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Hiv
Hiv
Hiv
HIV
(VACCINE DEVELOPMENT & PRODUCTION)
INTRODUCTION
H.I.V. stands for Human Immunodeficiency Virus. Discovered in 1984 and named HIV in 1986. A retrovirus (capable of converting RNA into DNA by Reverse transcriptase enzyme) Causes A.I.D.S. (Acquired Immune Deficiency Syndrome) in humans in which the immune system of the body fails leading to life threatening opportunistic infections and various un-usual tumors. HIV infects the Helper T (CD4) cells to which it binds First reported in young homosexual males but later found in nonhomosexuals possibly by blood transfusion.
Structure of HIV
VIRAL ENVELOPE
Outer coat of the virus .Diameter of 1/10000 of a millimeter. Spherical in shape. Composed of 2 layers of fat, called lipid. Recent evidence suggests HIV may Enter or exit cells through LIPID RAFTS present on cell membrane. 72 spikes on average made of complex protein protrude from the virion surface. This protein is called ENV made of a Cap of Glycoprotein 120 and a stem of GP41. Primary focus of VACCINE development
Viral Core
Bullet shaped core called Capsid made of 2000 copies of a protein called P24. Capsid protects 2 single strands of HIV RNA,each with a copy of 9 genes. Gag, Pol and Env gene encode for structural proteins. 6 regulatory genes control viral replication. Include; Vif, Rev,Nef,Tat,Vpu,Vpr.
Other core protein include: p7- HIV nucleocapsid protein, and 3 enzymes- Protease, Reverse transcriptase,integrase. p17 lies between protein core and envelope and is embedded in the internal portion of the envelope. Two additional p55 products, p7 and p9, are nucleic acid binding proteins closely associated with the RNA
Genome
Structural genes
gag-group specific antigen gene, encodes viral nucleopcapsid proteins: p24, several internal proteins, p7, p15, p17 and p55. pol-polymerase gene; encodes the viral enzyme, protease (p10), reverse transcriptase (p66/55; alpha and beta subunits) and integrase (p32). env-envelope gene; encodes the viral envelope glyocproteins gp120 (extracellular glycoprotein) and gp41 (transmembrane glycoprotein).
Regulatory genes
tat: encodes transactivator protein rev: encodes a regulator of expression of viral protein vif: associated with viral infectivity vpu: encodes viral protein U vpr: encode viral protein R nef: encodes a 'so-called' negative regulator protein
Mechanism of pathogenesis
Viral infection
First step, HIV attaches to susceptible host cell.
helper T cells macrophages monocytes B cells microglial brain cells intestinal cells
ATTACHMENT
HIV binds to receptors on CD4 T-cell A message is sent to the CD4 T-cell to let the virus in
FUSION
Once bound, the virus is allowed to dump its contents into the CD4 T-cell Included in its contents are HIV RNA and reverse transcriptase
REVERSE TRANSCRIPTION
The HIV RNA is turned into double-stranded DNA within the CD4 Tcell The enzyme reverse transcriptase aids in this process
INTEGRATION
Once the DNA is formed, it hides itself in the human DNA housed in the CD4 TCell nucleus
TRANSCRIPTION
Copies of HIV DNA are made and released from the nucleus in small packages Each of the small packages contains information for creating a new HIV
ASSEMBLY
The protease enzyme in the cell combines the DNA packages to create active virus
BUDDING
Once the new HIV is formed, it pushes itself out of the CD4 T-cell The virus steals part of the CD4 T-cells protective coating
Viral-host Dynamics
About 1010 (10 billion) virions are produced daily Average life-span of an HIV virion in plasma is ~6 hours Average life-span of an HIV-infected CD4 lymphocytes is ~1.6 days HIV can lie dormant within a cell for many years, especially in resting (memory) CD4 cells, unlike other retroviruses
2. Syncytium formation gp120/41 proteins on infected cells bind to CD4 receptors on normal cells, causing cell fusion. The giant multi-nucleated syncytium dies before long.
3.Apoptosis An infected helper T cell can direct an uninfected T helper cell to undergo apoptosis (programmed cell death). Apoptosis can be normal, for example, to eliminate auto-reactive T lymphocytes to establish self-tolerance
Sexual transmission
Contaminated needles
Mother to fetus
Stage 1 - Primary
Short, flu-like illness - occurs one to six weeks after infection no symptoms at all Infected person can infect other people
Stage 2 - Asymptomatic
Lasts for an average of ten years This stage is free from symptoms There may be swollen glands The level of HIV in the blood drops to very low levels HIV antibodies are detectable in the blood
Stage 3 - Symptomatic
The symptoms are mild The immune system deteriorates emergence of opportunistic infections and cancers
Vaccine strategies
peptide vaccine: made of tiny pieces of proteins from the HIV virus. recombinant subunit protein vaccine: made of bigger pieces of proteins that are on the surface of the HIV virus. Examples of a recombinant subunit protein are gp120,gp140, or gp160 produced by genetic engineering. DNA vaccine: uses copies of a small number of HIV genes which are inserted into pieces of DNA called plasmids. The HIV genes will produce proteins very similar to the ones from real HIV
live vector vaccine: non-HIV viruses engineered to carry genes encoding HIV proteins. The genes are inserted into another vector, which carries them into the body's cells. The genes in turn produce proteins that are normally found on the surface of the HIV virus. Vaccine combination: uses any two vaccines, one after another, to create a stronger immune response. Often referred to as "prime-boost strategy. Virus-like particle vaccine (pseudovirion vaccine): a non-infectious HIV look-alike that has one or more, but not all, HIV proteins.
Protocol Number
HVTN 055 HVTN 065 HVTN 060
Number of Participants
150 120 144
Testing Locations
USA USA USA, Thailand
Producer
Therion GeoVax Wyeth Bavarian Nordic A/S Pharmexa-Epimmune NIH VRC Merck Epimmune
HVTN 067
108
USA
HVTN 073
48
HVTN 069 HVTN 049 HVTN 071 HVTN 050 HVTN 070 HVTN 063 HVTN 503
USA, Peru USA USA International USA USA, Brazil South Africa
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