HIV infection Flashcards
(38 cards)
what is HIV?
HIV is a retrovirus, an RNA virus which uses reverse transcriptase (RT) to make a DNA copy that becomes integrated into the DNA of the infected cell
outline the characteritics of the HIV Genome Structure.
- Small RNA virus (~ 10KB): expresses just 10 genes
- Member of retrovirus family (uses reverse transcriptase to make DNA copy of itself)
- Lentivirus - means its slow and characterized by long incubation period
- has regulatory, structural and accessory genes
- accessory genes help it t o overcome herd immunity
- structural gene creates the viral capsid
outline the Mechanism of viral replication of HIV.
- GP160 on HIV allows it to dock onto the CD4 and CCR5 receptors on host cell
- The capsid enters the cell and enzymes and nucleic acid are released
- Using reverse transcriptase, single stranded RNA is converted into double stranded DNA
- Viral DNA then is integrated into the cells own DNA by integrase
- When the infected cell divides the viral DNA is read and proteins are made
- the proteins are assembled
- Budding of new immature virus
- Immature virus breaks free to undergo more maturation
- Maturation protein chains in the new viral particle are cut by the protease enzyme into individual proteins that combine to form a working virus
what HIV gene is most targetted for treatments?
pol - this encodes reverse transcriptase, integrase and protease
name the HIV primary and co-receptors.
primary = gp120 - binds to CD4 on T cell
- GP41
- GP120
co-receptors = CCR5 and CXCR4 chemokine receptors
CCR5 is prominant in early infection
- CXCR4 - later in infection - development of X4 strain mutation
what are the anti-retroviral therapy targets to target HIV replication?
- integrase inhibitors
- protease inhibitors
- reverse transcriptase inhibitors
- fusion / entry inhibitors
what are the characteristics of HIV which allows it to mutate rapidly?
- Error-prone replication (the enzyme reverse transcriptase makes at least 1 error in every replication cycle)
- Rapid viral replication (generation time ~2.5 days)
- Large population sizes (~1010 new virus particles produced each day)
what are the clinical features of untreated HIV-1?
Vaginal/oral candidiasis
skin disease
fatigue
bacterial pneumonia
herpes zoster
oral hairy leukemia, thrush, fever, diarrhoea, weight loss
Kaposi’s sarcoma, non-Hodgkin’s lymphoma
Pneumocystis carinii pneumonia
Toxoplasmosis, oesophageal candidiasis, cryptococcosis
cns lymphoma
outline HIV pathogenesis
- HIV is integrated into the DNA of the infected CD4-expressing cells
- HIV infects a range of CD4, helper T, dendritic cells, macrophages and thymocytes cells
- evades antibodies
Why does the immune response to HIV-1 fail to clear the virus?
- The immune system generates a massive immune response involving up to 20% of all circulating T and B lymphocytes
- neutralising antibodies take months to develop - rarely neutralise the HIV strains
- CD4+ T-helper response is lost because these are infected first
- vigorous response from cytotoxic CD8+ but ultimately fail when “immune exhaustion” sets in
when antibodies are created for HIV antigens, why do these not completely neutrilise the virus?
- surface is derived from the host cell membrane
- spike is heavily glycosylated (with sugars resembling human types)
- spikes either in deep pockets overhung by sugar molecules or only revealed when the virus docks onto the CD4 molecule
- The envelope (gp120/41) proteins can change
- virus can evolve to avoid antibody recognition
- the circulating neutralising antibodies rarely recognise their own viral envelope variants
cytotoxic t-cell role in the control of HIV-1
- Cytotoxic T-Lymphocytes (CTL) appear early in HIV infection, coincident with a rapid drop in viral load
- Depletion of CD8+ T-cells leads to marked rise in viral load
- CTL causes HIV-1 to mutate different varients to evade immune system
- CTL selection leads to HLA-class I associated “foot-prints” on viral evolution
How does HIV-1 evade the CTL response ?
- Mutant HIV variants that evade the T-cell response appear within weeks of HIV infection
- Initially responses develop to the new variants, but these are undermined by the failure of CD4+ cell and dendritic cell function
- HIV-1 nef protein - reduces cell-surface expression of HLA class I molecules, on the virus, needed for CTL recognition,
- upreg of the “death” molecule Fas that can kill virus-specific CTL
- HLA- A and B molecules are down-regulated to undermine CTL killing of infected cells but HLA-C expression is maintained to prevent NK cell killing
- Ultimately CTLs develop functional “exhaustion”, associated with expression of inhibitory molecules
Summary of immune response to HIV
- Vigorous immune response but no demonstrable protective immunity with rare exceptions
- Excessive immune activation which favours viral replication
- Immunological dysfunction with involvement of all elements of host defence
- Ongoing viral replication with progressive immunological impairment leading to clinical manifestations of immunodeficiency
Why is life expectancy still reduced in HIV-infected people on cART?
