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5. HDS Neuro Psych > HIV Infection > Flashcards

HIV Infection Flashcards

1
Q

HIV

Overview

A

Human: infects human beings

Immunodeficiency: Decreases or weakens the body’s ability to fight infections or illnesses

Virus: pathogen having the ability to replicate only inside a living cell

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2
Q

HIV

Classification

A
  • HIV is a retrovirus
    • Subfamilies are characterized according to pathogenesis, host range, viral structure, genomic organization, tropism, and disease spectrum
  • 2 major types of HIV: HIV-1 and HIV-2
    • HIV type 1
      • Most common in sub-Saharan Africa and throughout the world
      • Groups M, N, and O
        • Pandemic dominated by Group M
        • Group M comprised of subtypes A-J
        • Difference subtypes more prevalent in different geographic areas
      • HIV-1 is one of several lentiviruses ⇒ causes slowly progressing disease in the immune system and nervous system
        • Defining characteristics include:
          • Reverse transcriptase enzyme to transcribe RNA genome → proviral DNA
          • Integration of proviral DNA into host cell genome
    • HIV type 2
      • Most often found in West Central Africa, parts of Europe, and India
      • Has a slower progression of disease when compared to type 1
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3
Q

HIV-1

Structure

A
  • Spherical, enveloped RNA virus
  • Contains a nucleocapsid
    • Cone-shaped core
    • Contains two copies of genomic ⊕-sensessRNAand viral proteinsreverse transcriptase (RT)andintegrase (IN)
  • Viral envelope
    • Lipid bilayer derived from the host cell
    • Peplomers (glycoproteins spikes) ⇒ viral glycoproteins gp120 and gp41
    • Function in attachment, entry, and antigenicity
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4
Q

HIV-1

Genome

A
  • HIV-1 genome includes elements found in other retroviruses:
    • LTR (long terminal repeat) ⇒ regulates viral gene expression in its proviral DNA form
    • gag ⇒ encodes nucleocapsid, capsid (p24), and matrix proteins
    • p24 ⇒ structural protein that makes up most of the HIV viral core or ‘capsid’
    • Measurement of p24 ⇒ indicator of HIV-1 infection & indication of viral load
    • Detectable early in infection (before Ab, after viral RNA)
    • pol ⇒ codes for viral enzymes RT, IN, and protease
    • env ⇒ encodes envelope glycoproteins gp120 and gp41
  • Viral genome also includes genes unique to HIV-1 including:
    • tat ⇒ ↑ expression of viral genes
    • rev ⇒ ↑ viral RNA transport from nucleus to cytoplasm
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5
Q

HIV-1

Polymerase (POL) Gene

A

Most highly conserved region of HIV genome

Encodes 3 enzymes:

  • Reverse transcriptase (RT)
    • Required for reverse transcription of viral RNA genome → dsDNA copy
  • Integrase (IN)
    • Required for integration of viral DNA into host cell chromosome
  • Protease (PR)
    • Critical role late in viral life cycle by modulating production of mature, infectious virions
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6
Q

HIV-1

Reverse transcriptase (RT)

A
  • Reverse transcriptase (RT)
    • DNA polymerase that can use RNA or DNA strand as a primer
      • Produces dsDNA copy of ssRNA genome
  • RNaseH component of RT ⇒ degrades RNA genome once it has been copied
    • Key target for chemotherapeutic strategies effective against HIV-1
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7
Q

HIV-1

Variants

A
  • RT inherently error-prone w/ no proofreading capability
  • HIV-1 evolves over time through sequence changes in viral genes and non-coding regions
    • Makes vaccine efforts difficulty
  • Viral variants classified according to group:
    • Group M: “major” group ⇒ 90% of all HIV-1 infections
      • Group M viruses divided into genetically distinct subtypes (clades) according to gag and env genes
      • Subtypes A, B, C, D, F, G, H, J, K
      • Circulating Recombinant Forms (CRF)
    • Group O: “outlier” group ⇒ west-central Africa
    • Group N: “new” group ⇒ Cameroon, 1998; very rare
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8
Q

HIV-1

Envelope

A

Peplomers facilitates attachment and entry into host cell:

  • gp160 expressed and cleaved by cellular proteases → gp120 + gp41
  • gp120 is heavily glycosylated ⇒ “glycan shield”
  • gp120 binds first ⇒ confirmational ∆ ⇒ allows gp41 to bind
  • Non-covalent heterodimers of gp120 and gp41 assembled into trimers on surface of viral envelope
  • Variable regions in gp120 ⇒ antigenic diversity of HIV-1
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9
Q

