HIV Flashcards
Describe the innate immune response upon HIV infection:
–Langerhans cells in vaginal & foreskin epithelia; macrophage, dendritic cells, NK cells in subepithelium, etc.
–The innate immune response plays a role in early virus restriction, shaping adaptive response, but also in virus spread. With virus spread, rapid increase viral load, CD4+ T cell decline; with host immune response, decline in viral load, depletion of CD4+CCR5+ memory cells in mucosa
Describe what happens with the adaptive immune response towards HIV:
- p24 antigen appears, then decreases with seroconversion
- Antibody response to envelope (most) and core antigens
- CD8+ T cells become activated CTLs – detectable throughout infection
- CD4+ T helper response with stimulation of various cytokines (IL-2, IFN-gamma, TNF, etc.) leading to multi-cellular CMI response
When is viral load generally the highest? What brings it down?
Viral load is generally the higest about 3-4 weeks post-exposure. Eventually the load drops off and reaches a viral set point.
Specific antibody against HIV starts a few weeks after exposure. Doesn’t seem to be having a huge effect on suppressing viral load. Onset of generation of CD8 cytotoxic lymphocytes is really what helps bring virus down
What changes are associated with the progressive deterioration of the immune system?
•Impact of viral factors (usage of CCR5 [M-tropic / R5] vs CXCR4 [T-tropic / X4]
Accessory gene function (e.g. deleted nef gene, slower loss),
MHC & co-receptor genotypes,
Th1 to Th2 switch, et al.
Anti-virus specific CD4+ T helper cells:
There are some virus specific CD4+ T cells that are important for initial T and B cell responses and are thought to be required to efficient CD8+ cytotoxic responses.
Problem: these are the cells that HIV likes to take out (HIV loves activated T cells), so these are lost early in infection and can’t help with virus elimination.
Some “elite controller” patients seem to keep more of these around (HIV-1 RNA < 50 c/mL without therapy).
HIV specific CD8+ Cytotoxic T Lymphocytes:
Present in early numbers in HIV infection
Involved in initial control of viremia
Control is strongly associated with HLA (MHC 1) genotype
See a decline associated with progressive CD4 cell loss in most individuals
There is a high binding affinity by TCRs of CD8 cells to MHC I to conserved ______ in HIV
epitopes
Antiviral effect of cytotoxic T lymphocytes:
- Lysis of virus-infected cell before virions are released
- Inhibition of viral replication (IFN-gamma)
- Inhibition of viral entry into surrounding cells (produce MIP-1a, RANTES; block CCR5 usage)
How are CD4+ T cells lost in HIV?
–Direct lysis of cells by HIV
–Virus mediated killing of bystander CD4+ T cells
–Lysis of infected CD4+ T cells by immune response (CTL, ADCC)
–Chronic immune activation – apoptosis
Why can’t we just replace lost CD4 cells?
–Thymic dysfunction
–Bone marrow dysfunction
–Limited ability of T cells to expand in the periphery
Often acute HIV infection will present with ____-like symptoms, such as (list 5):
Mono-like symptoms;
fever, sore throat, swollen lymph nodes, faint rash, mucosal ulcers
If a cell contained HIV virion is lysed, are these virions infectious or not?
No, this cell needs to be enveloped (last step resulting of budding) in order to be infectious
Describe the consequences of the high rate of viral mutation:
Allows changes in HIV proteins and escape from immune control
- Neutralizing antibody (envelope, esp. V3 binding loop)
- CTL epitopes (peptides presented by MHC-I)
- T helper epitopes (peptides presented by MHC-II)
However, some mutations come with a high fitness cost for the virus
Virus with a deleted ____ gene leads to low viral load and slow loss of CD4 T cells in some individual
Nef gene
CCR5 vs. CXCR4 usage affects disease progression - ____ and ____ are associated with rapid loss in CD4 T cells
DM and X4-virus
HIV pathogenesis involves ____ latency but no _____ latency
Has clinical latency but no virological latency
The level of _____ predicts CD4+ T cell loss
Viremia
As CD4+ T cells are lost, immunity to _____ and _____ is lost
immunity to opportunistic pathogens and cancers is lost
Clinical AIDS is a result of the HIV-induced loss of ________
pathogen-specific immunity
_______ is the best predictor of current immunodeficiency
CD4+ T cell number
(but additional predictive power with both this and viral load)
Diagnostic Testing:
Performing an HIV test based on clinical signs or symptoms
Targeted Testing:
Performing an HIV test on subpopulations of persons at higher risk
Screening:
Performing an HIV test for all persons in a defined population
Opt-out screening:
Performing an HIV test after notifying the patient that the test will be done; consent is inferred unless the patient declines
Diagnostic tests for HIV can test for ____, ____, or ____
HIV antibody, virus protein (p24 antigen), or virus
What is the test for HIV antibody?
