HIV Flashcards
How does HIV enter cells?
This enters cells through penetration and this is fusion at the plasma membrane. Attachment is mediated by non-specific engagement with cell surface lectins (DC-SIGN). The HIV-1 envelope glycoproteins gp120/41 bind to the CD4 cell receptor and this induces a conformational change in gp120 that exposes a binding site for the chemokine coreceptor (CCR). Binding of gp120 SU to CCR induces a conformational change in gp41 TM that leads to insertion of the fusion peptide into the membrane.
What type of virus is HIV?
It is a lentivirus that is able to infect terminally differentiated cells/non-dividing cells and this is a feature that distinguishes it from simple retroviruses.
Are there NFkB binding sites in the LTR of HIV provirus?
Yes there are and when T cells are activated, NFkB is expressed and the viruses blast off.
What does the 5’ LTR act as?
The 5’ LTR acts as the HIV gene promoter. This is greatly increased in expression in response to the HIV Tat protein, silences HIV expression soon after initial replication and responds to cellular proteins made during T cell immune activation to dramatically increase expression.
What is the role of Tat and Rev?
These are essential for HIV replication and there are exon sequences (tat and rev) within the provirus that encode for these proteins.
What is Tat responsible for?
Tat is a transactivator of HIV transcription and binds to the TAR RNA element (trans-activation response). This is the first segment of RNA in the genome length RNA. TAR is a stem loop structure and Tat binds to the uracil bulge. It recruits a series of cellular proteins that serve to phosphorylate the carboxy terminus of the RNA polymerase II. It boosts transcriptional elongation and prevents the RNA pol II from stalling at the end of this structure.
What is Rev responsible for?
The Rev protein is the regulator of structural gene expression and it also works through a structured RNA element called the Rev-responsive element or RRE. This is like a time switch that defines early and late gene expression.
Early (low REV):
- When the initial transcripts begin to be produced, the 9kb RNA’s are very efficiently spliced within the nucleus.
- The unspliced RNAs contain the RRE that sits within the envelope coding sequence. This leads to a high rate of decay of these partially spliced and full length RNAs. It is only the fully spliced 2kb class of RNAs that are efficiently transported to the cytoplasm and are translated to these regulatory and accessory proteins including Rev.
Late (high rev):
- This rev protein has a nuclear import signal that is translocated back into the nucleus and it begins to accumulate and bind to the RRE. It has the ability to stabilise the RNA preventing its degradation and allows for unspliced and partially spliced mRNAs to efficiently be exported from the nucleus into the cytoplasm. Allows for the translation of the structural proteins gag, gag-pol and env.
What is the difference between the regulatory proteins and accessory proteins?
The Tat and Rev regulatory proteins are essential for HIV replication. The Vif, Vpr, Vpu and Nef proteins are not essential for HIV replication in vitro, but are important for in vivo pathogenesis.
What is the role of the accessory proteins?
Vif - promotes infectivity of cell free virus, blocks cell defences targeting single stranded cDNA
Nef - aims to down-modulate cell MHC-1 and CD4.
Vpu - also downmodulates MHC-1 and CD4 and promotes particle release.
Vpr - it is a weak transcription factor and promotes cell cycle arrest.
These are immune evasive mechanisms.
What are the differences between the CCR5 and CCR4 chemokine co-receptors?
Binding of CD4 in the binding site is essential to induce conformational changes that allow binding of a second receptor (co-receptor) and there are two co-receptors used including CCR5 and CXCR4. It is CCR5 that is necessary for entry and transmission of the virus from the very first phase. Early in the viral infection, CCR5 is the most important, but once it burns through all of this it then switches across through mutation to utilise the CXCR4 co-receptor.
What are the stages of HIV?
There are three stages and they include primary infection, asymptomatic infection and symptomatic infections/AIDS.
