HUMAN IMMUNODEFICIENCY VIRUS (HIV)

STRUCTURE OF HIV
THREE main structural genes: 1. Group Specific Antigen (gag)
p17, p24 codes for core proteins

2. Envelope (env)
gp120 binds CD4 for infection gp41 required for viral fusion with cell

3. Polymerase (pol)
Reverse transcriptase transcribes single-stranded RNA into doublestranded DNA Integrase inserts viral DNA into host DNA Protease cleaves itself and other enzymes and structural protein from polyproteins

PATHOGENESIS OF HIV

Transmission of HIV
Transmission of HIV including: During sex
May become infected if have vaginal, anal or oral sex with an infected partner.

Blood transfusions
HIV may be transmitted through blood transfusions.

Sharing needles
HIV can be transmitted through needles and syringes contaminated with infected blood.

From mother to child

Infected mothers can infect their babies during pregnancy or delivery, or through breast-feeding.

Mechanism of HIV
HIV enter the host cell via mechanism: 1. Binding and fusion
Fusion of HIV cell to host cell surface. HIV RNA, reverse transcriptase, integrase, and other viral proteins enter host cell.

2.
3.

Reverse transcription
Viral DNA is formed by reverse transcription.

Integration
Viral DNA is transported across nucleus and integrates into host DNA.

4.
5.

Replication
New viral RNA is used as genomic RNA and to make viral proteins.

Budding
New viral RNA and proteins move to cell surface and a new, immature, HIV virus forms.

6.

Maturation
Virus matures by protease releasing individual HIV proteins.

Binding and Fusion

Envelope proteins gp120 and gp41 bind to CD4+ cell receptors and coreceptors on CD4+ cells and macrophages. Chemokine receptors CCR5 and CXCR4 facilitate viral entry. T-cell tropic viruses require CXCR4 to bind and macrotropic viruses require CCR5. The joining of proteins and receptors and coreceptors fuses HIV membrane with CD4+ cell membrane and virus enters CD4+ cell and macrophage. HIV membrane and envelope proteins remain outside of CD4+ cell whereas the core of virus enters CD4+ cell. CD4+ cell enzymes interact with viral core and stimulate the release of viral RNA and viral enzymes reverse transcriptase, integrase, and protease.

Reverse Transcription
HIV RNA must be converted to DNA before it can be incorporated into DNA of CD4+ cell. This incorporation must occur for virus to multiply. The conversion of HIV RNA to DNA is known as reverse transcription and is mediated by HIV enzyme reverse transcriptase. The result is the production of a single strand of DNA from viral RNA. The single strand of this new DNA then undergoes replication into double-stranded HIV DNA.

Integration
Once reverse transcription has occurred, viral DNA can enter the nucleus of CD4+ cell. Viral enzyme integrase then inserts viral DNA into CD4+ cells DNA. This process is known as integration. CD4+ cell has now been changed into a factory used to produce more HIV.

Replication
New DNA which has been formed by the integration of viral DNA into CD4+ cell causes the production of messenger DNA that initiates the synthesis of HIV proteins.

Budding
HIV proteins and viral RNA, all components needed to make a new virus gather at CD4+ cell membrane to form new viruses. These new viruses push through the different parts of cell wall by budding. Many viruses can push through the wall of CD4+ cell. These new viruses leave CD4+ cell and contain all components necessary to infect other CD4+ cells.

Maturation
New virus has all components necessary to infect other CD4+ cells but cannot do so until it has matured. During this process, HIV protease enzyme cuts the long HIV proteins of virus into smaller functional units that then reassemble to form a mature virus. This virus is now ready to infect other cells.

 HIV can infect many types of cells. Table below gives a partial list of cells susceptible to HIV infection:

Immune Response to HIV

Innate Immune Response
Monocyte-Macrophage
In infected monocytes and macrophages, interleukin 1 (IL-1), IL-8, and tumor necrosis factor (TNF)- strongly upregulates viral replication of HIV-1. TNF- is cytokine secreted by T cells, NK cells, and macrophages.

NK Cells
NK cells are first line of defense to control virus by mediating the non-specific lysis of targeted cells. Strong adaptive immune response is activated that leads to T cell proliferation and reduction in viral replication through the release of various cytokines (IFN-, TNF-, and chemokines). Disruption of NK cell function can result in weakening of innate immunity of host during HIV infection.

Immune Response to HIV (cont.)

Adaptive Immune Response CD4+ T-cells
CD4 T cells are part of second line of immune system defense along with CD8+ T cells and B cells. CD4 T cells differentiate into effector T cells that activate their target cells through production of cytokines to help destroy pathogens. IL-2 is one type of cytokine secreted by an effector T cell that upregulates HIV-1 replication in certain cells. But it can also stimulate CD8+ T cells that result in suppression of HIV-1 replication in other cells.

REFERENCES
http://www.slideshare.net/JansellJaneReyes/13 acquired-immunodeficiency-syndrome-aids http://www.mayoclinic.com/health/hivaids/DS00005/DSECTION=causes http://www.aegis.org/Basics/HIV%20Replication %20Cycle.aspx http://www.bipai.org/Curriculums/HIVCurriculum/Pathophysiology-of-HIV.aspx http://pt851.wikidot.com/hiv-aids-cell-bio