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
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
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2 major types of HIV: HIV-1 and HIV-2
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HIV type 1
- Most common in sub-Saharan Africa and throughout the world
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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
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Defining characteristics include:
- Reverse transcriptase enzyme to transcribe RNA genome → proviral DNA
- Integration of proviral DNA into host cell genome
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Defining characteristics include:
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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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HIV type 1
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)
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Viral envelope
- Lipid bilayer derived from the host cell
- Peplomers (glycoproteins spikes) ⇒ viral glycoproteins gp120 and gp41
- Function in attachment, entry, and antigenicity
4
Q
HIV-1
Genome
A
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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
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Viral genome also includes genes unique to HIV-1 including:
- tat ⇒ ↑ expression of viral genes
- rev ⇒ ↑ viral RNA transport from nucleus to cytoplasm
5
Q
HIV-1
Polymerase (POL) Gene
A
Most highly conserved region of HIV genome
Encodes 3 enzymes:
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Reverse transcriptase (RT)
- Required for reverse transcription of viral RNA genome → dsDNA copy
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Integrase (IN)
- Required for integration of viral DNA into host cell chromosome
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Protease (PR)
- Critical role late in viral life cycle by modulating production of mature, infectious virions
6
Q
HIV-1
Reverse transcriptase (RT)
A
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Reverse transcriptase (RT)
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DNA polymerase that can use RNA or DNA strand as a primer
- Produces dsDNA copy of ssRNA genome
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DNA polymerase that can use RNA or DNA strand as a primer
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RNaseH component of RT ⇒ degrades RNA genome once it has been copied
- Key target for chemotherapeutic strategies effective against HIV-1
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
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Viral variants classified according to group:
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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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Group M: “major” group ⇒ 90% of all HIV-1 infections
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
9
Q
HIV-1
Replication Cycle
A
Full replication cycle:
- 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
- Capsid uncoating and release of viral components
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Reverse transcription of viral RNA into DNA
- Reverse transcriptase (RT) brought along in viral capsid
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Integration of the proviral DNA into host genome
- Integrase (IN) brought along in viral capsid
- Viral gene transcription and translation
- Assembly
- Budding and maturation
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
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
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
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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
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
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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%
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
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
16
Q
HIV-1 Infection
Immunopathogenesis
A
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Direct cell killing caused by:
- Toxicity of unintegrated proviral DNA
- Changes in cell membrane permeability associated with virus budding
- Syncytia formation
- Induction of apoptosis
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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)
17
Q
Natural History of HIV Infection
A
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Acute HIV Syndrome
- Primary infection
- Extensive HIV replication ⇒ sig. ↓ in CD4 T cells & ↑ in viral RNA
- Non-specific flu-like sx
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Clinical latency
- Viral RNA stabilizes to baseline amount
- CD4 count slightly improves then slowly ↓
- ± Clinical sx
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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
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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
22
Q
HIV-1 Infection
Serologic Profile
A
28
Q
HIV Infection
Sequence of Laboratory Markers
A
29
Q
HIV Testing
Algorithm
A
All reactive (⊕) HIV tests require confirmatory testing
CDC testing algorithm ⇒ better dx of acute HIV infection, ↓ “indeterminant” results, and faster results
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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
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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
Q
HIV 1/2 Antigen/Antibody Combination Immunoassay
“4th generation test”
A
- 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)
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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
Q
HIV-1/HIV-2 Antibody Differentiation Immunoassay
A
- 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
Q
HIV
Nucleic Acid Test (NAT)
A
- 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
Q
Antibody-Based HIV Tests
A
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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
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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%
