lecture 15

Question 1

What reduces female acquisition?

Answer 1

• tenofovir containing microbicide reduces female acquisition by 40%
• BAT 24 coitally-related gel use
• • insert 1 gel up to 12 Before sex
• • insert 1 gel as soon as possible within 12 hours After sex
• • no more than Two doses in 24 hours

(tenofovir is a nucleotide reverse transcriptase inhibitor)

• mimiced how we control reducing mother to child transmission
• if you give the mother drugs just before and just after delivery you can dramatically reduce transmission of virus from mother to baby (HIVNET 012 nevirapine regimen)
• this mimics the same approach but uses CAPRISA 004 tenofovir gel regimen

Question 2

What is PREP?

Answer 2

• pre-exposure prophylaxis
• give daily antivirals (tenofovir or truvada) either orally or vaginally
• highly effective in preventing transmission in monkey models
• oral truvada as PREP reduced risk of transmission amongst gay men by 40% (up to 70% if compliance is high)

Question 3

What is treatment as prevention?

Answer 3

• decreases in community viral load are accompanied by reductions in new HIV infections in SF
• heterosexual HIV-1 transmission after initiation of antiretroviral therapy: a prospective cohort analysis
• association of highly active antiretroviral therapy coverage, population

HPTN 052

• N=1763
• discordant couples in Africa, South America and US
• enrolled patients with CD4 counts 350-550
• randomised to either immediate HAART or defer until CD4< 0.001
• so significant majority were in people not on treatment
• ART reduces HIV transmission by 96% in HIV serodiscordant heterosexual couples

Question 4

Can universal cART end HIV?

Answer 4

• projections suggest that no intervention will lead to continued transmissions at a level similar to current
• ART CD4+ count <350 per µl will lead to a decrease but not particularly significant
• universal voluntary HIV testing and immediate ART could dramatically affect incidence

Question 5

What is the efficacy of HIV prevention?

Answer 5

• ART to prevent transmission most effective (96%)
• Male medical circumcision (70%)
• PREP (less effective according to studies in women than in gay men)
• vaginal microbicides showing efficacy

Question 6

What is the end of AIDS?

Answer 6

• seek, test and treat (still not done super well)
• prevention: vaccine, needed
• cure

Question 7

What do we mean by a cure for HIV?

Answer 7

Cure

• infectious diseases model
• elimination of all HIV-infected cells
• HIV RNA < 1 copy/ml
• sterilising cure

Remission

• cancer model
• long term health in absence of cART
• HIV RNA < 50 copies/mL
• functional cure

Question 8

Is HIV cure possible?

Answer 8

The Berlin Patient (7 years off ART)
- bone marrow transplant from a donor naturally resistant to HIV infection

The Mississippi baby (2 years of ART)

• very early treatment, 30 hours post delivery
• very, very low levels (functional cure)

Post treatment controllers

• ART in acute infection (VISCONTI; n=18; 8 years off)
• ART in chronic infection (Belgium; n=4; 6 months off)

Question 9

What are barriers to cure?

Answer 9

• latently infected T cells
• residual viral replication
• anatomical reservoirs

Question 10

What is HIV latency and infection of resting T-cells?

Answer 10

• predominantly infects activated CD4+ T cells –> replicates, leaves and kills the cell
• but patients on therapy –> virus can’t infect new cells
• resting CD4+ T cells: if the virus manages to enter it can integrate in the genome and not complete the virus life cycle
• two ways latently infected cells can be derived
• • rarely an activated infected cell survives, reverts to become a central memory cell
• • direct infection, assisted by tissue chemokines

latently infected cells are very long lived cells

• persist in people even when the viral load is undetectable/less than 50 copies/mL
• at any time this virus is fully infectious
• if it becomes activated, releases pathogen
• it someone on treatment, the virus can’t go anyway, so stays at very low levels
• latently infected cells can undergo homeostatic proliferation
• estimated about 60/million T cells are latently infected
• can be established in naive T cells, transitional memory and central memory T cells, rarely in the thymus
  = latent reservoir

Question 11

What is residual replication?

Answer 11

• another way that HIV can persist
• residual viral replication
• few infected cells with ongoing rounds of replication
• ART blocks some of that
• evidence for residual replication in about one third of patients on cART

Question 12

What are anatomical reservoirs?

