3.3 HIV Infection Flashcards
DEVELOPMENT
Immature thymocytes express a diverse range of antigen receptors (often makes them self-reactive), and must undergo strict positive and negative selection:
• Only a small population (< 5%) of the thymocytes leave the thymus to become fully functional peripheral T cells (not self-reactive, not useless)
• Acquire their repertoire of specific antigen receptors to cope with the antigenic challenges faced during their lifespan
• Commitment to a particular T cell lineage leads to differentiation, proliferation and maturation under the influence of cell-cell contact and soluble mediators
All T cells express ____ (10% express ____ TCR, while the other 90% express αβ TCR):
• Of the 90% αβ TCR-expressing T cells, __________ expresses CD8 (cytotoxic T cells), while the other ________ expresses CD4 (helper T cells)
CD3;
γδ;
one-third;
two-thirds
- CD8 cells: Cytotoxic T cells (make up 40% of the peripheral T cells) which ___________(requires Th regulation due to cytotoxic nature)
- CD4 cells: T helper cells or regulatory cells (make up 60% of the peripheral T cells) which secrete cytokines to coordinate the immune response:
• Can recognise antigens in the context of MHC class II molecules (CD4 binding to the non-polymorphic region of MHC)
• Further classified as Th1 (T cell help), Th2 (B cell help), Treg (suppressor), Th17 (inflammatory) subsets
The antigenic peptide (small cell peptide fragment of the processed pathogen) is presented in the context of MHC molecules on the surface of infected cells/antigen-presenting cells:
• Antigen-presenting cells (APCs) are cells which engulf antigens and process them before presenting them as peptides to T cells (includes DCs, B cells and macrophages)
lyse infected cells and secrete cytokines ;
CD4+ cells can only recognise processed antigens (presented by APCs on MHC class II):
• CD4 binds to the antigen-MHC complex, and co-stimulatory signals (_____________ binding) cause activation and cytokine production
• Activated T helper cells also undergo clonal expansion (specific antigen + cytokines like IL-2), forming memory cells and activated T helper cells (stimulate other cells)
o Different cytokines drive different immune responses and T cell differentiation
• During generation of the humoral (antibody) response, activated T helper cells stimulate B cell proliferation
Helper T cells have receptors to Class II MHC, on certain immune system cells
- _____________ consumes foreign microbe, becoming an APC
- Class II MHC of APC picks up antigen in cytoplasm, moves into the surface and presents it to the TH cell.
- TH cells with the matching receptor (antibody) divides to produce memory cells and activated TH cells.
- TH cells stimulate other cells modulates both humoral and cell mediated immune response
T dependent antigens
- Activated TH cell stimulates the division of the B cell with the antibody.
- Most foreign proteins produce plasma cells which secrete antibody.
- Produces memory B cell for secondary response
CD28-CD80/86;
Macrophage or B cell;
CD8+ cells can recognise antigens in the context of MHC class I (by any infected cell): • CD8 binds to the \_\_\_\_\_\_\_\_\_\_\_ of MHC class I molecules, and co-stimulatory signals cause initial activation • Also undergo clonal expansion (with specific antigen, cytokines and T helper cells which provide cytokine growth factors) into effector cells and memory cells • Causes the destruction of the \_\_\_\_\_\_\_\_\_\_\_\_ by secreting perforin to lyse the cell (with circulating antibodies marking for disposal by B cells)
non-polymorphic region ;
nucleated cell with intracellular infection
HIV-1 targets the cells of the immune system (changes cellular functions), and induces a selective loss of the CD4+ T helper cells:
• Enters through the __________________, then picked up by Langerhans cells and some epithelial cells (expressing CD4)
• Virus may be taken up by some APCs (then remain intact in intracellular vesicles to be transmitted to T helper cells)
• Initial replication in mucosal site leads to rapid dissemination via lymph nodes (within 3 days of infection), then systemic spread via the bloodstream
• ____________ are specifically targeted early on in the infection
• Initial HIV infection → prompt immune response (primary HIV/seroconversion illness).
