Family Retroviridae Genus Lentivirus

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

Epidemiology- Transmitted 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

Treatment- First were nucleotide analogs like AZT Harsh side effects

Protease inhibitors- Replication 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.