- Issues of adherence, side-effects, drug resistance
- Increase in non-AIDS-defining illnesses (NADIs): lung, cardiovascular and renal disease
- Incidence of NADIs is related to:
- Size of latent HIV reservoir
- Persistent immune activation
- CMV co-infection
ART controls HIV replication but a viral reservoir persists, explain.
- Even with the most effective available ART, a poorly-defined reservoir of latently-infected cells persists for years, and HIV starts replicating again (to pre-treatment levels) within weeks of cessation of therapy
- HIV is thought to persist as DNA integrated into “resting” transcriptionally-silent CD4+ T-cells and other cells such as tissue macrophages and T follicular helper cells
- HIV may continue replicating in lymphoid tissue and other immune-privileged sites
- Reservoir size correlates with persistent immune activation, largely driven by translocation of microbial products across the gut (damaged gut-associated lymphoid tissue and leaky gut since primary infection)
outline the whole process of how HIV invades the immune system.
- HIV binds to CD4 receptor or co-receptor CCR5 or CXCR4
- HIV fuses with cell membrane and reeases its genetic material into it
- reverse transcriptase converts the rna into dna
- the now viral dna goes into the host cells genome using integrase
- the infected cell produced HIV particles, leading to cell destruction
cell destruction: - Direct viral destruction of CD4+ T cells.
- Indirect mechanisms, such as immune-mediated killing of infected cells.
- Chronic immune activation leading to exhaustion and apoptosis of uninfected CD4+ T cells.
- due to the loss of CD4 cells - the immune system lacks the same ability to combat infections and cancers
- persistant activation of the immune system occurs due to ongoing viral replication and contributes to immune exhaustion
- can lead to aids - CD4+ T cell count below 200 cells/µL
outline the tests used to diagnose hiv.
antibody test:
- detects antibodies produced in response to hiv
- may not detect recent exposures 3-12 weeks
antigen/antibody combination tests:
- detects HIV antibodies and the p24 antigen produced by HIV
- detectable after 2-4 weeks
nucleic acid tests (NAATs)
- detects viral rna in blood
- can identify hiv after 10-14 days of exposure
- most sensitive
- expensive
outline the diagnostic testing process of hiv.
a. Initial Screening:
First Test: Typically an antigen/antibody combination test (lab-based or rapid test).
If positive, further testing is required to confirm the result.
b. Confirmatory Testing:
A second test is performed using a different method (e.g., HIV-1/HIV-2 differentiation assay) to confirm the diagnosis.
This process rules out false positives from the initial test.
c. Additional Testing:
HIV RNA Testing (NAT): Used when confirmation is needed or to detect acute HIV infection during the window period.
Western Blot: Historically used for confirmation but now largely replaced by modern tests.
Describe how HIV is prevented.
- use condoms
- reduce number of sexual partners
- regular testing
pre-exposure prophylaxis:
- medication for those with a HIV-positive partner
- reduces risk of aquiring HIV
post-exposure prophylaxis:
- short course of antiviral drugs taken within 72 hours of potential exposure to HIV
- providing clean needles in drug programs
- ensuring safe disposal of sharps and needles
- education and awaereness
- public health campaigns
basic clinical features of HIV and aids
early/acute infection - 2-4 weeks:
- flu-like symptoms
chronic infection (clinical latency stage)
- can be assymptomatic
- persistant generalised swollen lymph nodes - Lymphadenopathy
- gradual decline in CD4 count
- diffuse symmetrical maculopapular rash
symptomatic HIV infection (CD4+ T cell count <500 cells/µL):
- Persistent fever
- Weight loss
- Chronic diarrhea
- Fatigue
- Night sweats
- Oral thrush (fungal infection in the mouth)
- Herpes zoster (shingles)
- Recurrent respiratory infections (e.g., sinusitis, bronchitis).
AIDS:
- Severe immune suppression leads to life-threatening infections and cancers.
eg
- Pneumocystis jirovecii pneumonia (PCP
- candidiasis
- cervical cancer
Have a basic understanding of the global burden of HIV infection.
hella hella crazy
- 38.4 million people globally are living with HIV.
- Of these, approximately 1.7 million are children (under 15 years old).
- 650,000 people died from AIDS-related illnesses in 2022, roughly 1 death every 49 seconds.
- 67% of global HIV cases are in Sub-Saharan Africa.
what 2 markers are used to monitor HIV infection?
- CD4 cell count
- HIV viral load
what is Acute HIV Infection (acute retroviral syndrome - ARS) and its presentation. what is the peak viral load called?
the initial, acute infection of aids
catagorised with high viral load
- peak viral load - viremia