vaginal or rectal mucosa or directly into the bloodstream;
GALT and microglial cells in the CNS
IMMUNITY IN HIV INFECTIONS
The points where HIV can interfere with an immune response include:
1. Activation of immune response
2. Activated infected CD4+ T helper cells die and are lost (_____ not activated → cannot prime ____________ → CD8+ and B cell response diminished → CD4+ memory lost)
3. Infected DCs are killed by the virus or CD8+ T cells (defect in antigen presentation or failure to activate memory CD8+ T cells)
4. Reduced _______________ (increased susceptibility to viruses and cancer)
5. Reduced macrophage (increased susceptibility to TB)
6. Abnormal humoral responses (_________ increase in abnormally functioning antibodies → increased susceptibility to bacterial infections)
7. Generalised inflammation caused by activation of immune response. Generalised inflammation increases the risk of heart and liver disease, possibly even dementia through _______________.
8. Interfere with lymphopoiesis (compensatory increase in both CD4+ and CD8+ T cell production → ratio of _______ may remain very high)
Therefore, HIV infection interferes with the basic aspects of CD4 and CD8 T cell activation and lymphopoiesis (production of B and T cells):
• Effective immunity may require antibodies to prevent infection and neutralise virus, and CD8+ cytotoxic T cells to eliminate latently infected cells → effective vaccines must elicit potent _______________
• Permanent control of ______________ by CTLs may prevent AIDS progression
DCs;
naïve CD8+ cells;
cytotoxic T cell surveillance;
polyclonal;
destruction of microglia cells ;
CD8 : CD4;
antibodies and CTLs;
latently infected cells
Immunodeficiency resulting from HIV-1 infections result in increased risk towards various infections, malignancies and diseases:
Conventional & opportunistic infections
- Conventional: ______, _______
- Opportunistic*: PCP, CMV, MAI, toxoplasmosis
Organisms requiring cell-mediated immune responses: Mycobacterial, viral, fungal infections
Viral-induced oncogenic cancers: __________ (HHV-8), __________ (EBV)
Heart, liver, kidney diseases: Due to immune activation
*Opportunistic infections are those which do not cause disease in immunocompetent individuals (e.g. PCP, MAI) or those which normally only cause a self-limiting illness (e.g. ______, _______)
TB, bacterial pneumonia;
Kaposi’s sarcoma; lymphoma
CMV, toxoplasmosis
PCP typically presents with cough (no sputum), shortness of breath (especially on exertion), and pyrexia (fever) with no physical signs:
• Investigations: CXR (often normal; may show ___________), ABG, exercise oximetry, induced sputum and bronchoscopy
• Rates of bacterial pneumonia are also increased in HIV patients (especially for those with lower CD4 counts → CD4 < 200/mm3 – 11 episodes per 100 people per year)
Findings (PCP)
- CD4+ count: _______
- symptoms: ________
- duration: a few weeks
- signs: occasionally _________
- lab tests: WBC variable
Findings (Bacterial)
- CD4+ count: any
- symptoms: ________
- duration: 3-5 days
- signs: focal lung signs
- lab tests: WBC frequently activated
perihilar opacities;
<200 cells/ mm3;
non productive cough;
bilateral fine crackles;
productive cough (purulent sputum)
Infections with the herpesviruses (HSV, VZV/HZV, CMV, HHV-8) are more common:
- HSV/VZV: More severe and last longer in immunocompromised patients (e.g. shingles may present ________ or in ___________ for HIV patients)
- CMV: Affects 40% of the global population; reactivation in immunocompromised hosts may result in retinitis (____________), colitis, oesophagitis, encephalitis, pneumonitis
- HHV-8: Causes Kaposi’s sarcoma (systemic disease with cutaneous presentation of _________________ → more common in MSM
• Diagnosis is via biopsy
• Treatment: local radiotherapy/chemotherapy/ARVs
bilaterally; multiple dermatomes;
retinal detachments, blindness;
purple/brown/red/black papules)
Candidiasis is the most common fungal infection affecting HIV patients, and may be mucocutaneous or disseminated/invasive (uncommon):
• Mucocutaneous: presents as
_________(common initial manifestation), ____________(AIDS-defining illness), or vulvovaginal disease
• Invasive: life-threatening condition (commonly nosocomial bloodstream infections) usually confined to severely immunocompromised patients → 50% mortality
