Lecture 10 AIDS Flashcards
What is AIDS?
A viral pathogen that avoids/subverts an immune response. Host fails to control and eliminate the pathogen. Immune response dominated by CD8 and TH1 cells.
What does HIV have?
An RNA genome flanked by long terminal repeats (LTR) involved in viral integration and regulation of the viral genome. Genome can be transcribed in overlapping reading frames allowing the virus to code many proteins in a small genome.
How does HIV enter a cell?
By means of a complex 2 virion envelope gycoproteins. 1. gp120 binds CD4 with high-affinity, this determines cellular tropism of HIV. Gp41 causes fusion of the viral envelope with plasma membrane. Major co-receptors on host cells are chemokines- GPCRs with 7 trans membrane spanning domains.
What are three main chemokine receptors used by HIV?
- CCR5 a major receptor used by HIV on dendritic cells, macrophages and CD4 T cells for its initial infection.
- CXCR4 present on activated T cells.
- DC-SIGN found on dendritic cells.
How does HIV infect CD4 T cells?
Virus particle binds to CD4 and co-receptor on T cell. Viral envelope fuses with cell membrane allowing viral genome to enter the cell. Reverse transcriptase copies viral RNA genome into double-stranded cDNA.
Viral cDNA enters nucleus and is integrated into host DNA.
How does HIV replicate?
T cell activation induces low-level transcription. RNA transcripts are multiply spliced, allowing for translation of early genes tat and rev. Tat amplifies transcription of viral RNA. Rev increases transport of singly spliced or unspliced viral RNA to cytoplasm. The late proteins Gag, Pol and Env are translated and assembled into virus particles which bud from the cell.
What is the innate immune response to HIV?
Activation of Toll like receptors e.g., TLR-4 on dendritic cells leads to transcription of many immune response genes via NFkB. Also regulate/enhance HIV expression by activation of viral RNA transcription.
What is the adaptive immune response to HIV?
CD8 and TH1 cells are associated with a decline in the detectable viruses after the initial infection but do not clear infection completely. Activation of high levels of HIV-1 specific CD8 T cells is crucial to killing HIV infected cell. CD4 TH1 cell count decreases- these are the majority of cells in which HIV replicates. Antibodies produced to gp120 and gp41 but not clear infection.
What are the three mechanisms of CD4 T cells after infection?
- Direct killing of infected cells. 2. Increased susceptibility to apoptosis. 3. Killing of CD4 T cells by CD8 cytotoxic cells which leads to opportunistic infections.
What do drugs against HIV do?
Powerful drugs that block HIV replication and prevent establishment of further infection. Reverse transcriptase and viral protease. Effect a decrease in plasma levels as replication in newly infected cells is prevented. HIV particles may be opsonised by antibody or complement and removed by monocytes. Immune reservoirs are resistant to drug therapy for HIV. Resistance to the nucleoside zidovudine reverse transcriptase inhibitor takes months to develop (three or four mutations in enzyme are required to develop resistance).
What are the difficulties with vaccinations against HIV?
10^9-10^10 virions per day, mutation 3 X 10^-5 per base per replication cycle. Rapid and sustained infection despite strong cytotoxic T cell and antibody response. Ability of HIV to persist in latent form (t1/2 of memory CD4 T cells around 4 months). May be difficult to develop and sustain strong CD8 and or other aspects of immune response through therapeutic vaccination. Recent MERCK vaccine failed.
What are the positives of vaccination?
Individuals exposed but resistant to HIV (lack antibodies but have CD8 T cells specific for HIV and variant CCR5). Administration of antibodies against HIV can protect experimental animals from mucosal infection. Live attenuated vaccines to Simian Immunodeficiency virus effective in protecting primates against subsequent infection by virulent viruses. Enhancing innate immunity may be more effective than boosting adaptive immunity.