HIV-1

Replication Cycle

A

Full replication cycle:

  1. Receptor-mediated binding and entry into host cells
    • Use of CD4 and CXCR4 or CCR5 defines cellular tropism of HIV-1
    • CD4 ⇒ primary receptor
    • CXCR4 or CCR5 ⇒ co-receptor
  2. Capsid uncoating and release of viral components
  3. Reverse transcription of viral RNA into DNA
    • Reverse transcriptase (RT) brought along in viral capsid
  4. Integration of the proviral DNA into host genome
    • Integrase (IN) brought along in viral capsid
  5. Viral gene transcription and translation
  6. Assembly
  7. Budding and maturation
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10
Q

HIV

Epidemiology

A
  • ~ 38 mil people currently living w/ HIV worldwide
  • Heterosexual contact is main risk factor for HIV transmission worldwide
  • Women make up > 50% of people living w/ HIV worldwide
  • In the US, majority of infections due to male-to-male sexual contact
  • In the US, adults ages 25-34 are most likely to be infected, however, new diagnoses occur at any age
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11
Q

HIV-1

Routes of Transmission

A
  • Inoculation by HIV-1-infected blood or blood products
  • Transmission via sexual contact (across cervicovaginal or rectal mucosal tissues)
  • In utero or perinatal transmission
  • Transmission via HIV-1-infected breast milk
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12
Q

HIV

Risk Factors

A
  • Sexual contact is the biggest risk factor in US for both men and women
  • Men who have sex w/ men (MSM) = ⅔ of new infections annually in the US
  • Racial and ethnic disparities in HIV infection
    • More pronounced in the MSM and transgender communities
    • Important to consider these disparities to provide screening and preventative treatment (PrEP) if appropriate
  • Less common risk factors: babies born to women w/ HIV infection, healthcare workers, organ/blood recipients
  • People who present w/ other STIs or have STI hx at ↑ risk
    • Risky behavior, inflammation and/or mucosal breakdown 2/2 STI
  • People w/ HIV who have higher HIV RNA levels and lower CD4 counts are more likely to transmit to others
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13
Q

HIV

Infectivity

A

Risk of HIV infection from a known HIV-⊕** **source varies:

  • Blood transfusion: ~93% risk
  • More historical now w/ screening of the blood supply
  • Receptive anal intercourse: 1.4% risk per single act
  • Needle-sharing during IV drug use: 0.63% risk per single act
  • Lower risk from percutaneous (needle-stick), insertive anal intercourse, receptive penile-vaginal intercourse, insertive penile-vaginal intercourse
  • Perinatal Transmission: ~ ¼ of infants born to pregnant individuals w/ HIV who are not on treatment will become infected
    • Use of antiretroviral therapy during pregnancy ↓ risk of transmission to the infant to less than 1%
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14
Q

HIV-1

Cellular Tropism

A

Co-receptor usage designates viral phenotype:

  • Determined by sequence of gp120
  • CXCR4 ⇒ ass. w/ infection of T cells
  • CCR5 ⇒ ass. w/ infection of MΦ
  • Strains can be dual-tropic
  • Absence of CCR5 (homozygous CCR5∆32) highly protective vs. HIV-1 infection and progression
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15
Q

HIV

Cellular Targets

A

Cells targets for HIV-1 in peripheral blood:

  • CD4-⊕T lymphocytes⇒ express CD4, CXCR4, and CCR5 ⇒ susceptible to infection byX4, R5, and R5X4 viruses
  • CD4-⊕MΦ⇒ express CD4 and CCR5 (but limited levels of CXCR4) ⇒ serve as hosts toR5 HIV-1and aremajor viral reservoirs
  • Other CD4-⊕ cell types susceptible to HIV-1 infection include dendritic cells and brain microglial cells
  • Proliferating CD4+T cells are highly susceptible to HIV infection and support efficient virus replication
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16
Q

HIV-1 Infection

Immunopathogenesis

A
  • Direct cell killing caused by:
    • Toxicity of unintegrated proviral DNA
    • Changes in cell membrane permeability associated with virus budding
    • Syncytia formation
    • Induction of apoptosis
  • Immunocompromise:
    • ↓ # of activated CD4-⊕T helper cells⇒ deficiencies incytokines necessary to initiate cellular immune responsesandregulate humoral responses
    • Resulting immune system dysfunction permits infection by opportunistic pathogens
    • HIV-1-infected MΦ ⇒ carry HIV-1 across BBB (Trojan Horse mechanism)
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17
Q

