauci AS: Science 239:617-622, 1988.)

8. CD4+ cell

9. Figure 65-6 Target cell binding of human immunodeficiency virus. (Redrawn from Balter M: Science 274:1988, 1996.)

10. Figure 65-7 Transcription and translation of human T-leukemia virus (HTLV-1). (A similar but more complex approach is used for human immunodeficiency virus [HIV].). All HTLV-1 and HIV messenger RNA (mRNA) include the 5'-end of the genome. The mRNA for tax and rex requires excision of two sequences (red X), the gag-pol and env sequences. The other mRNAs, including the env mRNA, require excision of one sequence. Translation of these mRNAs produces polyproteins, which are subsequently cleaved. Gene nomenclature: env, Envelope glycoprotein; gag, group antigen gene; pol, polymerase; rex, regulator of splicing; tax, transactivator. Protein nomenclature: C, Carboxyl terminus of peptide CA, capsid; MA, matrix; N, amino terminus; NC, nucleocapsid; PR, protease; SU, surface component; TM, transmembrane component of envelope glycoprotein. Prefixes: gp, Glycoprotein; gPr, glycosylated precursor polyprotein; p, protein; PR, precursor polyprotein.

11. Acquired Immune Deficiency Syndrome (AIDS) • caused by human immunodeficiency virus (HIV) • retrovirus • believed to have evolved in Africa from a monkey virus

12. Figure 65-12 Upper estimates of cumulative global distribution of human immunodeficiency virus (HIV) infections as of the end of 2003. The estimated cumulative global total of HIV-infected adults in 2003 was approximately 46 million. Infection rates vary widely in different regions of the world. The highest rates are in sub-Saharan Africa. (Modified from AIDS Epidemic Update, Dec 2003 www.unaids.org)

13. Transmission • direct exposure of person’s bloodstream to body fluid containing virus • groups most at risk are (descending order): • homosexual/bisexual men • intravenous drug users • heterosexuals who have intercourse with drug users, prostitutes, and bisexuals • transfusion patients and hemophiliacs • children born of infected mothers

14. Figure 65-8 Pathogenesis of human immunodeficiency virus (HIV). HIV causes lytic and latent infection of CD4 T cells and persistent infection of cells of the monocyte macrophage family and disrupts neurons. The outcomes of these actions are immunodeficiency and acquired immune deficiency syndrome (AIDS) dementia. DTH, Delayed-type hypersensitivity. (Redrawn from Fauci AS: Science 239:617-622, 1988.)

15. Clinical manifestations • four types of pathological changes • AIDS-related complex (ARC) • AIDS • central nervous system disease • AIDS-related cancers

16. Figure 65-9 Time course and stages of human immunodeficiency virus (HIV) disease. A long clinical latency period follows the initial mononucleosis-like symptoms. The progressive decrease in the number of CD4 T cells, even during the latency period, allows opportunistic infections to occur. The stages in HIV disease are defined by the CD4 T-cell levels and occurrence of opportunistic diseases. ARC, acquired immune deficiency syndrome (AIDS)-related complex. (Redrawn from Redfield RR, Buske DS: Sci Am 259:90-98, 1988, updated 1996.)

17. ARC • fever, malaise, headaches, macular rash, weight loss, lymph node enlargement, oral candidiasis, and presence of antibodies to HIV • occurs in first few months after infection; lasts 1 to 3 weeks • can develop to full-blown AIDS

18. AIDS • progressive destruction of CD4+ cells leads to collapse of immune system • patient susceptible to opportunistic infections

19. HIV pathogenesis • involves depletion of T cells, possibly by: • disruption of plasma membrane permeability • destruction by immune system cells due to presence of gp120 in membrane • syncytia formation • integration and transposition of HIV provirus • apoptosis • may cause disruption of balance between different T cell populations • may destroy or disable dendritic cells • HIV mutates rapidly, so that it evades immune system

20. Apoptosis and AIDS

21. Disease processes associated with AIDS

22. Central nervous system disease • headaches, fever, subtle cognitive changes, abnormal reflexes, and ataxia • dementia and severe sensory and motor changes observed in advanced cases • autoimmune neuropathies, cerebrovascular disease, and brain tumors are common

23. AIDS-related cancers • Kaposi’s sarcoma • caused by human herpesvirus 8 • carcinoma of mouth and rectum • B-cell lymphomas

24. Treatment • immunodiagnostic tests for HIV antibodies or antigens • treatment involves: • antiviral agents • nucleoside analogue reverse transcriptase (RT) inhibitors (e.g., AZT) • nonnucleoside RT inhibitors (e.g., delavirdine) • protease inhibitors (e.g., indinavir) • treatment of opportunistic infections and cancer

25. Prevention and control • screening and treatment of blood and blood products • education • protected sexual behaviors • search for vaccine is ongoing

26. Leukemia • two types of leukemias caused by retroviruses • adult T-cell leukemia • hairy-cell leukemia • both retroviruses spread: • by transfusions of contaminated blood • by needle sharing • by sexual contact • across placenta • from mother’s milk • by mosquitoes

27. Adult T-cell leukemia • caused by human T-cell lymphotropic virus I (HTLV-I), a retrovirus • integration of virus into host genome activates growth-promoting genes • death caused by proliferation of leukemia cells or from opportunistic infections • no treatment available

28. Hairy-cell leukemia • caused by HTLV-II • chronic progressive lympho-proliferative disease • death usually caused by opportunistic infections • IFN-a n3 used for treatment