HIV ELISA / Western blot
What are the tests for the virus?
HIV DNA PCR (for diagnosis of infection in infants)
HIV RNA PCR (for determination of viral load)
bDNA (branched chain assay for determination of viral load)
HIV culture
Fourth Generation HIV-1/-2 Immunoassay:
Abbott Architect HIV Ag/Ab Combo Assay
- Chemiluminescent microparticle immunoassay
- Detection of HIV p24 Ag and Ab to HIV-1 group M & O and / or HIV-2
- Does not distinguish between these
- In established infection, specificity 99.8%, sensitivity 100%
HIV-1/-2 Differentiation Immunoassay:
Bio-Rad Multispot HIV-1 / HIV-2 Rapid Test
- Rapid enzyme immunoassay
- Detection / differentiation of HIV-1 and HIV-2 antibodies
- Utilizes highly conserved recombinant & synthetic peptide sequences representing HIV-1 and HIV-2 envelope proteins
Rapid HIV tests:
E.g. OraQuick Rapid HIV Ab Test
Collect oral fluid specimens by swabbing gums with test device. If positive, need to then confirm with a blood test.
Concerns associated with OraQuick In-Home HIV Test:
Concerns with decreased sensitivity, misinterpretation of results, and less effective counseling
Diagnosing HIV in infants:
HIV DNA PCR; now Qualitative (or Quantitative) RNA PCR
- PCR at age 1-2 days detects 30-40% HIV infected infants; test at age 2-3 weeks >90%; 100% after 4 months of age
- HIV ELISA / Western blot adequate for diagnosis after age 18 months
What populations are screened for HIV?
Routine screening is done for everyone aged 13-64 as well as those at risk
You are called by a physician who wants to refer a 2 month old infant to your clinic because the HIV 4th generation screening test was positive. What should you recommend?
Obtain an HIV nucleic acid test / PCR for diagnosis
(At 2 months of age, the 4th generation test could be positive because it is detecting the presence of viral antigen in the child OR because the baby still has mom’s antibodies, which may be positive)
When should HIV+ patients begin treatment?
–Decision multifactorial: immune status (CD4), viral load, stage of disease (e.g. primary infection), age, likelihood of adherence, etc.
–Immediate vs delayed therapy: current guidelines say that ALL HIV+ individuals should be on therapy
Describe the immune reconstitution with HAART:
Initial rapid increase in CD4+ T cells (1-6 months)
- mostly memory CD4+ T cells
- skewed T cell receptor repertoire (“forgotten pathogens”)
- redistribution vs proliferation of memory CD4+ cells
- cannot replace lost T cell specificities
Subsequent gradual steady rise in CD4+ T cells
- mostly naïve CD4+ T cells derived from the thymus
- can replace lost T cell receptor specificities
Plasma HIV RNA level / viral replication correlates with the rate of ______ destruction, which indicates the extent of immune damage
Plasma HIV RNA level / viral replication correlates with the rate of CD4+ T cell destruction, which indicates the extent of immune damage
Goal of therapy is maximum viral suppression, which will limit _____
resistance
Changes in therapy may limit future regimens due to _______
cross-resistance
What are the modes of HIV transmission?
–Perinatal transmission (Vertical transmission, mother to child)
–Sexual intercourse / sexual abuse
–IV drug abuse (contaminated needles)
–Exposure to infected blood products / body fluids
–Occupational risks (laboratory worker, etc.)
Maternal risk factors for disease:
- Advanced disease (low CD4 count, high viral load)
- Prolonged rupture of membranes prior to delivery
- Obstetrical complications, etc.
Clinical signs and symptoms due to HIV / AIDS in children/adults:
Recurrent and/or severe bacterial infections, persistent / recurrent viral infections, thrush, parotitis, hepatomegaly / splenomegaly, failure to thrive / wasting, developmental delay, lymphadenopathy, LIP, various opportunistic infections, etc.
