Download HIV Infections

HIV Infections
4/17/13
Family Retroviridae Genus Lentivirus
Enveloped virus with trapezoidal capsid
RNA virus-two copies of + RNA in each particle
Each is bound to reverse transcriptase enzyme
Uses reverse transcriptase to convert RNA genome into DNA when in host cell
Reverse transcriptase has 3 activities
RNA-dependant DNA polymerase.
Uses + RNA to produce – cDNA
Ribonuclease
Degrades RNA genome while producing cDNA
DNA-dependant DNA polymerase
Uses –cDNA to produce + cDNA strand
Co-discovered by Gallo and Montagnier
Several names before HIV formalized (seen in older literature)
HTLV-III, ARV, LAV
Two types identified
HIV-I is more virulent, HIV-II is more frequently associated with non-progression
Both originated in Africa
Phylogenetic analyses have demonstrated 3 distinct groups of HIV-I
M group contains most HIV-I strains
O group contains outliers
N group between the two
Oldest documented human infection1956
HIV closely related to other slow lentivirus such as SIV
HIV-I and SIVcpz are closely related
HIV-II and SIVssm are closely related
This suggests that human and primate lentiviruses reflect recent divergence.
Earliest human infections may have been in late 1930s or early 1940s
EpidemiologyTransmitted by bodily fluids
Blood, plasma, and semen are most common
Urine, sweat, saliva, and vaginal secretions are less common
Typically transmitted as STD
IV drug use and transfusions are less common
US represents skewed system compared to rest of world
In US half of HIV infected are homosexual males
Worldwide only 10% are homosexual males
In US one third are IV drug users
Worldwide only 10% are IV drug users
Worldwide HIV infects heterosexuals
Routes of expansion often associated with industry
Africa-mine workers
China-trucking routes
Virulence and evolution
Rapid transmission rates allow pathogens to increase in virulence
More damaging to host in same time period
More likely to be transmitted during that same time
HIV was model organism
HIV transmitted by “professional sex workers” tends to be much more
virulent
Decreasing transmission rates can select for less virulent viruses
Selection at the cost of those currently infected
Public education and public health measures have had great effects
Education of gay community in US diminished transmission rate
Unfortunately this trend is reversing
Needle exchange programs also successful
Infection-general retroviral life cycle
Primarily infects T cells and macrophages
Evidence suggests macrophages may be infected first (M-tropic HIV)
M-tropic HIV replicates slowly, but is probably the virus that is transmitted
Evolution of glycoprotein structure results in viruses that infect T cells (T-tropic
HIV)
T-tropic HIV replicates faster and has increased virulence.
Envelope glycoprotein comprises two regions
TM-transmembrane portion (stem) gp41
SU-surface structure club gp120
Gp120 binds CD4 and coreceptor
CXCR4 is coreceptor for T-cell tropic HIV
CCR5 is coreceptor for macrophage tropic HIV
Binding CD4 causes conformational change that allows binding of coreceptor.
Binding of coreceptor causes conformational change that exposes gp41
Gp41 acts as fusion protein when in close contact with host cell membrane
CCR5 deletions are present in population and provide resistance to HIV infection
No obvious immune defect associated with deletion
Virus enters by fusion and uncoats
Genome is converted to DS DNA by reverse transcriptase
DS DNA enters nucleus through nuclear pores
Viral protein Integrase integrates viral genome into host chromosome
Produces 3 mRNA molecules
9 kb mRNA-produces Gag and Pol proteins
Gag is cleaved by viral protease to produce capsid, matrix, and
nucleoprotein
Pol is cleaved by viral protease to produce capsid, matrix, nucleoprotein,
protease, reverse transcriptase, and integrase
4 kb mRNA produces Env proteins
gp160 is cleaved to produce gp120 and gp 41
2 kb mRNA produces regulatory proteins
Viral particles are assembled with uncleaved proteins
Cleavage called maturation
Occurs during budding or after budding
Maturation is required to produce infectious particles
Course of Infection
Acute phase-initial days after infection
Flu-like symptoms:malaise, myalgia, fever, etc.
Rapid viral replication during this time resulting in viremia
Cellular response reduces viremia after 2-3 weeks (increase in CD 8+)
Strong antibody production
Asymptomatic phase
No obvious symptoms but may experience occasional fatigue or viral disease
May last from 2 years to 20+ years
Symptomatic phase
Decrease in CD4+ T cells (200-500 cells/ml blood)
Reactivation of latent infections (VZV, Myco tuburculosis, etc.)
Auto-immune disease due to B cell/T cell imbalance)
Late symptomatic phase
Further decrease in CD4+ T cells (under 200/ ml)
CD8+ cells also diminish
New infections by “rare” opportunistic pathogens
Fungal-candida albicans, Histoplasma capsulatum, Cryptococcus
neoformans
Viral- Herpes viruses are common (HSV, EBV, HHV8 Kaposi’s sarcoma)
Bacterial-Mycobacteria avium-intracellulare, Treponema pallidum,
antibiotic resistant Gram +
Parasites-Pneumocystis carinii, protozoans
Neurological damage as well
Prevention-avoid transmission
Abstinence, condoms, monogamy, no IV drug use, self-transfuse
TreatmentFirst were nucleotide analogs like AZT
Harsh side effects
Protease inhibitorsReplication requires viral protease to function
RT inhibitors
Cocktails include multiple classes of drugs
Vaccines
Several in trials unlikely that any will be used in next 5 years.