Natural History of HIV Infection

A
  • Acute HIV Syndrome
    • Primary infection
    • Extensive HIV replication ⇒ sig. ↓ in CD4 T cells & ↑ in viral RNA
    • Non-specific flu-like sx
  • Clinical latency
    • Viral RNA stabilizes to baseline amount
    • CD4 count slightly improves then slowly ↓
    • ± Clinical sx
  • Symptomatic chronic HIV syndrome
    • CD4 count low, viral count high
    • See constitutional sx, opportunistic infections, and eventually death
18
Q

Early HIV Infection

A
  • First 6 months after infection
  • Encompasses acute HIV infection
    • 40-90% symptomatic
    • Mononucleosis-like illness w/ non-specific signs and sx
    • Common signs & sx: fever, lethargy, myalgias, rash, headache, pharyngitis, lymphadenopathy
    • Less common symptoms: aseptic meningitis, oral ulcers, genital ulcers
    • Sx typically begin 2-4 weeks post-exposure to HIV
  • High index of suspicion critical if people have sx compatible w/ acute infection b/c standard testing algorithm may miss very recently infected individuals
  • HIV RNA level very high in acute infection ⇒ ↑ transmission risk (10-25% of HIV infections)
  • Progressive ↓ in CD4 T-cell count during first few weeks to months after infection
  • CD4 usually recovers but does not go back to baseline
  • Possible laboratory abnormalities: thrombocytopenia, leukopenia and transaminitis
19
Q

Established HIV Infection

A
  • Refers to the time after early HIV infection
  • Many pts who are not dx in the acute setting generally go into a period of “clinical latency” for years and may have no sx
  • Symptoms can include:
    • Lymphadenopathy, fevers, night sweats, fatigue, weight loss, chronic diarrhea
    • Skin manifestations including seborrheic dermatitis, psoriasis, tinea, onychomycosis
    • Oral manifestations including
  • *oral aphthous ulcers, oral hairy leukoplakia, gingivitis/periodontitis, candida infections**
    • Peripheral neuropathy
    • HIV associated nephropathy
    • Herpes zoster (shingles)
  • Laboratory abnormalities can include: leukopenia, anemia, thrombocytopenia
20
Q

AIDS

(Acquired Immunodeficiency Syndrome)

A
  • Most advanced stage of HIV infection
  • Main criteria: hx of CD4 count < 200 cells/mm3
  • AIDS Indicator Conditions: 26 specific conditions including certain infections and malignancies
    • Examples include Pneumocystis jirovecii pneumonia, Mycobacterium avium complex, Kaposi’s sarcoma, and invasive cervical cancer
  • Earlier dx and effective tx ⇒ ↓ opportunistic infections and AIDS-defining conditions
21
Q

Non-AIDS Related

Comorbidities

A

CKD, HTN, CAD, metabolic syndrome and DM

  • ↑ prevalence due to multiple factors:
    • People living w/ HIV are living longer
    • HIV causes inflammation ⇒ role in certain conditions such as CAD
    • Certain antiretroviral therapies ↑ risk of certain co-morbidities
    • HIV risk factors (obesity, smoking, and drug use) also ↑ risk for other co-morbidities
22
Q

HIV-1 Infection

Serologic Profile

23
Q

HIV Management

Initial Laboratory Evaluation

A
  • Confirm and document HIV status
  • CD4 Lymphocyte Cell Count
    • Used to stage disease
    • Guides DDx for opportunistic conditions
    • Wide normal range: 500-1,400 cells/mm3 (mean 800 to 1,050)
    • CD4 count can ↓ acutely during acute illness
  • HIV RNA PCR = “Viral Load”
    • Denotes quantity of virus in 1 mL of blood
    • Higher levels ⇒ ↑ risk of HIV transmission
    • Generally, higher viral load ∝ faster CD4 count ↓
    • Used for therapeutic monitoring
    • Goal w/ effective treatment is “undetectable”
  • HIV Resistance Testing
    • Use an HIV genotype to assess viral mutations associated w/ resistance to specific antiretroviral agents
    • Shows which medication are likely to work
    • Genotype recommended for everyone w/ HIV prior to starting antiretroviral therapy (ART) or if change in regimen needed d/t tx failure
    • Other initial labs include CBC, liver and kidney function, fasting BGL and lipid panel
24
Q

HIV-1

Testing Indications

A

Reasons for testing include:

