Chapter 18: HIV Flashcards
HIV
Human Immunodeficiency Virus
AIDS
Acquired Immunodeficiency Syndrome
1983
HIV discovered
AIDS
emerging infectious disease, now pandemic 78 million infected 5 million new infections/year 3 million deaths/year 4th leading cause of mortality
Transmission
fresh body fluid-“man-made” disease
Horizontal: sex, blood, needles…
Vertical: mother to fetus and infant
2 types
HIV-1: most prevalent
HIV-2: in West Africa
Group M: Major
A, B, C, D, F, G, H, J, K; 16 CRFs
Group N: non major
A few cases
Group outliers: unclassified
Predominants
Subtype B: USA, N. America, Europe
Subtype C: the world
Virion
Spherical enveloped particle
Conical capsid
~100nm in diameter
transmembrane protein: gp41(glycoprotein, 41 kD); C terminus bind MA protein
SU(surface protein): gp120 has 5 variable loops
Spike: a gp41-gp120 trimer
Genome
• “diploid”: 2 ss RNAs, each o 9.3 kb, “fake” (+) sense • 9 genes: 3 major structural o 6 Regulatory • Use all 3 reading frames • Extensive overlapping • 2 are split genes
Attachment
Interaction of gp120, CD4 and co-receptor-> conformational change in gp41-> membrane fusion
Anti-receptor
gp120
Receptor
CD4 on helper T, macrophage, dendritic cell-> cell tropic
A surface glycoprotein
Has Ab-like domains
Outer domain for viral binding
Co-receptor
CCR5 (used by most HIV-1 strains) or CCR4
Chemokine receptor: bind chemokines in immune system
leukocytes to infected area and control T cell differentiation
RNA processing
- 5’ cap; 3’ poly A
- Genome length mRNA contains overlapping genes differential splicing
- 3 size classes of viral mRNAs
- Unspliced (genome-length: 9.3 kb)
- Singly spliced (about 4.5 kb)
- Multiply spliced (about 2kb)
Maturation
• During and after budding
• Gag-Pol auto-proteolytic cleavage in nucleocapsid
o PolPR, T=RT, RNase H, IN
o Gag other structural proteins (MA, CA, NC)
• Capsid: spherical
High Mutation rate
10^-4 to 10^-5
Rt has inherently high error rate and no proof-reading activity
Maturation can be at any position in HIV genome
Each new HIV genome can contain one point mutation
High Recombination rate
During coinfection by 2 different but related strains by 3 mechanisms
Reassortment: “diploid” genome-> can be “heterozygous”
Cleavage/ligation: homologous,…
Template switching
Consequences of HIV genetic diversity: Rapid Evolution
o rabid antigen changes Evade host immune system Difficult for development of vaccines and diagnostic tests o rapid adaptation Drug resistance
Acquired Immunodeficiency Syndrome
Slow but deadly caused by HIV
Immunodeficiency: unable to respond effectively to pathogens
Initial Infection
viremia and flu-like symptoms (immune response)
Clinical “latent” phase
asymptomatic
HIV relocates to lymph nodes
CD4 T cell number in blood decreses progressively
8-10 years(rapid: 2-3 years)
AIDS
CD4 cells< 200/microliter
full blown immune deficiency
Susceptible to any infections
Immune Response
- Ab against HIV
- T cell responses to HIV
- Host immune responses can not clear HIV
Host immune Responses cannot clear HIV because
o Daily net loss of CD4 T cells immunodeficiency
o New variants hide from immune response and anti-HIV drugs
o Latency hide from immune response and anti-HIV drugs
o Syncytium rapid spread to other cells; also cell lysis
Clinical Diagnostic
• Test Ab against HIV by ELISA o If (+), confirmed by Western Blot o If (-), test again after 1-3 month “window”
Drugs
Cannot clear HIV
Only delay progress
Drug-resistant Variants
Cost, many pills/day, complex schedule
Vaccine
Some, but not so effective
No animal model except humans- big challenge to research
