BIOL 4576 1st EditionExam # 4 Study Guide Lectures: 12-16Lecture 12 HIV/AIDS-associated neurologic disease (opportunistic infections)Normal CD4 T-cell count: 700-1000 cells per microliter of bloodHIV count: greater than 500AIDS count: less than 200AIDS: acquired immunodeficiency syndromeHIV: human immunodeficiency virusThe depression of immunity in AIDS allows for opportunistic infections to invade. These may be infections that would not normally cause disease in a healthy person. Opportunistic infections are the most common complication of HIV.PMLProgressive multifocal leukoencephalopathy is caused by JC virus. JC virus antibodies are found in 70% of people and it usually acquired in childhood due to the fact that it is transmitted fecal orally. It is a polyomavirus that has dsDNA and minichromosomes. Symptoms:- fast behavioral and cognitive changes- No headaches or fever- Later: cortical blindness (problems in the occipital lobe not retina) and paralysis- Death in 1 yearPathology- Focal demyelination: lesions all over brain including brainstem and cerebellum- CSF normal- Oligodendrocytes have enlarged nuclei with inclusion bodies- Changes in astrocyte morphologyPathogenesis- JC virus enters brain either inside infected macrophages or infection of astrocyteswhich then spreads to oligodendrocytes- Doesn’t infect neurons- A LOT of virus in the brainDiagnosis and treatment- MRI shows white matter lesions in parieto-occiptal lobe- Viral DNA can be detected in some patients by PCR- cART (combo antiretroviral therapy) extends survival for another yearCMVCytomegalovirus is a beta herpesvirus that is found in 80% of people but doesn’t usually cause symptoms. It is spread through the respiratory route. It can also cause mono or a congenital disease called cytomegalic inclusion disease. It goes latent in macrophages. In AIDS, it causes hepatitis, colitis, retinitis, and neurologic diseases.Neurologic disease: it invades the brain through infected macrophages or it disseminatesthrough the CSF. It infects all types of brain cells including neurons, ependymal cells, and oligodendrocytes. It can have 2 different pathologies once the brain is infected. It can have a slow progressive panencephalopathy that causes death in 1-2 years. It can also infect ependymal cells that cause ventricle enlargement and brain herniation which results in death with weeks to months. HSVBoth HSV1 and 2 cause diseases that are different from the diseases that they cause in immunologically normal people. It causes 3 patterns of disease. 1. acute necrotic hemorrhagic disease in the temporal lobes caused by HSV22. chronic subacute panencephalitis without the temporal lobe caused by HSV13. subclinical infection of brain parenchyma by HSV1CMV and HSV can infect the same person at the same time. Lecture 13 HIV/AIDS-associated neurologic disease (HIV associated dementia)VisnaRetrovirus, lentivirus: enveloped, conical capsid, linear ssRNA, RDDP/RNA dependent RNA polymerase/reverse transcriptaseCharacteristics: 2 identical copies of genome per capsid, RNA converted to DNA after entry but before uncoating, a DNA copy called a provirus is integrated randomly into the host genomePathogenesis: it is spread horizontally via the respiratory route and vertically. It infects macrophages and it carries the provirus. It incubates for a long time (2-7 years). The immune system fails to clear it but there is no immune suppression. It enters the CNS through infected macrophages that then causes meningoencephalitis. The virus replicates in many cells in the CNS but mostly microglial cells. Pathology: white matter of brain and spinal cord- a lot of mononuclear infiltrates- gliosis (scar tissue) of astrocytes- microglial nodules: large clumps of microglial/monocyte cells- areas of demyelinationOnset of neurological symptoms is slow and without fever. It can have progressive or intermittent paralysis that occurs over months. CSF has pleocytosis and local antibody synthesis.Maedi: the respiratory disease that can be caused Visna virus. There are lesions with mononuclear cells around them in the interstitial space of the lungs. Visna and Maedi can affect the same sheep.HIVRetrovirus, lentivirus: 3 protein groups- gag-structural proteins, pol-enzymes, env-envelope proteins, regulatory genes- Tat: it increases transcription or DNA provirus. its released from infected cells andcan be up taken by other cells which will then kill them. - Nef-it increases viral replication, changes protein expression on cell surfaces, decreases MHC1 expression, and prevents apoptosis.Macrophages and CD4 T-cells are the target for HIV. CD4 is the primary receptor and it binds to viral receptor gp120. There are also coreceptors that are found on these cells that are usually for chemokines. These receptors bind to viral receptor gp41. The coreceptor on T-cells isCXCR4 and the macrophage one is CCR5. The macrophage tropic strain is called R5 and the T-cellone is called X4. HIV associated dementiaHIV enters the brain at or before 2 weeks after infection. HIV DNA and proteins can be recovered from the CNS at all points during infection after ~2 weeks. The symptoms usually associated with this are flu-like as well as headache, photophobia, and nuchal rigidity. The immune system usually keeps this in check but when AIDS hits, that is no longer possible. Symptoms: abrupt onset over weeks to months1. Forgetfulness and behavior changes2. Loss of motor control 3. Global cognitive dysfunction, spastic, incontinent4. Death within 3-6 yearsNeuropathology: - tissue wasting/deepened sulci- syncytia- microglial nodules- focal myelin lossNeuropathogenesisHIV entry into brain: HIV enters the brain through infected macrophages and CD4 cells. Viruses can also enter through direct infection of epithelial cells or astrocytes. This infection can cause disturbances in the BBB. Infection can cause release of TNFalpha which causes leakage. Tat can upregulate cell adhesion molecules which allows more macrophages to enter the CNS. Tat and gp41 production due to infection can cause the BBB to lose integrity. Also, the immune system secretes molecules which recruit more macrophages to the BBB.HIV neurotropism: when the virus enters the brain, the R5 macrophage strain emerges. Once there, it infected many types of cells like oligodendrocytes but not neurons. There are different cellular receptors in the brain. GalC is most likely to be the