• Risk factors: breakdown of mucosal barriers (____________), surgical procedures, neutropenia, changes in gut flora (antibiotics), invasive interventions breaching the skin (e.g. IV lines, drains)
oropharyngeal ; oesophageal ;
cytotoxic chemotherapy
Cryptococcus neoformans is the most common cryptococcal species to cause infection in humans (others include C. laurentii, C. albidus, C. gatti, C. uniguttulatus):
• Affects immunocompromised hosts (inhalation of fungal spores from soil contaminated with avian excreta leads to _______________)
• Infection often disseminates to the CNS (causing __________________), and spreads _______________ to the skin/urinary tract/eyes/bones
• Today, most cases of cryptococcal diarrhoea in the UK are ________
- Primary pulmonary infection: Fever, fatigue, malaise, chest pain, dry cough
- Disseminated CNS infection*: Nausea and vomiting, neck stiffness, photophobia, confusion, headache, blurred vision
- Disseminated skin infection: Umbilicated papules, abscesses, erythematous nodules, cellulitis
- The various CNS diseases causing mass lesions in patients with HIV may include ___________________, while those causing diffuse encephalitis include _____________
pulmonary infection;
cryptococcal meningitis;
haematogenously;
ARV-related;
primary cerebral lymphoma, toxoplasmosis, PML, CMV, TB, cryptococcosis, aspergilloma;
CMV, HSV, HZV.
COURSE OF INFECTION
There is an initial peak in the plasma viral load within 6 weeks of infection (seroconversion illness), followed by reduction (immune control):
• In untreated patients, viral load slowly rises, and patient succumbs to AIDS
• CD4 _________________
• CD8 ______________
The classic classification of AIDS is from seroconversion illness, to symptom-free illness and lymphadenopathy, then to one of the following: age-related conditions, dementia, AIDS:
- If left untreated, the median time from infection to severe immunocompromise is 8 -10 years, with disease progression predicted by viral load and rate of decline
o 10% of patients are rapid progressors (become severely immunocompromised in 2 – 3 years), while 5% are long-term non-progressors (stable CD4 counts, no symptoms even after 10 years)
drops significantly at first, followed by a slight recovery then slowly decreases over many years;
increases significantly during the initial stage, then gradually declines
COURSE OF INFECTION
There is an initial peak in the plasma viral load within 6 weeks of infection (seroconversion illness), followed by reduction (immune control):
• In untreated patients, viral load slowly rises, and patient succumbs to AIDS
• CD4 _________________
• CD8 ______________
The classic classification of AIDS is from seroconversion illness, to symptom-free illness and lymphadenopathy, then to one of the following: age-related conditions, dementia, AIDS:
- If left untreated, the median time from infection to severe immunocompromise is 8 -10 years, with disease progression predicted by viral load and rate of decline
o 10% of patients are rapid progressors (become severely immunocompromised in ____________) , while 5% are long-term non-progressors (stable CD4 counts, no symptoms even after 10 years)
drops significantly at first, followed by a slight recovery then slowly decreases over many years;
increases significantly during the initial stage, then gradually declines;
2 – 3 years);
LAB RESULTS
HIV infection leads to reduced number of T cells and less effective T cells (activated due to becoming infected by HIV):
• Number of CD4+ T cells in the blood is an important way to determine the ______________ (assessed by ___________ to analyse number of T cells) → about 1% of total body lymphocytes are in blood
o Helps to guide optimum time for starting ARV therapy
• Assessment of lymphocytes is the quantitation of different types of cells (determines the % of cells stained using antibodies to different cell surface markers):
o Number of cells in ul (mm3) of blood can be determined from this and the absolute number of lymphocytes in blood
• Viral load is assessed by PCR involving reagent preparation, specimen preparation (pre-PCR), amplification and detection (post-PCR)
o Predicts the __________________
immune status of a patient;
flow cytometry;
potential speed at which CD4+ T cell declines
