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Retroviruses Flashcards

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1
Q

Retroviruses

HIV

HTLV-1

Gene Therapy

XMRV (not really studied)

A

HIV causes aids, one of th emost important infectious diseases in the world

HTLV-1 (human T cell leukemia virus type 1), causes an adult T cell leukemia, rare in the US

Gene Therapy
- ability to integrate, retroviruses are sometimes used as gene therapy vectors to stably introduce genes into human cells

XMRV- link between this and chronic fatigue syndrome and prostate cancer but this virus was a lab contaminant so ignore this

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2
Q

Part 1: Retrovirus Basics

A

Enveloped virus

Spread by body fluids

Single enveloped spike protein (Env) RNA genome (single virally encoded glycoprotein called envelop protruding from the viral membrane)

Positive sense RNA

Two copies per virion

Lentivirus - type of virus that can infect non dividing cells, has 6 additional genes that control viral gene expression or subvert the host immune response (in addition to gag, pol and env)
- have to get into nucleus and most simple retroviruses cant get into nucleus until it breaks down during replication/ division but a lentivirus can

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3
Q

Schematic of a retroviral genome and proteins involved

A

LRT (U3 R U5) — gag — pol — env — LTR (U3 R U)

Gag: Group specific Antigen - polyprotein that is processed by viral protease to make the viral matrix and capsid proteins that surround the genome
- large protein cleaved by protease to produce proteins that form the nucleocapsid

Pol: polyprotein that contains the enzymes reverse transcriptase (RT) integrase and protease
- polymerase, produces a polyprotein that contains the three enzymes made by retrovirus: protease integrase and RT

Env: makes the envelope protein that protrude from the viral membrane

LTR: long terminal repeats - repeated sequences at the end of the 10 kB genome that help the virus replicate, play a role in replication and in gene expression

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4
Q

What makes Retroviruses Unique

Feature 1

Why is this important?

A

Retroviruses can make DNA out of RNA

Single Stranded RNA viral genome—> Viral reverse transcriptase enzyme (RT) —> double stranded DNA copy

Important bc

  1. RT is a drug target
  2. RT makes mistakes—> high error rate gives rise to drug resistance (because it has no proof reading ability) —> HIV can quickly evolve and adapt to selective pressures from antiviral drugs or immune system
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5
Q

What makes retroviruses unique?

Feature 2

Why does it matter

A

Retroviruses integrate their DNA into the host chromosome

Viral DNA + host cell DNA—> integrated viral DNA (via viral integrase enzyme)
- covalent insertion of the virus’s double stranded genome into the host genome via integrase

Important bc

  1. Integrase is a drug target
  2. Once integrated the viral dna becomes a permanent part of the cell, it can only be eradicated by killing the cell which makes HIV a life long infection and good for gene therapy
    - cannot clear the virus infection from a cell without killing the cell, retrovirus infections persist for the life of the organism

First integrase inhibitor was Raltegavir

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6
Q

How are retroviruses used clinically

A

As gene therapy vectors

Integration results in stable expression of the transgene but integration can also lead to tumor formation

Eg 11 male infants with SCID

  • bone marrow cells collected infected with mouse retrovirus expresses gene for IL2 receptor—> give cells back to patient —> SCID was cured but they developed leukemia
  • murine retrovirus liked to integrate into transcriptional start sites and in 4 pt it activated expression of a gene linked to leukemia
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7
Q

Where does HIV preferentially integrate?

A

At active genes, but not at transcriptional start sites

  • integration sites cluster around gene rich regions
  • chromosome 13 and 18 which are gene poor have few integrateion events while gene-rich chromosomes have many integrations bc HIV likes to integrate within active genes not start sites (also makes it safer to use for gene therapy than simple retroviruses)
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8
Q

How has gene therapy changed to reduce risks associated with integration

A

Retroviruses—> lentiviruses (can integrate into non-dividing cells )

Eg CAR-T therapy

  • genetically modified HIV expressing Chimeric Antigen Receptor in T cells
  • HIV integrated and CAR expressed, enabling T cells to bind to cells expressing protein CD19 (B cells) and kill them (have body kill Emily’s ALL)

Because lentiviruses have a lower prob to interfere with expression of genes involved in cellular transformation, they are being used in gene therapy trials

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9
Q

Transfection

A

Introduction of any DNA or RNA into cells by a method other than using a virus

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10
Q

Transduction

A

Delivery of a cellular gene to a new cell by using a virus

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11
Q

What is the enzyme other than RT and integrase that Retroviruses use

Why is it important?

A

Protease!!!

