Summary HIV COMPLETE NOTES

HIV Module 3
Topic 1 Global and Regional Overview, Structure Genome and Lifecycle, Current
Drugs

Global and Regional Overview

- New infections are still occurring
- Death still common
- Greatest number of HIV-1 positive people in world are in South Africa - >7 million
- Gender disparity – more women infected than men
o Mostly young childbearing age women
o NOTE that prevalence depends on who gets tested – women more likely to
seek healthcare
o Blesser Syndrome – old men sleep with and infect younger women
- Dependent on surveillance in a nation – may make numbers seem higher just
based on who is monitoring

HIV Structure, Genome and Life Cycle
- Structure of the HIV particle
o Two copies of ssRNA+
o Spherical
o Protruding proteins – recognize target cells
§ Envelope protein = Gp120, GP41 both in trimers
o Mature virus contain viral integrase and protease proteins and some
accessory proteins like Vpr
o P24 is abundant in the virus (capsid)
o Within capsid, two copies SSRNA+ and Reverse Transcriptase

, - Genome Organization
o HIV-1 vs HIV-2
§ HIV-1 is more virulent and pathogenic than HIV-2
§ Very similar in gene structure
• HIV-2 has Vpx where Hiv-1 has Vpr and HIV-1 has Vpu and
HIV-2 has Vpr at that point
o 9 genes, 9.7 kilobases
o LTRs = long terminal repeats
§ Initiate transcription
o Why small genome?
§ Co-opts host genome and host machinery – can have a smaller
genome
o GAG, POL, Envelope = main genes
o Vpr, Vpx, Vif, Vpu = accessory proteins

Gene GAG Pol Envelope
Function Capsid proteins Enzymes that are Envelope glycoproteins
(core = p24, p7, p6) important for - GP120 and GP41
and matrix p17 replication - GP120 recognizes cell
- Structural - Reverse surface receptors (CD4,
proteins transcriptase, CCR5, CXCR4) during
integrase, attachment
protease - GP41 facilitates fusion
of viral and cell
membranes

Genes that increase virulence (HIV Accessory Function
Proteins)
Tat Expressed after infection, promotes expression of
HIV-1 genes
- Very important for infectivity
Vif Enhances infectivity
Vpx Release of virus particle (HIV2 only)
Vpu Release of virus particle (HIV1 only)
Vpr Cause cell cycle arrest and apoptosis
Rev gene Export of mRNA and genomic RNA from the nucleus
Nef Signal transduction (T-cell activation – NB for viral
persistence)
- Down regulation of CD4 receptor
- Viral budding during late infection

, - HIV Replication Cycle

1) Binding, fusion and entry
a. Requires CD4 T cells with CCR5 receptors
b. Virus targets CD4 proteins on surface of T Cell – specificity to immune
cells
c. Membranes fuse between virus and cell
d. Viral material injected into the cell
2) Viral ssRNA becomes DNA using reverse transcriptase to produce viral
RNA/DNA hybrid (RNA dependent DNA polymerase)
a. Produce viral dsDNA using same RT enzyme (also a DNA dependent DNA
polymerase)
b. Important to move to dsDNA quickly à RNaseH degrades RNA from
RNA/DNA hybrid
c. RT = major target for ARVs
i. Pathogen specific target
d. Some evidence that capsid is still present and protects the virus from
degradation
3) Integration of viral dsDNA
a. dsDNA has to enter the nucleus via the NPC and using host importin
b. viral integrase cuts host genome and integrates viral dsDNA into host ds
DNA
c. Provirus has formed
4) Transcription of mRNA using host RNA polymerase
a. Must also replicate viral genome and proteins
5) Protein synthesis and assembly
a. Generally viruses have self assembly
6) Budding
a. New HIV particle released

Anti-HIV Drugs can Target Dieerent Stages of the HIV Lifecycle
- Every drug has side eeects
o Have to weigh up risks vs rewards/benefits
§ Dieerent in individuals
• Risk for exposure (when considering preventative
measures)
o Largely oe target eeects
§ Might end up aeecting host proteins or host factors
§ Want to design drugs that are largely pathogen specific and
minimize damage to host and host essential
processes/functioning
o Change in dose can lead to minimized side eeects
§ Want the minimal dose for optimal eeect on target and minimal
eeect on host
- Types of Drugs
o Coreceptor antagonists
§ Target CXCR4 and CCR5 co receptor proteins on target cell

, § Bind to coreceptor and inhibit virus from binding
o Fusion inhibitors
§ Preventing capsid entry into host cell
§ Preventing capsid insertion into host cell via membrane fusion of
virus and target cell
§ Targets viral GP41
o Reverse transcriptase inhibitors
§ NRTIs, NtRTIs, NNRTIs
• Mimic the nucleoside, nucleotide and non-nucleosides
needed by RT
§ Backbone of anti HIV drugs – main target of most drug cocktails
§ RT has low fidelity – makes lots of mistakes (low eeiciency)
o Integrase inhibitors
§ Prevent integration of viral DNA into host genome
o Protease inhibitors
§ Targets viral protease proteolytic processing that would produce
mature proteins from pre-proteins
- Why use cocktail approach to treatment??
o Pathogen can mutate that may escape aspects of a drug but not other
targets
o Decreases chance of viral escape
§ Would need many simultaneous mutations to escape all targets of
the drug – not possible

Mechanism of Action of Some Current Anti-HIV Drugs

- HIV Tropism
o M-tropic HIV (R5 virus) binds to CD4/CCR5 (mainly macrophages and T
cells)
§ Founder virus (first to infect genital tract) is mainly R5
o T-tropic HIV (X4 virus) binds to CD4/CXCR4 (mainly T cells)
§ Largely in the blood
o Dieerent strains of HIV-1 preferentially bind to T cells (CXCR4) or T cells
and macrophages (CCR5)
o Can have dual tropic X4R5
o Chemokines RANTES, MIP-1a/B ligands for CCR5 receptor suppress HIV-
1 infection (competition for binding)
§ Chemokines are cytokines involved in immune cell recruitment
o SDF-1 = natural ligand for CXCR4

- Attachment
o HIV-1 Gp120 trimer binds to host cell CD4 receptor
• GP120 has many variable loops
o Loop 3 recognizes CD4 receptor
§ GP120 changes shape and peels back
• Conformational change allows for exertion of protein
function – can expose active sites