Retroviruses and HIV

Retroviruses

Family gets its name from reverse transcriptase

Several human pathogens

Human T-cell Leukemia Virus 1-5 (HTLV)

Human Immunodeficiency Virus (HIV)

RNA genome is converted to DNA genome (multiple benefits)

HIV

Causes AIDS and ARC in humans

Two types HIV-I (more virulent) HIV-II (more frequently associated with non-progression)

Both originated in Africa

HIV closely related to other slow lentivirus such as SIV HIV-I and SIVcpz are closely related HIV-II and SIVssm are closely related (suggest that human and primate lentivirus reflect recent divergence)

Earliest documented human infection in 1959 (some cases may have been early 1930s or 40s)

Genome

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

Produces 3 mRNA molecules

Produces 3 polyprotein Gag, Pol, and Env

Gag: cleaved by viral protease to produce capsid, matrix, and nucleoprotein

Pol: cleaved by viral protease to produce protease, reverse transcriptase, and integrase

Env gp 160: cleaved to produce gp 120 and gp 41

Reverse Transcriptase

Three activities

RNA dep DNA polymerase (Uses +RNA to produce -cDNA)

Ribonuclease (degrades RNA genome while producing cDNA)

DNA dep DNA polymerase (uses -cDNA to produce +cDNA strans)

Viral genome integrase then integrates DS DNA genome into host chromosome

Persistent presence of viral genome in host cell

From +RNA to dsDNA

Structure

Enveloped virus with trapezoidal capsid

Also has small nucleoproteins associated with genomes

Envelope glycoprotein comprises two regions

TM (transmembrane portion stem) gp41

SU (surface structure club gp120 (attachment) must be distorted

Functional protease and integrase proteins are present with capsid

Structure assembles in a noninfectious form and matures after budding from host cell

Target Cells

Primarily infects CD4 positive cells so Th cells and macrophages

Evidence suggest macrophages may be infected first (virus undergo evolution in host) M-tropic HIV, transmission

Severe immune compromise when jump to T-cells (T-trophic) faster replication rates and increased virulence

Attachment

Gp120 binds to CD4 and coreceptor (CXCR4 for T-tropic, CCR4 for M-topic)

Binding CD4 causes conformational change that allows binding of coreceptor, binding then 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

Replication

Virus enters by fusion and uncoats

Genome is converted to dsDNA by reverse transcriptase

dsDNA enters nucleus through nuclear pore

Viral protein integrase integrates viral genome into host chromosome

Exit by budding exocytosis

Proteolytic cleavage required for maturation (occurs during budding or after, required to produce infectious particles)

Pathogenesis Stage 1

Acute stage

Initial days after infection

Flu-like symptoms, malaise, myalgia, fever,

Rapid viral replication during this time resulting in viremia

Cellular response reduces viremia after 2-3 weeks (increase in CD 8+)

Strong antibody production

Usually not discovered in this phase

Pathogenesis State 2

Asymptomatic phase

No obvious symptoms but may experience occasional fatigue or viral disease

May last 2 to 20 years

Virus tends to be extensively M-tropic in this phase

Pathogenesis Stage 3

Symptomatic Phase

Mutation results in T-tropic form of virus

Decrease in CD4+ T cells (200-500 cells/ml)

Reactivation of latent infections (VZV, Mycotubuerculosis)

Auto-immune disease due to B cell/T cell imbalance

AIDS

Pathogenesis Stage 4

Late symptomatic phase

Further decrease in CD4+ T cells )less than 200/ml)

CD8 cells also diminish

New infections by rare opportunistic pathogens

ARC

Transmission

Transmitted by body fluids

Blood plasma and semen are most common

Typically transmitted as STD

IV drug use and transfusion are less common

Demographics

70% of HIV infected are MSM

10% are IV drug users

20% are heterosexual who do not use IV drugs (many have MSM parters)

Other parts of work HIV is heterosexual (sex workers)

Prevention

Virus is not casually transmitted

Information behavioral changes is powerful (safe sex, screening, no sharing needles)

Vaccines (several trials, promising)

Treatment

HAART (Highly Active Anti-Retroviral Treatment)

Includes non-nucleoside reverse transcriptase inhibitors

Nucleoside reverse transcriptase inhibitors

Protease inhibitors

Entry inhibitors

Integrase inhibitors

Remarkably successful (life expectance went from 3 years to decades)

Public Health Approaches

Decrease transmission rates can select for virulent viruses

Public education and public health measures have had great effects

Education of gay communities in US diminished transmission rate (reversing)

Needle exchange programs

Screening for sex workers

Screening donated blood