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HIV Disease Processes Flashcards

1
Q

What type of virus is HIV-1?

A

Single stranded RNA virus

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2
Q

How is HIV-1 transmitted?

A

Sexually but can also be intravenously through either blood transfusion or intravenous drug use

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3
Q

What does HIV cause?

A

Establishes a chronic infection causing progressive immune deficiency and resulting in the onset of acquired immune deficiency syndrome, typically after 2-10 years of infection

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4
Q

Describe the HIV-1 genome

A

9.2 kilobase ssRNA genome
Multiple reading frames
9 genes producing 9 proteins
Gag and pol are processed to produce a further 4 proteins each

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5
Q

Describe the HIV-1 virion structure

A

Lipid membrane
Docking glycoprotein gp120
Transmembrane glycoprotein gp41
Matrix protein gag p17
Protease
Capsid gag p24
Reverse transcriptase
Nucleocapsid
Vid, Vpr, Nef and p7
Integrase
RNA

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6
Q

How is HIV infection usually diagnosed?

A

Through blood tests detecting the presence or absence of HIV Abs

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7
Q

How does the virus enter cells?

A

Via the genital mucosal epithelium or intravenous routes

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8
Q

What happens once the virus enters?

A

Entry virus reaches draining lymph nodes and spreads to the gut-associated lymphoid tissue (GALT)

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9
Q

Why is GALT susceptible to infection?

A

Has a large number of CD4+ T cells

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10
Q

What are the stages of the HIV life cycle?

A

Binding/Attachment
Fusion
Reverse transcription
Integration
Replication
Assembly
Budding

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11
Q

What is the binding stage?

A

HIV binds to receptors on the surface of a CD4 cell

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12
Q

What happens in fusion?

A

HIV envelope and the CD4 cell membrane fuse, which allows HIV to enter the CD4 cell

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13
Q

What happens in reverse transcription?

A

Inside the CD4 cell HIV releases and uses reverse transcriptase to convert its HIV RNA into HIV DNA
This allows HIV to enter the CD4 cell nucleus and combine with the cell’s genetic material (cell’s DNA)

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14
Q

Describe integration

A

Inside the CD4 cell nucleus HIV releases integrase
HIV uses integrase to insert its viral DNA into the DNA of the CD4 cell

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15
Q

Describe what happens in replication

A

Once the HIV DNA is integrated into the CD4 cell DNA, HIV uses the machinery of the CD4 cell to make long chains of HIV proteins
The protein chains are the building blocks for more HIV virions

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16
Q

Describe what happens in assembly

A

New HIV proteins and HIV RNA move to the surface of the cell and assemble into immature HIV (noninfectious)

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17
Q

Describe budding

A

Newly formed immature HIV pushes itself out of the host CD4 cell
The new HIV releases protease
Protease breaks up the long protein chains in the immature virus, resulting in mature virus

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18
Q

What drugs inhibit the binding stage?

A

CCR5 antagonist
Post-attachment inhibitors

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19
Q

What drug classes inhibit reverse transcription?

A

Non-nucleoside reverse transcriptase inhibitors (NNRTIs)
Nucleoside reverse transcriptase inhibitors (NRTIs)

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20
Q

What inhibits uncoating of the virus?

A

TRIM5a

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21
Q

What prevents reverse transcription of the virus?

A

APOBEC3G
SAMHD1

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22
Q

What inhibits virus release?

A

Tetherin

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23
Q

What does Vif do?

A

Inhibits APOBEC3G

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24
Q

What does Vpx do?