Important bc it is an important drug target (protease inhibitors)

GAG/POL polyprotein
GAG— Integrase— RT— Protease

Protease is part of a large polypeptide, protease cleaves the polypeptide into many component parts, including RT, integrase, and viral core proteins and when this occurs the virus ‘immatures’

  • if this does not occur, the virus cannot productively infect cells
  • some of HIVs proteins are made as a large polyprotein, part of this has protease function and after synthesis protease cleaves polyprotein into its various subunits—> produce many proteins from the single precursor
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12
Q

Basic Retrovirus Lifecycle: Where do the 3 viral enzymes act

A

HIV is a lentivirus, a type of retrovirus that can infect non-dividing cells. Other retroviruses only infect dividing cells

Basic retrovirus lifecycle
Receptor binding
- receptor for HIV is CD4 protein—> viral Env protein then mediates membrane fusion with the host cell—> viral core is now in the cell - it must ‘uncoat’ and reverse transcription begins and is completed in the cytoplasm
- Viral DNA enters the nucleus due to nuclear localization signals on several of its associated proteins, integrates and then is transcribed
- since there is but a single promoter but multiple genes, RNA splicing events occur to make the needed mRNAs
- MRNAs exported from the nucleus and proteins made in the usual way—> virus assembles and buds at the plasma membrane and then the virus matures due to the action of the protease

Steps:

  1. Receptor binding
  2. Membrane fusion and entry
    1. Uncoating and reverse transcription - TARGETTED BY REVERSE TRANSCRIPTASE
  4. Nuclear Uptake
  5. Integration in nucleus - TARGETTED BY INTEGRASE
  6. Transcription
  7. RNA processing
  8. Nuclear export
  9. Translation
  10. Assembly
  11. Budding
  12. Maturation - TARGETED BY PROTEASE
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13
Q

HIV epidemiology and definition of AIDS

GIEMSA STAIN slide 13

A

Pneumocystis pneumonia was rare until 1979 when 5 cases were found in LA

Over next year additional cases of this rare pneumonia were observed, patients all young, gay men

With giemsa stain at high magnification, the faint bluish dot like intracystic bodies of pneumocystis caring in lung are seen in this cytology preparation from a bronchoalveolar lovage

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14
Q

HIV and AIds
- infectious agent Kaposi’s sarcoma

Pic page 14

A

Before AIDS< kaposi’s sarcoma found in elderly Jewish men and immunocompromised, rare here

But cluster in SF and NY - young gay men

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15
Q

Morbidity and Mortality weekly report- summer of 1981

A

First description of AIDS, pneumocystis pneumonia and kaposi’s causes

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16
Q

AIDS described December 1981

A

By end of 1981 syndrome described- acquired immunodeficiency syndrome, 234 had died in US

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17
Q

HIV discovered, 1983

A

Cultured in vitro in 1984–> tests to screen blood but many ppl became infected with HIV following blood transfusions eg hemophiliacs screwed

2304 Americans died of aids in 1984

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18
Q

Definition of AIDS

A

HIV infected persons with CD4 < 200

HIV infected and have had an AIDS defining illness (opportunistic infection)

AIDS doesnt equate to HIV
- once a pt is diagnosed with AIDS they maintain this diagnosis even if CD4 counts increase above 200 due to effective therapy

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19
Q

HIV in US

A

45000 new HIV infx in US and 20,000 deaths due to aids per year—> total number of people in US HIV infected increasing —> 1.2 mill living with HIV in the US, 1/8 dont know they are infected

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20
Q

Important modes of HIV transmission

A

IV drug abuse (IVDA)

MSM

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21
Q

What parts ot eh country and sub pops have high HIV prevalence rates?

A

MSM = 70% new infx

African descent - nearly half of all new infx

Infx rate of women of African decent is 20 fold above that of whitte women and 5 fold above Hispanic women

Prevalence of HIV in DC is 2.5%

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22
Q

HIV has infected 70 million people; half have died

A

In 2016, there are 37 million people living with HIV infx—> 2.1 mill new infections and 1.1 mill death in 2016

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23
Q

Where is HIV particularly prevalent

A

Underdeveloped countries eg subsaharan Africa, Botswana, highest infection rates in the world

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24
Q

HAART therapy

A

Highly Active Antiretroviral Therapy

Reversed trend of increasing AIDS deaths in the US, greater prevalence because more people living with AIDS

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25
Q

Treatment in the developing world

A

Being expanded

New infections and deaths due to aids have fallen by 1/3 and people being treated has increased

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26
Q

When and Where did HIV come from?

A

Construct phylogenetic tree that shows genetic relationships between hundreds of virus strains isolated throughout the world

A and B have 98% sequence identity and are connected by a horizontal line, the length of which is proportional to genetic disease - 2% in this case

C and D are 96% similar etc

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27
Q

HIV family tree - what does it tell you?

