HIV Flashcards
What does the HIV gag gene code for?
Structural proteins of the capsid, matrix, core and nucleocapsid.
What does the HIV pol gene code for?
Viral enzymes: protease, reverse transcriptase, RNase H and integrase enzymes. Expressed as a Gag-Pol polyprotein before autocleavage.
What is the structure of HIV’s genome?
+ sense ssRNA
What are the co-receptor sites involved in HIV binding to T cell?
CCR5 and CXCR4
Outline the general steps involved in HIV becoming disseminated throughout the body.
Mucosal exposure to HIV-1
Selective infection by R5 strains
HIV binds to dendritic cell by DC-SIGN
Transport of virus to regional lymph nodes
Spread of infection to activated CD4 T lymphocytes
Entry of virus infected cells into the bloodstream
Widespread dissemination
What is the most common drug target against HIV?
Reverse transcriptase
What does the Long Terminal Repeat do?
Assists the virus in integrating its reverse-transcribed DNA into the host DNA by binding to HIV integrase.
What does HIV integrase do?
catalyses the random integration of HIV cDNA into cell DNA
What is integration required for?
Production of new virus.
What does 5’LTR do?
Acts as HIV gene promotor
How does 5’LTR respond to viral Tat protein?
It is greatly increased in expression.
What does the Tat protein do?
Binds to TAR RNA to promote transcriptional elongation
Downregulates MHC-1 gene transcription
Which two regulatory proteins are essential for HIV replication?
Tat and Rev
Which proteins interfere with MHC-I and why?
Tat, Nef and Vpu
Prevents MHC-I presenting HIV particles to Cytotoxic Lymphocytes
What does vif protein do?
Promotes infectivity of cell-free virus, blocks cell defences targeting single stranded cDNA.
What is the function of nef?
Multifunctional -> important for in vivo pathogenesis
Down-modulates cell MHC-1 and CD4.
What is the ‘Natural combination therapy’ developed by humans before HAART therapy?
TRIM5a: destabilisation of the viral capsid
APOBEC3G: induces lethal hypermutations in viral genome (G-> A)
Tetherin: inhibition of virus release
What were the Counter-measures developed by HIV to counteract the ‘natural combination therapy’ developed by the human immune defense?
HIV-1 Vpu: Degrades CD4, antagonises tetherin, inhibits surface expression of CD1d, facilitates the release of fully infectious virions and counteracts innate immunity factors
HIV-1 VIf protein: Degrades APOBEC3
Where is the main latent HIV reservoir?
in the Central and transitional memory cells
What is acute HIV characterised by?
Rapid and massive loss of the body’s CD4+ T-cells
Generally, how long is clinical latency period in untreated and undiagnosed HIV? i.e. before the patient starts to develop constitutional diseases.
~7 years
What are the effects of HIV on the Gut?
Massiv eloss of memory T-lymphocytes in Gastric Associated Lymphoid Tissue (GALT)
Gut Epithelial cell apoptosis
What is the HIV viral load?
Amount of HIV RNA in the plasma
Why is there limited effectiveness of IgG specific for HIV envelope?
Most antibody to Env does not neutralise HIV.
High levels of Env glycosylation means that immunogenicity of virus-bound gp120 is reduced
Give three reasons why an HIV-1 vaccine has been so difficult.
High error rate of Reverse transcriptase -> huge diversity
Envelope gp120 timers have highly variable regions exposed on the outer surface.
Envelope trimer: evolved to resemble self antigens
Glycans mask Env and provide greater evolutionary diversity and antibody evasion.
What are the two causes of CD4+ depletion in HIV?
CD4+ T cell destruction
Chronic immune-activation
Impaired T-cell production by thymus
How does chronic immune-activation lead to CD4+ T-cell destruction?
Integrity of gut mucosal barrier lost, which leads to microbial products leaking into systemic circulation, which results in stimulation of immune cells and elevation of pro-inflammatory cytokines -> CD4+ T-cells enter cell-cycle and die/
What type of pneumonia is considered an AIDS related illness?
Pneumocystis jirovecii
What are the host factors that may determine disease progression?
Genetic
HLA type
Immunology
Age
What immunological features of a host may determine disease progression?
High titre of neutralising antibody
High level of CD8+ HIV-I specific T cells
High level CD4+ HIV-1 specific proliferative responses
What are four types of inhibitors used in HIV-1 antiviral chemotherapy?
Fusion/entry inhibitors
Reverse transcriptase inhibitors
Protease inhibitors
Integrase inhibtors
What is a nucleoside?
Nucleotides without a phosphate group
What are nucleotides?
mono, di and tri-phosphate forms of the nucleosides
What is acyclovir? How does it work?
Herpesvirus drug (prodrug - activated by herpesvirus thymidine kinase) Nucleoside (guanosine) analogue - lacks the 3' hydroxyl group required to form DNA polymer
What is Valacyclovir?
A proprodrug derived from acyclovir.
Improved bioavailability
What is Ribavirin?
Guanosine analogue
Inhibits many RNA and DNA viruses in vitro.
Influenza, haemorrhagic fevers, Hep C, Respiratory syncitial virus, bronchiolitis, pneumonia
What does NRTI stand for?
Nucleoside Reverse Transcriptase Inhibitors for HIV-1.
How do NRTIs work?
Viral reverse Transcriptase uses them in preference to cellular nucleosides; prevent chain elongation.
Reduces infection of new cells but cannot eliminate virus completely.
What is Zidovidine (AZT)?
Thymidine analogue (NRTI)
What does NNRTI stand for?
Non-nucleoside Reverse transcriptase inhibitor
What are NNRTIs NOT?
Do NOT bind nucleotide bindign site of RT
Are NOT DNA analogues
Directly inhibit the Reverse Transcriptase inhibitors by other mechanisms
Do NOT have close structural similarity to the nucleotides
What is Raltegravir?
Integrase inhibitor
What to protease inhibitors prevent?
maturation of virus
What mechanisms drive ongoing immune activation in an HIV-infected person?
HIV replication/virion production
HIV gene expression
Co-infections (CMV, HCV)
Homeostatic mechanisms following T-cell loss
Dysregulation of Type 1 interferon and other cytokines due to loss of Tregs
What are the co-morbidities to which chronic immune activation and inflammation may contribute?
Cardiovascular disease Cancer Bone fractures/osteoporosis Liver failure kidney failure cognitive decline frailty