Also autoimmune disease; malignancy
Physical exam flags:
Oral candidiasis, Kaposi sarcoma, leukoplakia, angular cheilitis, seborrheic dermatitis, zoster (shingles), herpes simplex
What 5 opportunistic infections of HIV patients are especially significant?
Pneumocystis Pneumonia
Toxo encephalitis
Crypto meningitis
MAC Bacteremia
CMV Retinitis
Why? These indicate extremely low CD4 counts and very sick/immunocompromised patients
What are some common infections in HIV+ patients with CD4 cell counds above 200?
More frequent disease from true pathogens
–Streptococcus Pneumonia (up to 100-fold increased risk)
–M. tuberculosis
–Herpes Simplex
–Varicella Zoster (Shingles)
–Syphilis
–Salmonella
–Staph. aureus
How does TB present in HIV patients?
Chest x-rays often do not show the classic upper lobe cavities (atypical presentations are common)
Extra pulmonary (not just in lung) TB is common
PPD skin tests may be negative as immune suppression can lead to anergy (need functional T cells to have response)
Response to therapy is usually the same [also antiretroviral therapy is super important component in TB treatment]
What fungal infections are common in patients with CD4 counts below 200?
Pneumocystis jiroveci pneumonia (PJP or PCP)
- most common OI causing pneumonia
Candida
- esophagitis
Cryptococcus
- meningitis, disseminated infection
Histoplasmosis
- disseminated, pulmonary
Pneumocystis jiroveci pneumonia (PJP)
Most common opportunistic AIDS-defining infection
Almost always presents with CD4 < 200
Prominent symptom is shortness of breath (Non productive cough, fever also occur)
Minimal findings on physical exam
Hallmark is hypoxemia or O2 desaturation
LDH (lactic dehydrogenase) is frequently elevated
Prominent symptom of PJP is ______, which corresponds to findings of low ______ on physical exam.
Prominent symptom is shortness of breath
Low O2 saturation findings
What is frequently elevated in HIV patients with PJP?
LDH (lactic dehydrogenase)
CMV infections in HIV patients leads to (list 5)
Retinitis (leading cause of blindness)
Esophagitis
Colitis
encephalitis
myelitis
Human Herpes Virus (HHV-8) in AIDS leads to:
Kaposi’s sarcoma and primary effusion lymphomas
CMV disease in adults is due to _____ due to a CD4 count generally below _____
reactivation; <50 cells
Kaposi’s Sarcoma is caused by what virus?
HHV-8
How is HHV-8 spread?
–spread sexually in US and western Europe
–Direct contact in children in endemic countries
Protozoan infections with AIDS infections:
Toxoplasma gondii
Cryptosporidia, isospora, microsporidia (watery diarrhea)
Bacterial infection associated with AIDS
Mycobacterium avium complex (disseminated infection)
Mycobacterium Avium Complex:
Diffuse infection of multiple organs (GI tract, liver, spleen, bone marrow)
–Occurs with CD4 < 100 (usually <50)
–Fevers, Night sweats
–Diarrhea, Weight loss
–Elevated alkaline phosphatase, anemia
–Diagnosis- lysis centrifugation culture
Patients with Mycobacterium Avium Complex have elevated _____
alkaline phosphatase
Unique considerations of HIV infection in children/infants:
–Impact of route of acquisition
–Possible effects of in utero exposure to antiretroviral agents
–Methods for diagnosis of HIV infection
–Age-dependent normal values for immune markers / laboratory values
–Altered drug metabolism
–Different clinical / virologic manifestations
–Issues affecting adherence to therapy
–Varied psychosocial issues
…and many others!
What are the clinical categories for the degree of immune deficiency?
N: asymptomatic
A: mild
B: moderate
C: severe
Immunologic categories of the degree of immune deficiency:
- Based on CD4 count and percentage
1: >25%; no suppression
2: 15-25%; moderate
3: <15%; severe
Considerations of vaccinations and children with HIV:
–Immunization does not accelerate HIV progression
•Children not on ARVs may have transient increased HIV VL
–HIV+ children often have lower specific Ab and CMI responses, but thought to still be protective
–Vaccine-induced responses correlate with adequacy of CD4 & T cell pools and plasma HIV VL independently
–Specific Ab levels may increase on cART even before boosters; after 3mo cART, better response to vaccine
