AIDS #3

symptomatic phase of HIV

detected at or below 350 cells/ul

pathologies (early OIs) start to be seen

cell count when you get AIDS

< 200 CD4 cells/ul, host is vulnerable to AIDS defining OIs

> 350 cells/ul

malignancies, direct effects of HIV on brain

asymptomatic phase

CDC definition of AIDS

be HIV positive

have CD4 count of <200 cells/ul

have any variety of pathologies that are considered AIDS-defining illnesses

AIDS defining illnesses categories

viral, bacteria, fungi, protozoa

also worst OIs are only seen at very low CD4 cell count which is rare in US

neurological disease and malignancies can occur at higher CD4 count

factors that affect HIV disease course

viral load

host factors (overall physical health, immune response, extent of lymph node damage during acute infection, CCR5 levels and ligand diversity)

• low level of CCR5 means more reistant to immunodepletion

comorbid conditions (other bad pathogens exacerbate disease)

health consequences of ARV managed HIV (these will persist despite ARV)

associated with heightened inflammation (which can lead to scarring which makes it harder for cells to move and communicate with each other aka compromising immune system function), excess risk of cardiovascular disease (due to medication), cancer, neurocognitive dysfunctions

immune system fails because there is collateral damage to immune tissues

acute HIV infection decimates CD4 in gut (major place of HIV infection) and so gut mucosa remains damaged throughout HIV infection

chronic exposure of gut to pathogens yields chronic activation of immune responses which causes collateral damage to uninfected CD4 and CD8 cells

lymph nodes suffer structural damage over time

SIV

animals can be chronically infected but don’t develop AIDS

health levels of peripheral CD4 cells are maintained

less chronic immune activation

mucosal CD4 cells are initially depleted but no progressive loss

memory CD4 cells resist infection due to lower CCR5 lebels

less damaging to mucosal immune system overall

bystander apoptosis

killing of cells nearby that were not intended to be killed

low grade and part of chronic inflammatory response

(a contrast to cytokine storm which is a profound acute inflammatory response)

causes death of neurons (not opportunistic, due to HIV in brain)

can cause HIV related dementia

lymph node/lymphoid tissue destruction: chronic (ongoing) infection yields

involution (return of enlarged organ to its original size; for this it is excessive) of germinal center (inside lymph node and where B cells proliferate)

break down of the follicular dendritic cell network which in germinal centers release the HIV particles that they accumulated on their surfaces

• scar tissue building up and affects entire node, compromises ability of B cells to do their job and for cells to move around so downstream consequence of scarring

immune reconstitution inflammatory syndrome (IRIS)

immune reconstitution can be dangerous and you have to treat OIs before giving a patient ARVs

can occur in newly diagnosed HIV+ patients with very low CD4 < 50 cells/ul

a condition where an exaggerated inflammatory response occurs after the immune system improves, often due to antiretroviral therapy (ART) in people with HIV. This inflammatory response can lead to a worsening of existing infections or the appearance of new ones

overly exuberant immune response to pathogen is tissue inflammation at site of infection can cause tissue inflammation at site of infection

likelihood of IRIS depends on type of pathogen and what cells are helped by T cells

• macrophages - fungal infections, intracellular bacteria (TB)

lethality of IRIS depends on site in body

• brain: tightly enclosed space

• lung: breathing

• liver: inflammation is bad

antibiotic prophylaxis (common antibiotics) plus ARVs can be used for initial treatment of AIDS patients

TMP-SMX (Bactrim)

Minocycline

Bactrim (TMP-SMX)

early antibiotic which is combination therapy

many people take it and is well tolerated

take for > 72 weeks

used against pneumonia (bacterial), toxoplasmosis (apicomplexan), reduces frequency of malaria (apicomplexan)

targets bacterial dihydrofolate reductase (DHFR)

minocycline

anti-inflammatory used for acne

reduces T-cell activation

inhibits HIV release from latently infected memory T cells

early oral symptoms at CD4 200-350 cells/ul

thrush → can spread down throat and into esophagus, swallowing will be painful

Hair leukoplakia (Epstein-Barr virus, herpes) → not painful and change in taste perception

aphthous ulcers (canker sores) → very painful and can be chronic

early dermatological symptoms at CD4 200-350 cells/ul

shingles (Herpes zoster, re-eruption of chickenpox virus) → chickenpox goes into latent form in nerves and when reactivated, outbreak of herpes blisters along where nerve path is; very painful

catc-scratch (Bacillary angiomatosis, bacterium)

early genital symptoms (female)

yeast infection → overgrown yeast

cervical dysplasia (human papilloma virus) → pre-cancerous cells in cervix; If virus proliferation is not being kept in check by CD4 cell activity on the various killer T cells, you will see evidence of cervical dysplasia

salmonella infections (intracellular bacterium)

