HIV

• Hiv-1- most common in U.S. and Europe
• HIV-2- prevalent in Africa (50% homology w/ HIV-1)
• Retroviruses- from DNA from RNA genome
• There are oncogenic (HTLV) and cytolytic (HIV)
• Lentiviruses- slow acting cytolytic retroviruses (HIV)

HIV Genome and Structure

• 9000 bp segment of s.s. RNA
• gene products are cleaved by HIV protease
• Important proteins
• gp120 & gp41 (precursor gp160)- envelope glycoproteins (env)
• group antigen proteins (gag)- p24 (major core protein) and p17 (forms scaffold during virion assembly
• pol proteins- p66 and p51 (form the reverse transcriptase), protease, and p32 (endonuclease)
• Regulatory proteins- tat, rev, vif, nef (regulate HIV virus gene expression and assembly

HIV replication and Gene expression

1.     Binding and internalization

• gp120 on the virion surface binds to CD4 on surface of CD4+ T cells.
• gp 120 is removed which exposes gp41. gp41 promotes fusion between the cell membrane and viral membrane
• as a result, the viral core is released into the cytoplasm of the cell
• On the other hand, Ab or C3b bound to the surface of the Ag can bind to Fc or complement receptors on macs resulting in antibody dependent enhancement
• other types of cell receptors can react w/ HIV, which allows infection of other cell type, but not with as much affinity as CD4.

2.     Reverse transcription and incorporation

• Reverse transcriptase
• results in D.S. DNA copy of the viral genome
• this DNA becomes circularized and then incorporates into the hosts genome

3.     Transcription and translation of viral genes

• host transcription factors as well as tat activate transcription
• large precursor proteins are cleaved intot their final products by HIV protease
• This is the step where protease inhibitors work

4.     Assembly and Budding

• viral core + RNA genome bud through the cell membrane to form infectious virion

5.     Latent infection vs. virus production

• Resting CD4+ T cells- usually Latent
• High levels of virus production requires cell activation by expression of HLA-DR and other Class II MNHC proteins
• Enhanced viral production linked to nuclear factor kappa B (NF-kB) and other host transcription factors
• Tissue macrophages are an important reservoir of infection

Clinical Course of HIV infection

• HIV infection and AIDS are not equivalent
• HIV progresses to AIDS in time usually

1.     8-12 years for sexually contracted

2.     less than that for blood transfusions

3.     < 1 year for congenital infection

Primary Infection

• sex, blood, maternal/fetal
• blood, semen, and other body fluids contain HIV, most sexual trans. dur to transfer of INFECTED CELLS; Virion and infected cell levels are highest during primary infection and late stages.
• sex trans. enhanced by tissue disruption or ulcerative diseases
• Primary infection symptoms (1-3 weeks post-exposure)- headache, retro-orbital pain, muscle ache, low to high grade fever, lymphadenopathy. Also maculopapular erythematous rash on trunk and extremeties
• 90% of HIV-infected patients have seroconverted within 3 mths of infection
• A small % may be sero (-) after 6 mths

VIRAL LOADS

Stage                     Virions/ml of blood

1^o infection                        5 x 10⁶

asymptomatic        8 x 10⁴

Early symptomatic 35 x 10⁴

AIDS                      2.5 x 10⁶

Asymptomatic Infection (Category A)

• appear healthy
• normal CD4+ levels and normal immune responses
• involves MASSIVE TURNOVER of both new virions and newly produced CD4+ T cells

Early Symptomatic Infection- (Category B)

• CD4+’s begin to decline in number
• count is between 200-499 per mL
• CD4+ function declines before numbers do
• accompanied by fever, chronic diarrhea, oral or persistent vulvovaginal candidiasis, etc.

Late Symptomatic Infection- AIDS (Category C)

• AIDS defintion- HIV infection with occurrence of unusual infections, tumors, or other manisfestations, or blood CD4+ cell level of less than 200 per mL of blood
• Infections usu include: Pneumocystis carinii, fungal infections, TB, M. avium, Herpes, CMV, parasitic
• Tumors- Kaposi’s sarcoma, cervical cancer, lymphomas
• HIV-related encephalopathy, progressive multifocal leukoencephalopathy, generalized wasting

HIV infection and the IMMUNE RESPONSE

Ø  virtually every area of immune system involved in combat

Ø  remember CD4+’s important in DTH and Helper cells

Antibody Responses

1.     Ab against a variety of HIV proteins are expressed following 1^o infection

a.  These can be detected by ELISA or Western Blot

DIAGNOSTIC —TWO POSITIVE ELISAs WITH A POSITIVE WESTERN

BLOT!!!!!!!!!!!

b. SIX month repeats

2.     Neutralizing activity- some anit-HIV Ab can inactivate the virus through ADCC; targets gp120 and 41

3.     Anti-gp 120 Ab can increase the infection by Antibody Dependent Enhancement (ADE)

4.     Immune complexes can also increase the efficiency of the infection

5.     during late infection,  not just CD4+ cells are diminished, but Ab levels decline also

6.     Vaccination protocols due to ADE

CD4+ T Cell responses- help and DTH

1.     principle target

2.     remember that even though patient is asymptomatic, CD4+’s are getting blown away so the CD4+ factory workers are working overtime to kepp the production number up.

3.     After a certain time, you can’t make them fast enough, productivity declines, here comes the symptomatic phase

4.     When CD4+ counts are below 200, watch out, no DTH or helper activities in force.

5.     Remember, contrary to popular belief, some CD4+s have cytotoxic activity and can combat infection (Undercover agents)

6.     TH₁ cell cytokine production declines long before numbers decrease (IL-2, IFN-g) and TH₂ cytokine production increases (IL-4, IL-10)

CD8+ T Cell Activities- cytotoxicity and antiviral activity

1.     CD8+’s can kill HIV infected cellsÞ CTL activity is high during asymptomatic phase and decreases with progression of the disease

2.     T_CTL cells can kill non-infected CD4+ cells

• soluble gp120 binds to receptors on CD4 uninfected cells which results in expression of fas. fas ligand on T_CTL cells will thus bind and cause apoptosis
• see fig on p. 22.8

3.     Cell Antiviral Factor- (CAF) inhibits HIV replication in infected cells without killing the cells.  Expressed by CD8+’s

Tags: aids immunology, cervical cancer, clinical cours HIV, CMV, early symptomatic Infection, encephalopathy, fungal infections, generalized wasting, herpes, HIV infection, Kaposi's sarcoma, Late Symptomatic Infection, lymphomas, M. avium, parasitic infection, Pneumocystis carinii, primary infection, progressive multifocal leukoencephalopathy, TB, tumors

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