Slide 28

A

HIV strains are grouped into ‘clades’, in the US almost all infections are caused by Claude B virus

This is why there is no AIDS vaccine— lots of diversity!

Star burst pattern- terminus of each line represents a virus strain and they are connected to eachother

Sequences cluster into groups termed clades and given letter designations

Virus strains within a clade are more similar to eachother than they are to viruses in other clades

In North America, virtually all HIV + ppl have a clade B virus, in other parts of the world, other clades predominate

**alll HIV strains arose from a common ancestor - single introduction of HIV into humans at some point in the past

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28
Q

Genetic Distance vs Year graph - what does it tell you?

A

Introduced into the population around 1910, cake from nonhuman primates

Year virus was isolated on the x axis and its genetic distance from the ancestor on the y axis—> linear regression—-> pandemic arose from single transmission event around 1910

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29
Q

What is HIV closely related to and what does this mean

A

SIV (Simian immunodeficiency virus)

Virtually all old world primates have their own strain of SIV - infected animals dont get sick- perfect host parasite relationship

SIV from African green monkey, when introduced into Asian rhesus macaques causes AIDS like illness bc the macaques do not have their own SIV

30
Q

What is HIV1 most closely related to

What does this tell you about transmission

A

SIV from chimpanzees—> HIV1 arose by transmission of SIV from a chimp into a human

HIV2 arose via transmission of SIV from sooty mangabeys

HIV is an example of zoonosis

31
Q

Where di HIV come from - non invasive SIV CPz detection

A

Extract RNA from poop of gorillas and chimps - have their own SIV—> likely that a hunter who killed and butchered an SIV-infected chimp, was exposed to its blood and became infected—> HIV spread up and down Congo and through African and the world

32
Q

Distribution of chimps in Africa- Where did HIV come from?

A

Southeastern Cameroo, hunter butchered SIV infected chimp—> blood infx and this is how the infx started

33
Q

Congo river provided a route for virus to spread

A
  1. Humans butcher chimpanzees infected with SIV
  2. Virus is carried by people travelling alon teht river
  3. To Kinshasa, where the epidemic begin

In 2008 preserved tissue from 2 men who died in Kinshasa in 1959 were discovered with HIV

34
Q

Spread of HIV in Africa

A

Explosion pop growth in 20th Century

Chimps carrying SIV related to HIV1 in Southeast Cameroon
- people died of “slim disease” which was related to aids

Oldest evidence in Kinshasa

35
Q

HIV1: a retrovirus and HAART therapy

A

Perhaps only 10 spike trimers per virion

Three enzymes mentioned previously: reverse transcriptase, protease, and integrase

  • use three different drugs to treat HIV, use of multiple antiretroviral drugs
High cost (improving)
Side effects (improving)
Difficult regimens (rapidly changing)
Multi-drug resistant viruse (Getting worse)
36
Q

HIV - why is it a moving target?

A

Genetically diverse!

High replication rate: 10^9 - 10^10 virus particles made each day in untreated individuals

High error rate: reverse transcriptase makes one error every 10^4 bases

Bad combination: high replication and error rates mean that every base in the viral genome mutates to every other possible age every day

Implication: monotherapy is likely to fail
- get partially resistant virus strains that emerge and are selected for

COMBINATION THERAPY IS ESSENTIAL

37
Q

How does HIV enter a cell?

A
  1. Attachment - vurs attaches to the Cell surface and
  2. Receptor engagement - engaged specific receptors (CD4)
  3. Trigger event - causes Env to Change its conformation (pH independent to get triggered)
  4. Conformational change of Env
  5. Membrane fusion
38
Q

How is HIV entry triggered?

A

Receptor engagement

  1. Bind to cd4
    - induces structural changes in Env that enable it to bind a coreceptor
  2. Bind to coreceptor
    - trigger that leads to final conformational changes that lead to fusion between virus and cell
  3. Membrane fusion

If you express CD4 in monkey, HIV will bind but not fuse and infect so Coreceptor CCR5

Coreceptor binding essential for fusion inducing conformational changes

39
Q

What is needed in addition to CD4 to bind?

A

A coreceptor

M tropic strains use chemokine receptors CCR5

T tropic strains use chemokine receptor CXCR4

CCR5 - associated with virus transmission
——> Co receptor switch—->CXCR4 - associated with disease progression

Coreceptor are chemokine receptors with 7 transmembrane domain receptors
HIV can use two of these receptors

  • most virus strains use receptor CCR5 with CD4, vast majority of new infections are caused by viruses that use CCR5

In 1/2 of ppl who progress to AIDS< AA changes that occur in the Env protein enable virus to use a related chemokine receptor terms CXCR4, dont need CXCR4 to get aids but if you see it it is a poor prognostic indicator

By undergoing coreceptor switch, HIV can change its tropism and infect cells that express CD4 and CXCR4 not just CD4 and CCR5

40
Q

Delta 32 - CCR5 polymorphism

A

Homozygotes for this mutation in CCR5 are highly resistant to HIV - no significant side effects

CCR5 is a good drug target; many drugs target 7 TM receptors CCR5 and CXCR4 antagonists are in phase 1 trial

41
Q

How does HIV Env protein cause membrane fusion?

