HIV Disease Processes Flashcards
What type of virus is HIV-1?
Single stranded RNA virus
How is HIV-1 transmitted?
Sexually but can also be intravenously through either blood transfusion or intravenous drug use
What does HIV cause?
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
Describe the HIV-1 genome
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
Describe the HIV-1 virion structure
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
How is HIV infection usually diagnosed?
Through blood tests detecting the presence or absence of HIV Abs
How does the virus enter cells?
Via the genital mucosal epithelium or intravenous routes
What happens once the virus enters?
Entry virus reaches draining lymph nodes and spreads to the gut-associated lymphoid tissue (GALT)
Why is GALT susceptible to infection?
Has a large number of CD4+ T cells
What are the stages of the HIV life cycle?
Binding/Attachment
Fusion
Reverse transcription
Integration
Replication
Assembly
Budding
What is the binding stage?
HIV binds to receptors on the surface of a CD4 cell
What happens in fusion?
HIV envelope and the CD4 cell membrane fuse, which allows HIV to enter the CD4 cell
What happens in reverse transcription?
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)
Describe integration
Inside the CD4 cell nucleus HIV releases integrase
HIV uses integrase to insert its viral DNA into the DNA of the CD4 cell
Describe what happens in replication
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
Describe what happens in assembly
New HIV proteins and HIV RNA move to the surface of the cell and assemble into immature HIV (noninfectious)
Describe budding
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
What drugs inhibit the binding stage?
CCR5 antagonist
Post-attachment inhibitors
What drug classes inhibit reverse transcription?
Non-nucleoside reverse transcriptase inhibitors (NNRTIs)
Nucleoside reverse transcriptase inhibitors (NRTIs)
What inhibits uncoating of the virus?
TRIM5a
What prevents reverse transcription of the virus?
APOBEC3G
SAMHD1
What inhibits virus release?
Tetherin
What does Vif do?
Inhibits APOBEC3G
What does Vpx do?
Inhibits SAMHD1
What does Vpu do?
Inhibits tetherin
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
What are the 3 main stages of HIV disease?
Acute
Chronic
AIDS
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
What are the symptoms?
Fever
Enlarged lymph nodes
Sore throat
Muscles and joint pain
Lethargy
Describe the chronic phase
Lasts between 2-10 years
Characterised by low level viral replication and gradual decline in numbers of CD4+ T cells
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)
What are the HIV-1 patient phenotypes?
Fast progressor
Slow progressor/long term non progressor (LTNP)
Elite controller
Resistant
What factors influence disease progression and pathogenicity?
Both host and viral factors
Gut microbiota
What are the host factors affecting pathogenicity?
Receptor polymorphisms
HLA alleles
What are viral factors affecting pathogenicity?
Genomic variability
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
What is the most widely used measure of infection pathogenicity?
Set point viral load
What is set point viral load?
The viral load that the body settles at within a few weeks to months after infection with HIV
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
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
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
What does immune activation predict?
Disease progression, pathogenicity and morbidity in HIV-1 infection
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
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
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
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
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
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
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
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
What is Zidovudine?
First drug to demonstrate efficacy against HIV-1
However, high doses are toxic and are associated with escape mutations
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
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
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
What are some of the most common comorbidities in HIV-1?
Hepatitis
Mental health disorders
CVD
What patients are more likely to have comorbidities?
Male, White and older patients
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
What are the 2 vaccines for mpox?
JYNNEOS
ACAM2000 - increased risk of serious side effects in people with HIV-1
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)
What does Romidepsin do?
Activates latent infection
What does Vacc4x vaccination do?
Primes CD8+ T cells in a shock and kill strategy
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
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
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
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
What is the aim of immunotherapy?
To enhance the ability of the immune system to combat infection or cancer
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
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
