1. ß5 Integrin Is the Major
Contributor to the åv Integrin-
Mediated Blockade of HIV-1
Replication
Diego Herrera
2. What is HIV?
• Retrovirus which infects lymphocytes
º Helper T-cells
º Macrophages
º Dendritic Cells
• Transmission
º Sexual Intercourse
º Blood products
º Mother-to-child
º Multiple Infection
• Diagnosis
º Enzyme-Linked Immunsorbent Assay (ELISA),
then confirmed by Western Blot
3. History
• Originated from non-human primates in sub-
Saharan Africa
º Zoonosis in West-Central Africa in late 19th or
early 20th century
• Simian Immunodeficiency Virus (SIV)
º Infects chimpanzees
º SIV evolved to HIV-1
º Bushmeat hunters and vendors commonly
acquire SIV
5. Antiretroviral Therapy and its
Impact on the HIV-1/AIDS
Pandemic
• Perception has changed from untreatable to
having approved drug therapies
º Retrovir® (zidovudine, AZT)
• Challenges
º Continued pace of new infections worldwide
º Role of pre-exposure prophylaxis (PrEP)
º Drug resistance and viral genetic diversity
º Cross species transmission
º Side-effects (cardiovascular and toxicity)
6. Nucleotide Reverse
Transciptase Inhibitors (NRTIs)
• Foundation of antiretroviral drugs
º Competitive inhibition and chain termination
against the HIV-1 DNA polymerase
- Mammalian DNA polymerases contain enzyme,
polymerase gamma
- Replicated mitochondrial DNA
• Biases slowed down drug development
º No retroviruses associated with human disease
º If they did exist, minor role in public health
11. Overview
• Influence of different åv-coupled ß integrins
in HIV-1 replication in macrophages
• Integrin-mediated blockade of HIV-1
replication
º Specific monoclonal antibodies (mAbs)
º Small arginine-glycine-asparic acid (RGD) mimetic
compounds
º RNA interference
• Role of integrin dimmer åß5 in HIV-1 infection
of macrophages
12. Integrins
• Family of transmembrane receptors
º Mediate cell adhesion cells to extracellular
matrices
º Control complex cell functions
- Proliferation
- Differentiation
- Survival
- Regulation of gene expression
- Promote viral replication
13. Monocytes and Macrophages
• Targets of HIV-1 infection and multiple
aspects of viral pathogenesis
º Trojan Horse
- Differentiation of monocytes to macrophages
- Integrins are upregulated, contolling differentiation
- Macrophages become more susceptible to HIV-1
infection
14. NF-kB-dependent HIV-1
Transcription
• Inhibition by åv integrin-mediated adhesion
and signaling in HIV-1 infection of
macrophages
º Mediated by MAPK signalling cascade
º Revealed significant role of åv integrin
26. RNA Interference
• Discovered by Andrew Z. Fire and Craig C.
Mello
º Gene silencing by double-stranded RNA
º Degrades mRNA from a specific gene
º Mechanism
- Activated by dsRNA in cells
- Activates biochemical machinery which degrades
mRNA with genetic code identical to dsRNA
- Gene is silenced and no encoded protein is made
• Research
º Used to study function genes
º Will be used in future drug therapies
31. Conclusions
• Monocytes and macrophages play a major
role in HIV transmission in all stages of
disease and infection
º Macrophages important cellular reservoir for the
virus
• Cell-to-cell contacts, cell adhesion to the
substrate and cell differentiation state
enhance HIV replication
32. Conclusions (cont.)
• Downregulation of ß5 integrin leads to the
blockade of HIV replication in MDMs
º Demonstrated by RNA interference
- Proven as useful too specifically test effect of a single
gene or protein
- Clearly distinguished between ß3 and ß5 functions
• Integrin Antiretroviral Effect
º Integrin-triggered signals cause activation and
nuclear translocation of MAPKs
º However, there are other signals (i.e PI3K
activation and downstream phosphorylation)
33. Conclusions (Cont.)
• siRNA Therapuetics
º Temkira
- Zaire Ebola Virus (ZEBOV)
- Targeted RNA Polymerase L Protein
- Delivered in stable-nucleic acid-lipid particles
· Complete post-exposure treatment against ZEBOV in non-
human primates
· Model to treat ZEBOV-induced haemorrhagic fever
· May be useful for other viral infections
