HIV

 

World wide prevalence–some places only babies and grandparents alive.

 

first US cases 1981

 

now about 500,000 with 300,000 dead*

 

combo therapy has cut death rate about 4fold

 

HIV in Arkansas pdf

 

comparisons

 

the virus

 

the viral genome
I. Infects CD4 and macrophages [and mac-like cells like those in the brain] and intestinal epithelium. Impairs their function for
example,

 

nef decreases CD4 expression –compromises T cell function;

 

syncytia are fragile, easily lysed
Why infect these cells?
1. BINDING Virus has a receptor [determines both the host [species] and tissue tropism]
CD4 plus CXCR4 on T, plus CCR5 on mac so ATTACHMENT
2. TRANSCRIPTION –lots of viral DNA, RNA and protein made in these cells

 

HIV replication cycle
a. other viral infections in these cells often activate the HIV by acting on LTR [theirs and its]
b. growth signals [generic, antigen stimulation plus growth factors = lymphokines
c. tax gene product causes cells to make IL2, IL3, GM-CSF, and IL2R more virus,
thus more viral “apartments”
II. Alters antigenicity this includes by mutation to new forms
Error prone pol 1/2000 is error thus ~5/genome
a. immune escape especially gp120 [SU]
b. new tropisms, new disease characters
Course of infection
1. inf. Mac [CD4+CCKR5], these become major reservoir, WHEN lots of virus in blood=viremia
fatigue, flu-like symptioms, sometimes fever and big lymph nodes [l.n.].
2. T cells [CD4 + CXCR4], virus replicates in l.n., much less virus in blood until
l.n. destryed [down # CD4 T cells]
now immunosupression a symptom.
infection stages

III. Ways HIV can kill cells
DIRECT:
1. cDNA[lots] correlates with death [reason unknown]
2. increase permeability of cell mb
3. syncytia formation
4. induction of apoptosis [programed cell death]
INDIRECT:
5. opsonization and phagocytosis by mac, virus still infectious
6. CTL killing of HIV infected CD4 T cells
7. AntibodyDependent Cellular Cytotoxicity [ADCC] kill of mac and T
8. Death induced by high amounts of antigen stimulating the T cell receptor without
any other positive growth signals –death by the mechanism normally used to maintain
tolerance to self.

More on the non-structural proteins:

The HIV non-structural genes

 

Nef     1. initiates T cell activation. This enables persistent infection.

  1. Lowers the amount of CD4 and CD28 on CD4+ T cells. This lowers their specific immune responses and lowers infection by a second HIV virus  
  2. Decreases the expression of both MHC class I and MHC classII genes on antigen presenting cells. This lowers host immune function.

 

Vif       lowers the amount of a cellular protein [by ubiquinating it so it gets degraded] that would normally cause a hypermutation of HIV into a useless genome.

 

Vpr     1.Causes apoptosis in replicating cells

  1. needed for viral replication in non-dividing cells [such as macrophages]
  2. signals nuclear import and makes a pre-integration complex of the retrovirus genome
  3. immunosuppressive. Normally that is a proinflammator trans-activator that would go to the nucleus and activate genes, Vpr keeps it in the cytoplasm.

 

Tat     1. This is a molecule that in HIV promotes attachment to almost anything that has a membrane and also interacts with the actin in the cytoskeleton. So it is a key supplement for endocytosis of the virus. Biotech is exploring using the tat peptide to shuttle nano sized particles or even large DNA fragments into cells to deliver therapeutics.

  1. increases transcription of HIV double stranded RNA
  2. has a nuclear localization peptide signal, might cause apoptosis

 

 

Rev      regulation of virion expression product especially transfer of products from the nucleus to the cytoplasm. So without Rev only rev, tat and nef are made and spliced. With Rev the structural proteins and the RNA genome are made. This means it controls time dependent regulation of virion production.

 

AIDS has complications of the following infections and malignancies:

 

Kaposi’s sarcoma

 

pneumonia due to Pneumocystis carinni, a fungus that forms cysts

 

former leading cause of death in AIDS patients now prevented by medication. Most humans infected in early childhood

 

usual inf 2.5 y.o. and gone in a year

 

 

 

Toxoplasmosis

 

CMV –owl eyes in sections to blindness

 

Mycobacterium avium complex [M. kansasii, scrofulaceum,xenopi,szulgai,, ganavense, haemophilum,celatum] jointly called MAC