Human Immunodefiency Virus Type 1 Lentivirus

1. Human Immunodefiency Virus Type 1Lentivirus Virion Genome Genes and proteins Viruses and hosts Diseases Distinctive characteristics

2. Human Immunodefiency Virus Type 1Lentivirus • Virion • Spherical enveloped particle. • Diameter 100 nm. • Conical capsid.

3. Human Immunodefiency Virus Type 1Lentivirus • Genome • Linear ss RNA, positive sense. • Two identical segments, each 9.3 Kb. • Cellular tRNAlys3 molecules packaged in virions used as primers for reverse transcription.

4. Human Immunodefiency Virus Type 1Lentivirus • Genes and proteins • Four capsid proteins : MA, CA, NC,p6 • Three enzymes : PR, RT, IN • Two envelop proteins : SU, TM • Six regulatory proteins : Vif, Vpu, Vpr, Tat, Rev, Nef

5. Human Immunodefiency Virus Type 1Lentivirus • Viruses and hosts • Human immunodeficiency virus types 1 and 2 (HIV-1, HIV-2). • Simian immunodeficiency virus. • Equine, bovine, feline immunodeficiency viruses.

6. Human Immunodefiency Virus Type 1Lentivirus • Diseases • Acquired immune deficiency syndrome (AIDS) first described in 1981. • A major global pandemic today (more than 30 million people infected). • HIV replicates in and kills lymphocytes and macrophages. • Results in depletion of CD4 T cells to render host immune-incompetent. • As a result, opportunistic infections by other pathogens are often fatal. • HIV is transmitted through sexual contact and blood exchange.

7. Human Immunodefiency Virus Type 1Lentivirus • Distinctive characteristics • Proviral DNA can enter nucleus without requirement for cell division. • Lentiviruses make a complex set of singly and doubly spliced mRNAs. • Six regulatory proteins control virus production and pathogenesis.

8. Virion • Human immunodeficiency virus type 1 (HIV-1) and acquired immunodeficiency syndrome

9. Virion • HIV-1 infection leads to a progressive loss of cellular immunity and increased susceptibility to opportunistic infections

10. Virion Fig. 26.2 Diagram of structure of HIV-1 virion.

11. Genome • HIV-1 is a complex retrovirus Fig. 26.3 Genome structure and RNA splicing pattern of HIV-1.

12. Genes and proteins • HIV-1 is a complex retrovirus

13. Genes and proteins • HIV-1 is a complex retrovirus

14. Genes and proteins • HIV-1 targets cells of the immune system by recognizing CD4 antigen and chemokine receptors • gp120 on the virion binds to CD4 on the cell surface • gp120 undergoes a conformational change that exposes regions that bind to chemokine receptors (CCR5 or CXCR4) • The close proximity of the viral and cellular membranes results in their fusion Fig. 26.4 Model of HIV-1 entry.

15. Genes and proteins • Virus mutants arise rapidly because of errors generated during reverse transcription • Unlike other retroviruses, HIV-1 directs transport of proviral DNA into the cell nucleus • MA and Vpr facilitate nuclear transport • Can infect cells that are not actively dividing • Latent infection complicates the elimination of HIV-1 • ~1 in 100 infected cells actively express viral RNA • Cannot be readily distinguished from uninfected cells by immune system

16. Genes and proteins • The Tat protein increases HIV-1 transcription by stimulating elongation by RNA polymerase II (a) In the absence of Tat, RNA polymerase II molecules that initiate transcription at the HIV-1 promoter lack processivity and most are released (b) Tat recruits cyclin T and cyclin-dependent kinase-9 (Cdk9) to the transcription complex shortly after initiation (C) Hyperphosphorylation of C-terminal domain (CTD) of RNA polymerase increases processivity Fig. 26.5 Mechanism of Tat function.

17. Genes and proteins • The Rev protein mediates cytoplasmic transport of viral mRNAs that code for HIV-1 structural protein • CRS • RRE Fig. 26.6 Mechanism of Rev function.

18. Genes and proteins • Together, the Tat and Rev proteins strongly upregulate viral protein expression • The Vif protein increases virion infectivity by counteracting a cellular deoxycytidine deaminase • The Vpr protein enables the preintegration complex to be transported to the nucleus

19. Genes and proteins • The Vpu protein enhances release of progeny virions from infected cells • Degradation of CD4. • Enhancement of virus release from the plasma membrane. • The Nef protein is an important mediator of pathogenesis • Decrease in the surface expression of CD4 and MHC 1. • Enhancement of virus infectivity. • May induce phosphorylation of matrix protein, which could increase virus infectivity

20. Genes and proteins (a) In the absence of Vpu, CD4 interacts with gp160 in the endoplasmic reticulum, Vpu binds to the cytoplasmic domain of CD4 and through interaction with –TrCP directs CD4 to the proteasome degradation pathway. (b) Nef binds to the cytoplasmic tail of CD4 at the inner surface of the plasma membrane, and via interaction with AP-2 increases uptake of CD4 into clathrin-coated pits Fig. 26.7 Down-regulation of CD4 expression.

22. Azidothymidine CD4 antigen CD4-positive T lymphocytes Chemokines Cytokines Cytotoxic T lymphocytes Dendritic cells Epitopes Importin Latent infection Macrophage Major histocompatibility complex (MHC) protein Myristate NF-kB (nuclear factor-kB) Opportunistic infections Preintegration complex Proteasomes Src-related kinases T-cell receptor Transgene Ubiquitination Key Terms