  • ID of infected individuals in need of therapy
  • ID of carriers who could spread the virus (needle sharing, blood donation, sexual transmission)
  • Confirmation of the diagnosis
25
HIV-1 Infection Diagnosis Overview
_Order of detection:_ viral RNA → viral proteins (p24 is most commonly assessed) → antibodies * **_Serology-based methods_** ⇒ initial and routine screening * **ELISA, latex agglutination, and rapid oral antibody test** ⇒ initial screening * **Western blot and immunofluorescence** ⇒ confirmatory testing * Viral infection ⇒ viral load and p24 antigen * **_Immunological studies_** ⇒ more detailed analyses of HIV-1 infection and disease progression * Antibodies ⇒ IgM, IgG * Cellular response ⇒ CD4 cell count, CD4:CD8 T cell ratio * **_Genomics-based approaches_** ⇒ measure of viral load ⇒ monitor disease course and assess antiretroviral therapy effectiveness * Real-time PCR * Branched-chain DNA amplification
26
HIV Testing Guidelines
* **Everyone** (ages 13-64 years) _should be tested at least once_, regardless of risk factors * **Repeat HIV testing** should be performed based on the _individual’s risk factors_ * Opt-out HIV screening w/ opportunity to ask questions and option to decline * Include HIV consent w/ general consent for care * Prevention counseling in conjunction w/ HIV screen not required
27
HIV Infection Timing Definitions
* **Eclipse period**: initial interval after a person acquires HIV where _no tests can detect the infection_ * **Window period**: generally defined as the _time between acquisition of HIV and when a test will detect HIV infection_ in most people * **Acute HIV infection**: period between _detection of HIV RNA_ and _detection of Ab to HIV_
28
HIV Infection Sequence of Laboratory Markers
29
HIV Testing Algorithm
**All reactive (****⊕****) HIV tests require confirmatory testing** **CDC testing algorithm** ⇒ better dx of acute HIV infection, ↓ “indeterminant” results, and faster results * _Step 1:_ **HIV 1/2 Antigen/Antibody Combination Immunoassay (“4th generation test”)** * Detects **p24 Ag** ⇒ dx HIV earlier (**~1-3 wks** after infection) * May be ⊖ if tested very early in course of infection * ⊕ result requires confirmation * _Step 2:_ **HIV-1/HIV-2 Antibody Differentiation Immunoassay** * Confirmatory test used if Ag/Ab test ⊕ * Assesses for presence of HIV-1 and HIV-2 Ab
30
HIV 1/2 Antigen/Antibody Combination Immunoassay “4th generation test”
* Used for serum/plasma specimens * **Preferred test for HIV dx** ⇒ dx HIV earlier vs traditional Ab (EIA) test * **45-day window period** (compared to 90 days) * **p24 antigen** ⇒ **2nd** marker of HIV infection to be seen ⇒ **detectable 4-10 days after HIV RNA** * May be ⊖ if performed very early in course of infection * **⊕ Result requires confirmation** w/ HIV-1/HIV-2 Ab differentiation immunoassay * Sensitivity almost 100% / Specificity ~98-100%
31
HIV-1/HIV-2 Antibody Differentiation Immunoassay
* **Confirmatory test** used if _antigen/antibody test_ _⊕_ * Only run if HIV Ag/Ab combo test ⊕ * Assesses for HIV-1 and HIV-2 antibodies * Differentiates HIV-1 or HIV-2
32
HIV Nucleic Acid Test (NAT)
* Only used for dx if **antigen/antibody immunoassay** **⊕** _and_ **HIV-1/HIV-2 Ab differentiation immunoassay indeterminate or** **⊖** * NAT assesses for **presence of HIV-1 RNA** * **⊕** **~ 10 days after HIV infection** (1st marker of HIV infection) * Also necessary to make dx if **acute HIV is suspected** _and_ **antigen/antibody test** **⊖** * Not used routinely for HIV diagnosis ⇒ more expensive, takes longer, false-⊕ results
33
Antibody-Based HIV Tests
* **_Enzyme immunoassay (EIA)_** * Main HIV test performed from 1985-2014 * **Measures presence of HIV Ab** ⇒ misses earlier cases of HIV infection compared to p24 Ag testing * Still see these done in certain settings: rapid POC testing in the ED, a woman in labor w/o prior testing, or at-home testing * **⊕** **EIA Result Requires Confirmation W/ Western Blot Test** * **_Western blot_** * Based on identifying **Ab bands associated w/ viral antigens of HIV** * ⊕: at least 2 out of 3 of p24, gp41, or gp120/160 * ⊖: no bands * Indeterminate: any HIV band, but not meeting criteria for ⊕ * **EIA + Western blot** ⇒ Sensitivity of 99.5% / specificity of 99.99%