Answer 12

• virus can be sequestered into unique tissue compartments
• brain, lymphoid tissue, genitourinary tract and GIT
• in each of these there are latently infected cells, and other cells that can become infected e.g. DCs, macrophages, astrocytes

Question 13

What are strategies for cure?

Answer 13

• eliminate latently infected cells
• make cells “resistant” to HIV
• eliminate residual virus replication
• enhance HIV-specific immunity

Question 14

How can we eliminate late infection?

Answer 14

Activating latent infection

• if you activate the integrated virus you’ll start making RNA/viral proteins etc, virions when they exit
• this leads to cell death
• shock and kill
• things that activate latent infection = HADACi, Cytokines e.g. IL-7, disulfiram, quinolines, methylation inh, histone methyl transf inh, BET inh
• histone deacetylase inhibitors turn HIV genes “on”
• HDACi
• latently infected cells are rare but this affects all cells - big problem

Question 15

How can we make cells resistant to HIV?

Answer 15

• gene therapy
• block the action of an HIV protein
• • RNA interference
• express an anti-viral factor
• • mutant APOBEC 3G
• eliminate integrated HIV
• • LTR
• remove an essential host protein
• • CCR5

Question 16

How can nucleases help eliminate HIV?

Answer 16

• zinc finger nucleases chop up DNA
• can eliminate CCR5 expression of eliminate HIV
• zinc finger nuclease heterodimer
• DNA double-strand break at zinc finger nuclease target site
• gene disruption
• leukapharesis, CD4+ T cell isolation, treat with zinc finger nucleases, expansion of autologous R5-disrupted T cells ex vivo, re-infuse into person with HIV
• most recent results suggest modified cells are safe and that they survive
• didn’t control virus replication because only small numbers of T cells were modified - if you could boost to much high levels might mean that you have cure/immunity

Question 17

When did Paul get infected? What was it like when he was diagnosed?

Answer 17

• doesn’t know when he got infected with HIV
• probably around 1985, when he was 21
• tested in 1991
• difficult to hear
• at this time it was like being told he was going to die
• wasn’t a great shock

Question 18

What was happening with friends/community?

Answer 18

• 91 - 93 was the peak of the epidemic on the gay community in sydney
• gay men in sydney at that time were dying of AIDS left and right
• people got sick of going to funerals
• massive community impact
• the doctor’s prognosis was about 4 or 5 years
• with treatment more

Question 19

What was the response of family and friends?

Answer 19

• didn’t tell everyone at first because it’s a very stigmatised disease
• association with anal sex/drug use etc can make people scared to admit
• eventually realised that it was good to speak out about it
• by 95 very public about living with HIV

Question 20

What treatment has Paul had?

Answer 20

• a long period of time kept taking drugs to take the newest that had become available
• started out with AZT
• AZT monotherapy for 3 - 4 years
• constant nausea, weight loss, anaemia, muscle loss, generally feeling sick
• most drugs induced nausea up until about the turn of the century
• now takes raltegravir and tenofovir and FTC
• zero side effects
• tolerability - early drugs highly toxic (e.g. pancreatitis due to DDI)
• last decade and a half a lot easier
• 3 tablets a day
• anti- hypertensive
• baltrax

Question 21

What other diseases has Paul had?

Answer 21

• Hep C
• cured
• got Hep C because he had HIV
• acquired it sexually (normally a rare way to acquire)
• predisposition in people with HIV
• bit of a blow
• in some ways harder because unexpected
• current standard treatment for Hep C is based on interferon (significant unpleasant side effects)
• new treatments coming along at a great rate
• last year was in a clinical trial for sephozmavir
• taken orally twice a day + ribavirin
• on that for 6 months
• cured
• had all the sexually transmitted infections
• syphilis
• gonorrhea and chlamydia a couple of times each

Question 22

What’s the response now when people get the diagnosis?

Answer 22

• still very hard
• in australia have so much access to treatment –> not a medical issue, but a social issue
• layer of stigma – makes you question your own worth as a person
• people inevitably question themselves
• still a lot of bad press around HIV treatments - incredibly difficult

Question 23

What is known of sex with HIV+ people?

Answer 23

• sometimes safer because they take all the precautions whereas someone who says they are negative may not know it

Question 24

What is the cost of treatment for HIV?

Answer 24

• about $20,000 supported by the government
• $37 for individuals in treatment
• cost effective for the government
• low income countries use generic drugs