GI symptoms (severe)

flu-like symptoms

neurological disorders associated with HIV

not an OI

direct consequences of HIV infection

• HIV-associated cognitive disorder (HAND)

• peripheral neuropathies → erroneous sensory information; problems in spinal neurons and tinging/burning/numbness in extremities

opportunistic infections

• cryptococcal meningitis (fungus)

• toxoplasmosis (parasite; latent infection)

• JC virus (virus; latent infection)

Almost every AIDS patient has brain damage post mortem

HIV associated dementia

blood-brain barrier

brain has 2 layers of cells

• capillary lining makes tight boundary

• second layer of cell fencing around capillaries made up of astrocyte cells

monocytes (PBMCs, undifferentiated that will turn into macrophages and dendritic cells), B cells, and some medications can go in but T CELLS CANNOT

Trojan Horse hypothesis

HIV enters CNS by infected PBMCs that go into brain and produce HIV

HIV in brain impacts

macrophages, microglia (type of macrophage), astrocytes (glia)

does not infect neurons

CNS can evolve separately from circulating forms and infected cells in brains are a reservoir distinct from memory T cells

initial infection usually asymptomatic but can cause early encephalitis or meningitis

If you can’t detect HIV in blood, you can’t get it in the brain → undetectable = untransmittable even in your own body

• however, CNS inflammation can occur even with undetectable viral load in cerebreospinal fluid (CSF)

progressive multifocal leukoencephalopathy

demyelination (holes in multiple areas of brain)

rapid and aggressive progression

• develops over days or weeks

• death in weeks to months

Symptoms depend on affected area but generally clumsiness, weakness, and acting different

Diagnosis

• tricky cause a lot of symptoms are also true for other pathologies

• you look for JC virus in CSF

• you can look at MRI

• best way is brain bopsy

Treatment

• HAART helps have people

• CAN CAUSE IRIS

Prognosis

• 50% of patients are cured but may have long term brain damage

Severe combined immunodeficiency syndrome (SCID)

no T or B cells so need to be protected from everything

B cells make antibodies and CD8 kill infected cells for

some chronic virus infections (herpes and papilloma)

intracellular protozoa (apicomplexa)

cytokines stimulate macrophages to kill pathogens for

intracellular bacteria (mycobacteria in lung and gut, salmonella in gut)

fungi (extracellular like candida, pneumocystis and cryptococcus)

toxoplasmosis

most common CNS OI

CD4 < 100 cells/ul

caused by toxoplasma gondii

• protozoan parasite

• present worldwide si common endemic

90% of Parisian adults have Abs and 1/3 of humans carry encysted parasites in muscle and brain

sources of exposure: uncooked meat, cat litterbox, produce harvested near cat feces, raw shellfish harvest downstream of cat feces

Apicomplexan parasites

morphological specialization at apical end

• allow parasites to crawl along surfaces and burrow into cells

• apical complex has organelles that contribute to attachment and invasion of host cell, and establishment of internal vacuole where it divides

allows for invasion, gliding motility, and other specialized behaviors

include malaria, toxoplasmis, and a bunch of gut things

You start with oocyst (egg) which is ingested in both and is very stable. This gets into (excysts) in host bowel and then releases 4 sporozoites and the apical surface of those will allow them to to hang at apical surface of cells. This makes them become trophozoite and they can then divide further, have names, and then proliferate.