A

Inhibits SAMHD1

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25
What does Vpu do?
Inhibits tetherin
26
What components of the immune system are involved in anti-HIV immune response?
Cytotoxic CD8+ T cell response targets infected cells presenting antigens restricted to HLA class I alleles Generation of neutralising Ab to gp160 envelope glycoprotein ADCC mediated by NK cells
27
What are the 3 main stages of HIV disease?
Acute Chronic AIDS
28
What happens within 4 weeks of infection?
Significant damage has occurred to the lymphoid and germinal centres Viremia exceeds 1 million RNA copies/ml of blood CD4+ T cell numbers decline dramatically
29
What are the symptoms?
Fever Enlarged lymph nodes Sore throat Muscles and joint pain Lethargy
30
Describe the chronic phase
Lasts between 2-10 years Characterised by low level viral replication and gradual decline in numbers of CD4+ T cells
31
What are the HIV-1 associated co-morbidities?
Opportunistic infections - pneumonia, Salmonella, candidiasis, toxoplasmosis Co-infection - M.tb, influenza, cryptococcal meningitis Cancer Autoimmune and inflammatory diseases CVD Liver disease HIV-associated neurological disease (HAND) Immune reconstitution inflammatory syndrome (IRIS)
32
What are the HIV-1 patient phenotypes?
Fast progressor Slow progressor/long term non progressor (LTNP) Elite controller Resistant
33
What factors influence disease progression and pathogenicity?
Both host and viral factors Gut microbiota
34
What are the host factors affecting pathogenicity?
Receptor polymorphisms HLA alleles
35
What are viral factors affecting pathogenicity?
Genomic variability
36
How does the gut microbiota affect pathogenicity?
HIV-1 alters the microbiota This influences infection of CD4+ T cells Microbial diversity predicts immune status in HIV-1 infection
37
What is the most widely used measure of infection pathogenicity?
Set point viral load
38
What is set point viral load?
The viral load that the body settles at within a few weeks to months after infection with HIV
39
What determines set point viral load?
Host factors Copy number in KIR genes Age and sex Only 22% of SPVL is explained by these variables About 33% of SPVL variation is based on variability within HIV-1
40
What are factors influencing the pathogenicity of HIV-1?
Strong and consistent relationship between level of viremia and level of CD4+ and CD8+ T cell activation in acute HIV infection
41
Does progressive disease result in increased viral load or does increased viral load cause disease?
High viral load can be observed without disease progression But immune activation is more closely associated with disease progression because disease is required for immune activation to occur
42
What does immune activation predict?
Disease progression, pathogenicity and morbidity in HIV-1 infection
43
What is transmitter virus?
The virus transmitted from one person to another Has low replicative ability because has evolved evasion strategies to avoid host immune response When this virus is transmitted from one person to another, it does not have the same immune pressure on it so it reverses the mutations evolved to evade immune response, which reduces replicability Cannot then increase its viral load after replicability is reduced
44
What are markers of immune activation in HIV-1 infection?
CD38 and HLA-DR on CD4+ and CD8+ T cells Monocyte activation Serum LPS Soluble CD14 D-dimer CRP PD-1 - associated with suppression and exhaustion of immune responses
45
Describe immune activation in HIV-1 infection
Precedes immune deficiency Involves multiple aspects of the immune response Not fully understood how HIV-1 infection causes immune activation and disease progression Even after successful antiretroviral therapy, patient immune systems may fail to fully recover
46
What are possible causes of immune activation?
LPS translocation across the gut mucosa Co-infection - coinfections such as CMV, EBV, HBV or HCV are not always present Innate immune activation Pyroptosis during cell-cell infection by HIV-1
47
What happens in immune activation in HIV?
Inflammation Damage to lymphoid and germinal centres in the gut B cell dysfunction Innate immune activation - triggers not known CD4+ T cell decline AIDS Co-infection
48
What are the consequences of immune activation?
Inflammation caused by pyroptosis and microbial translocation Dysregulation and chronic activation of CD4+ and CD8+ T cells by inflammatory cytokines Activation and preferential depletion of HIV-1 specific CD4+ T cells Subsequent depletion of follicular CD4+ T cells and disruption of the humoral immune response Chronic activation and dysregulation of CD4+ and CD8+ T cells results in onset of exhaustion A failure of CD4+ memory T cell population to be restored and maintained
