HIV and AIDS

L22

How long did it take for the virus responsible for aids to be identified? Which virus is it?

2 years

HIV

Which cells can be infected by HIV?

CD4+ T helper cells, macrophages, monocytes, dendritic cells, B cells

What type of virus is the HIV virus?

lentivirus (slow) and retrovirus aka tumour virus that converts RNA into DNA

What is a virion?

complete structure capable of infecting a host - made up of viral genome (DNA or RNA) and a capsid (protein coat)

What is the structure of the HIV virion?

• lipid envelope made up of glycoproteins (gp) 41 and 120 that act as a viral receptor

• 2 copies of single stranded RNA replicating through reverse transcriptase

What does HIV stand for? And AIDS?

human immunodeficiency virus
acquired immunodeficiency syndrome

What are the steps of HIV infecting a cell?

• virus binds to host cell CD4 +ve receptor

• virus envelope fuses with plasma membrane

• nucleocapsid enters cytoplasm

• viral RNA reverse transcribed into double stranded DNA

• viral DNA transported to nucleus and integrates into host cell genome (provirus)

Where is the newly formed RNA and mRNA following retrotranscription made? What do these allow the production of?

cytoplasm

viral protein

What does a new HIV nucleocapsid form from in the host cell? How does the become a new virus?

from the viral proteins made from the new viral mRNA

virus buds from cell, acquiring a lipid envelope

What are the 3 types of infection that HIV can cause? Explain each

• latent - present in host but not replicating

• permissive - full viral replication occurs

• lytic - active replication leads to host death

Which protein and therefore cells are the target for HIV?

CD4 +ve so T helper cells

How are T helper cell numbers affected throughout the progression of HIV infection?

virus initially cleared

pool of infected cell gradually increases bc T cell stimulation = more HIV provirus transcription

How does each round of viral replication impact the number of t cells infected?

increases the infected t cell count

Why is expression of CD4 said to not be sufficient for HIV infection?

CCR5 (chemokine receptor) co-receptor required for virus fusion with host cell

Which cells present the HIV antigen to t cells in lymphoid tissue leading to infection? What type of infection occurs?

dendritic cells

permissive infection - patient acting as a reservoir of virus

How can the CNS be infected by HIV?

monocytes infected can traverse the blood/brain barrier

How do virus levels in the blood evolve over the course of HIV infection?

initially high levels of virus in blood are cleared but virus mutates avoiding immune system then virus levels increase dramatically 2 to 3 years after infection

Describe seroconversion

process where an individual's blood serum develops detectable antibodies against a specific antigen, typically after exposure to a virus

When does seroconversion occur in patients?

sometimes not until after 3 months - ie antibodies to HIV virus protein not made until 3 months after infection

Through which cells does the immune system mount a response to HIV infection?

particularly through CD8 +ve cytotoxic T cells

What are the 3 phases of HIV infection leading up to AIDS?

flu like disease from 2 - 8 weeks after infection

asymptomatic phase and symptomatic phase over the next 10 years

leading to the 4th step: AIDS

What does t helper cell depletion lead to?

AIDS

At what DC4 +ve t cell concentration in the blood is a patient considered to have AIDS?

under 200 mm³

Where are infected t cells, considering they’re not in the blood?

in lymphoid tissue

What are 3 ways in which infected t helper cells are killed, leading to their depletion in the blood?

• direct lysis by virus

• killed by cytotoxic t cells or other immune mechanisms

• apoptosis

What symptoms are associated with AIDS and how does this highlight the role of t helper cells?

all adaptive immune responses compromised so:

• opportunistic infections

• rare cancers

• CNS degradation, dementia

• reactivation of latent viruses

in absence of t cell = no adaptive immune response

What type of cancer is associated with AIDS? Briefly describe it

Kaposi’s sarcoma caused by Herpes virus - cancer of blood vessel endothelial cells

Where did the 2 types of HIV originate from? Which came first?

HIV - 1 from central african chimpanzees

HIV - 2 from west african sooty mangabees

second came first, also the less virulent and less easily transmitted form

How many people have died from HIV? How many currently live with it?

over 32 million lives

38 million

What are HIV transmission pathways?

• 70% from unprotected sexual intercourse

• 28% through blood and blood products mainly drug use

• breast-feeding

• mother to foetus

Why is HIV not an easily transmitted virus (ie what does it require for transmission)? When are individuals most infectious?

required direct contact with mucous membranes

early stages of disease when virus titre highest

What is virus titre?

lowest concentration of a virus that still infects cells

What are preventative methods to avoid AIDS?

changes in behaviour - blood testing, decreased drug use/needle sharing, treat HIV +ve pregnant women

Is global incidence of new HIV infections rising or decreasing?

decreasing by about a million over the last 10 years

What are problems that limit HIV vaccines?

• high mutation rate of the virus

• humoral immunity may not be protective = need for cytotoxic T cell introduction

Which vaccine is currently the most efficient?

RV 144 thai trial - shows 31% protection against the virus

What is the current therapeutic focus in developing HIV vaccines?

Vaccines inducing “broadly neutralising antibodies”

- self-assembling nanoparticles (recombinant HIV proteins)

- mRNA

Engineered virus vaccines (induce cytotoxic T cells)

How does the mutation rate of HIV virus compare to that of the flu virus, itself considered to have a high mutation rate?

60 more !

What are limits of currently used drug therapy options to treat HIV?

• high mutation rate of virus

• toxicity

• viral latency

• cost

What are the 2 types of drug therapy used despite difficulty of treating HIV and their respective mode d’action?

• combination therapy - cocktail of drugs directed at different viral targets

• preventative drugs - twice yearly injections of Lenacapavir (multistage HIV-1 capsid inhibitor with long half-life) prevented infection

What are different targets of combination therapy drugs?

specific viral targets like:

• AZT and other nucleoside reverse transcriptase inhibitors

• protease inhibitors to stop virus protein production = no more capsule made = n new virus

• fusion inhibitors = no viral entry

• capsid inhibitors = no assembly of viral capsid

Essentially which 3 mechanisms of viral spread are targeted by combination therapy HIV drugs?

fusion and entry of virus; retrotranscription; and assembly of the new viral capsid

What are future treatment ideas for HIV?

• “Kick and Kill” – re-activation of latent virus + immunotherapy

• “Passive immunisation” using human monoclonal antibodies (broadly neutralising antibodies) or engineered T cells

• Gene editing with CRISPR/Cas9?

• Engineered T cell receptors (TCRs) recognising reservoirs of infected CD4+ve T cells

Which patient inspired the new stem cell therapy for HIV? Why is it too risky for current general use?

berlin patient with bone marrow cells lacking CCR5 = HIV can’t infect cells bc CCR5 is required for infection

endogenous bone marrow has to be destroyed and transplanted from a donor with a CCR5 mutation

Of the 67% of HIV +ve patients receiving antiretroviral therapy, how many had suppression of the virus?

59%

What have been 2 social/political barriers to HIV treatment recently?

2020 covid outbreak + 2025 Trump US funding cuts to science

Which HIV protein binds to CD4 on helper t cells? What receptors are also required?

gp120

chemokine like CCR5

Why does viral latency make a cure for HIV difficult?

virus hides in dormant cells = difficult to eradicate the HIV virus completely, treatment has to be continuous