34
HIV False ⊕ Ab / Western blot
_Reasons for false_ _⊕_ _results can include:_ * Cross-reactive antibodies (pregnancy or blood transfusion) * Recent vaccination * Epstein-Barr infection * ⊕ RPR * Some liver diseases, cancers, and rheumatologic diseases
35
Viral Load
* Copies of HIV-1 RNA per ml of peripheral blood * **PCR test**: undetectable @ \< 50 copies/ml; high \> 100k copies/ml * **b-DNA test**: undetectable @ \< 400 copies/ml * Sample-to-test time: up to 7 days
36
CD4 Count
* **CD4-****⊕****T cells per mm3 of peripheral blood** * Normal range: 600-1,200 cells/mm3 * AIDS defined as \< 200 cells/mm3 * Sample-to-test time: up to 14 days
37
HIV Resistance Testing
* **Genotypic tests** ⇒ known resistance mutations * **Phenotypic tests** ⇒ effective drug concentrations * **Virtual phenotype tests** ⇒ genotype/phenotype database matching
38
HIV Co-infections
_Assess for common co-infections including:_ * **Viral Hepatitis** – A, B, and C * **STIs** such as Syphilis, Gonorrhea, Chlamydia, and Trichomoniasis * **Cervical Pap test** (Human Papilloma Virus related) * **Anal Pap test** (HPV related) * Consider in high-risk individuals * Assess for **latent tuberculosis** w/ tuberculin skin testing or interferon gamma release assay (IGRA)
39
Antiretroviral Therapy (ART)
* _Rationale for ART_ * **Improves and preserves immune function** in most pts * **Reduces AIDS- and non-AIDS-associated morbidity and mortality** * ART use can **reduce risk of HIV transmission** to others * _Timing of starting ART_ * **ART is now recommended for everyone regardless of CD4 count and viral load** * **HIV virus can develop resistance to treatment** ⇒ pt must be willing and able to commit to tx and take medication consistently * _Treatment for Pregnant Individuals w/ HIV_ * **ART during pregnancy dramatically reduces risk of transmission** * For individuals w/ higher risk of transmission based on elevated HIV RNA, **intravenous** **zidovudine** (AZT) and C-section reduce risk of transmission
40
Pre-exposure Prophylaxis | (PREP)
* **2 antiretroviral agents** given to **HIV-****⊖****individuals** @ very high risk for HIV infection to _prevent HIV infection_ * People engaged in sex w/ HIV-⊕ or high-risk HIV status unknown individuals * People how have injected drugs in past 6 months and have shared needles * Heterosexual couples desiring pregnancy where one partner has HIV * **Risk of infection linked to adherence** (i.e. the more consistently it is taken the better it works) * 90% ↓ risk in sexual exposure * 70% ↓ risk in people who inject drugs * **Need HIV testing every 3 months d/t risk of developing resistance if infected while taking PREP** (because not taking a full treatment regimen) * Also need to **monitor creatinine** as PREP can affect the kidney
41
Post-exposure Prophylaxis | (PEP)
* **3 antiretroviral agents** given to **HIV-****⊖****individual** to _prevent infection after being exposed to HIV_ * For use in emergency * Ex. condom breaking, sexual assault, needle stick * **~80% reduction in risk of HIV infection** in healthcare workers w/ needle stick * **Start within 72 hours of exposures, ideally within 1 hour** * Can give initially while awaiting source individual’s HIV testing * Take for 28 days after exposure
42
HIV-1 Infection Cure
A cure for HIV-1 infection may be an achievable goal: * **“Berlin Patient” case** ⇒ functional cure * Long-term control of HIV by CCR5 ∆32/∆32 stem cell transplant * **“Boston Patients”** provided further insights into mechanisms that could lead to a functional or actual cure * Pts received BMT w/o CCR5 ∆32/∆32 mutation ⇒ tx failed to eliminate HIV infection * **Shock and Kill** * Latency-reversing agents given to reactivate latent HIV hiding in immune cells * Reactivated cells then targeted and killed by immune system or anti-HIV drugs * **CRISPR/Cas9** * Cut out virus’ DNA from genomes * May lead to eradication therapies * Current challenge is to develop curative regimens that can be **implemented effectively and economically across HIV-1-infected populations**

5. HDS Neuro Psych (46 decks)

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