49
Why do the vaccines developed for HIV not work?
The gp120 antigen used in vaccination does not accurately reflect the complexity of gp160 trimers present on the virus HIV-1 is a highly mutable virus due to a high error rate in the reverse transcriptase - allows the virus to quickly generate mutations and escape from vaccine induced immunity HIV-1 establishes infection and dysregulated host immunity within the first 48hrs of infection
50
Describe the HVTN 702 vaccine
129 infections in the vaccinated group and 123 in those who received placebo Trial stopped early as was 'futile' to continue Cost $104 million No evidence of efficacy
51
What is Zidovudine?
First drug to demonstrate efficacy against HIV-1 However, high doses are toxic and are associated with escape mutations
52
How did combined antiretroviral therapy come about?
Between 1994-1998 many new antiviral drugs gained FDA approval 30 FDA approved antiretroviral drugs targeting viral entry, reverse transcriptase, protease and integrase Allowed for first time combinations of antiretroviral therapy (cART) Dramatically increased the efficacy and durability of therapy by reducing ability of the virus in generating escape mutations
53
What are problems with cART?
Cannot clear HIV-1 infection due to reservoirs of latent virus May be unable to penetrate viral reservoirs such as CNS Toxicity and need for cART for life results in non-compliance with treatment Access to cART is low in LMICs and Cost of cART creates significant financial burden on healthcare Interruption of cART associated with increases in morbidity and mortality
54
What characterises HIV-specific CD8+ T cell responses of early treated individuals?
Increased CD127 and BCL-2 expression Greater in vitro IFN-g secretion Enhanced differentiation into effector memory T cells Robust HIV-specific CD4+ T cell responses Reduced expression of genes associated with activation and apoptosis, with concurrent upregulation of pro-survival genes
55
What are some of the most common comorbidities in HIV-1?
Hepatitis Mental health disorders CVD
56
What patients are more likely to have comorbidities?
Male, White and older patients
57
What is the relationship between Mpox and HIV-1 infection?
A recent outbreak of Mpox in 2022 in London was a public health emergency of international concern Current data indicate that 40% of people with mpox in the USA have HIV-1 Unknown whether existing HIV-1 infection increases likelihood of symptomatic HIV-1 infection Individuals with severe immunodeficiency are more at risk of sever mpox infection and possibly death
58
What are the 2 vaccines for mpox?
JYNNEOS ACAM2000 - increased risk of serious side effects in people with HIV-1
59
What is a functional cure for HIV-1?
Promote strong anti HIV-1 immune responses (Vacc4x) - CD8+ T cell responses, ADCC, immune modulation Reactivate latent HIV-1 infection - TLR agonists, HDAC inhibitors (Romidepsin)
60
What does Romidepsin do?
Activates latent infection
61
What does Vacc4x vaccination do?
Primes CD8+ T cells in a shock and kill strategy
62
Give some other approaches to prevent, treat or cure HIV-1 infection
Stem cell transplant Early, intense ART Antibody therapy with broadly neutralising antibodies Pre-exposure prophylaxis Immunotherapy
63
What do broadly neutralising antibodies do?
Bind to conserved regions of viral envelope protein Develop and used in combination as an alternative to cART Bispecific antibodies in development
64
What are bnABs characterised by?
Long HCDR-3 regions High frequency of somatic hypermutations and V(D)J rearrangements which are associated with their potency
65
How are bnABs developed?
Through a process of B cell affinity maturation Germline B cells and cognate antigen in development for use as a vaccine
66
What is the aim of immunotherapy?
To enhance the ability of the immune system to combat infection or cancer
67
Describe immune checkpoint blockade (ICB) using checkpoint inhibitors as immunotherapy for HIV-1
ICB reactivates exhausted T cells, allowing them to target infected cells/tumours PD-1 blockade potentiates HIV latency reversal ex vivo in CD4+ T cells from ART-suppressed individuals Anti-PD-1 monoclonal Abs reversed HIV latency in CD4+ T cells after first infusion in 32 patients with both HIV and cancer on ART undergoing immunotherapy
68
Describe cytokine therapy for HIV-1
Interleukin 7 repeated cycles were well tolerated and achieved sustained CD4 T cell restoration to >500 cells/ul in majority of study participants Decreases in colonic and systemic inflammation in chronic HIV infection after IL-7 administration

Infection and Immunity (33 decks)

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