• sporozite associates with intestinal epithelial cell surface

• becomes trophozoite intracellular at apical surface and trophozoite divides forms meront structure which can get released and infect other cells

Names would be like tachyzoite, trophozoite, mereozite and this mitotically divide form can form a meront which has 8 that infect more cells

• zoites are mobile and can spread from cell to cell

merozoites can exit gut and infect muscle and brain

latent infection is controlled in immunocomponent host because CD8 T cells kill cells that present Ags via MHC I and CD8 cells also invade cysts to kill Toxo directly

unchecked Toxo replication in brain (or fetus) can cause severe pathology

bradyzoites are the slowly proliferating form in muscle and brain

merozoites differentiate into gametes and can fuse to form diploid zygote but then undergoes meiosis (divide into 4 haploid sporozoites which are packaged into oocyst which is then released in feces of cats)

toxoplasma form cysts containing ___ in host muscle and brain

bradyzoites

CD8 control by killing this

PV = parasitophorous vacuole

formed by secretion of special lipids

how toxoplasma goes into the intestinal mucosal epithelium

HIV associated toxoplasmosis treatment

anti-parasitic drugs like pyrimethamine and Daraprim

HAART to restore CD4 cells

if no obvious symptoms or lesion, you can give TMP-SMX antibiotic prophylaxis if they have Toxoplasma Abs

treatment discontinued once CD4 > 6 months without viral load

IRIS not issue because the drug kills parasite directly

dihydrofolate reductase (DHFR)

important metabolic enzyme in cells that is responsible for making folic acid which is needed for a white variety of molecules → if you inhibit, you can’t get folic acid and so cells die because they can’t make their normal molecules

• interfere with bacterial synthesis of folic acid

targeted by TMP-SMX

crytpococcal meningitis

dessicated spores rehydrated in lung

capsule interferes with normal uptake and Ag presentation by macrophages

can get across blood brain barrier and infected macrophages can bring them across

CD4 < 100

symptoms

• nausea, headache, fever, confusion

Diagnosis

CAT scan or MRI for brain atrophy

fungus in CSF via India ink stain

• cryptococcal antigen in CSF are best indicator

treatment is anti-fungals

can possible lead to IRIS so antifungals for 2-10 weeks before ARVs

pneumocystis pneumonia (PCP)

caused by Pneumocystis jirovecii

most humans exposed early in life

symptoms include fever, night sweats, malaise, weight loss which are all nonspecific

the more specific symptoms include non-productive cough and dyspnea (shortness of breath)

Diagnosis can be hard

chest x-ray doesn’t always reveal various pathologies

sputum analysis may reveal fungi

Bronchoscopy and BAL (bronchoalveolar lavage) yields results half the time

treatment

TMP-SMX which cures initial infection but relapse rate is high

bacterial pneuomonia: streptococcus pneumoniae

very common

recommended for people to get vaccine

diagnosis:

x-ray opacity

sputum sample

culture bacteria from blood

Treatment

antibiotics

if PCP is suspected cause of dry cough you can augment with TMP-SMX

Legionella pneumophila

Legionnaire’s disease

occasional

Haemophilus influenzae

childhood meningitis

Hib vaccine

Myobacterium avium complex (MAC)

uncommon

lung disease

usually precedes GI disease

Tuberculosis

caused by Myobacterium tuberculosis

historically associated with povery and easily spread from person with active TB to another

provided basis for Koch’s postulates of infectious disease

vaccine since 1921 but reemerged in mid 1980s and new vaccine needed

treatment issue is lack of compliance to drugs *usualy one or two because multi drug resistant with MDR TB)

• also problem is many TB drugs induce cytochrome P450 so pepatotoxicity

granuloma

pocket of bacteria surrounded by other material like collagen and immune cells to wall off this pocket

protects intracellular bacteria like for TB

Mycobacterium tuberculosis (MTb)

in soil

many genes are devoted to lipid synthesis which contributes to maintenance of chronic latent infection

How Tb remains latent

Tb Ags are hidden in macrophage endosomes, presentation to T cells is impaired in lung walls of infected cells by forming a granuloma = tubercle

infection becomes latent and asymptomatic

diagnosis of latent tuberculosis

Mantoux test: skin test reaction to see if TB antigen is resent by testing for evidence of Abs

also can do MTb specific T cells in blood assay

Not HIV: viral pneumonias - influenza, SARS CoV-2

can lead to ARDS (acute respiratory distress syndrome)

ARDS (acute respiratory distress syndrome)

epithelial cells lining air sacs die so that air sacs fill with fluid and patient drowns

in order to treat this, the lung epithelium needs to regrow completely throw patient being dehydrated (so less edema fluid) and low pressure ventilator (enough air to get in lungs without demaging regrowth of lining of lung) and patient lying in prone position (on stomach)