Schematics on slide 50 and 51

A
  1. trimeric Env protein bind to CD4 which induces conformational changes in gpl20 that results in the exposure of conserved region in gp120 that is important for coreceptor binding
  2. Env protein can now bind to its coreceptor, CCR5 or CXCR4
  3. As a result of coreceptor binding, the fusion peptide at the amino terminus of gp41 becomes exposed and inserts into the membrane of the cell. The cell fusion peptide is a hydrophobic stretch of AA and when it is exposed to stabs the membrane of the cell
  4. Gp41 transiently becomes an integral component of two membranes: viral membrane in which it is lodged,
    and the cellular membrane that it has stabbed with its fusion peptide

Coreceptor binding: variable number of CoR binding events needed, fusion peptide exposed, not known if gp120 dissociates

42
Q

Slide 51 - how does fusion occur

Describe the gp41 protein

A

Gp41 peptide - in addition to the fusion peptide, it has two helical regions terms HR1 and HR2, HR2 likes to bind HR1 and does so with high affinity—> molecule folds back on itself like closing an umbrella with 6 helix bundle formed

This brings the fusion peptide and its associated cellular membrane and transmembrane domain with its associated viral membrane into close proximity, resulting in membrane fusion

Enfuvirtide is a peptide that is injected subcutaneously twice a day and is based on HR2 domain—> binds HR1 domain and prevents formation of 6 helix bundle and blocks fusion as a result

43
Q

HIV Entry and Its inhibition

A

Native trimer—> CD4 binding—> coR binding (maraviroc is a CCR5 inhibitor)—> 6 helix bundle formation (t - 20 enfuvirtide inhibits binding of HR1 to HR2)

In addition to RT, protease, and integrase inhibitors there are now entry inhibitors that can be used to treat HIV infx—> 4th class of antiretroviral agents

44
Q

Disease Course

What is the risk of getting infected?

A

Vaginal intercourse

  • risk increases with STI coinfection
  • 1 in 1000 from having sex with HIV+ male
  • 1 in 20000 risk to male from having sex with HIV+ female

Receptive anal sex

  • 1 in 150 circumcised
  • 1 in 70 uncircumcised

Insertive anal sex

  • 1 in 900 circumcised
  • 1 in 150 uncircumcised

Oral sex
- much less risk but not zero

45
Q

How do you measure infection and assess disease progression? What are the laboratory markers of HIV infection?

A
  1. Counts of helper/CD4+ T lymphocytes
    - measured by flow cytometry
    - normal CD4+ cell count = 800-1200
    - levels fall during course of disease, AIDS = CD4 < 200
    - measures immunologic damage by HIV

CD4 levels tell you how far your patient has progressed to AIDS

  1. Level of HIV RNA in plasma (viral load), good measure of treatment
    Measured by PCR and used for:
    - diagnosis confirmation
    - prognosis - predicts CD4 decline, clinical events and survival
    - therapeutic monitoring- is antiretroviral treatment working?
46
Q

How do virus load and CD4 counts change over time in a typical infection?

A

Acute phase
- dont have Ab for HIV yet so look at viral RNA

Latent or asymptomatic phase

AIDS

47
Q

Acute HIV infection

A

Acute retroviral syndrome (often mistaken for the flu)/ mononucleosis like syndrome

  • occurs in about 50% of newly infected individuals
  • occurs 2 - 6 weeks following infection and lasts 1 - 3 weeks
  • symptoms: pharyngitis, fever, adenopathy, skin rash, nausea or vomiting, neurological signs or symptoms

Patients become Ab positive 4 - 6 weeks following infection so for the first couple weeks HIV serology may be negative but the virus can be detected by PCR (virus load)

After several weeks, the immune system kicks in, and virus load decreases to a new, steady state level = set point (constant for years)

During this window period, diagnosis is made by viral RNA

Circulating virus levels can peak in excess of 1,000,000 ml

48
Q

How does HIV result in mucosal damage

Slide 58

A

HIV causes depletion of Gut-associated CD4+ T cells and breakdown of Mucosal Barrier
- this leads to translocation of bacterial products into the blood stream

During acute HIV infx, GALT is decimated—>Breakdown of mucosal barrier—> mucosal damage allowing bacterial products like LPS to enter the blood stream, which in turn activates T cells and makes them more susceptible to HIV infx

49
Q

Clinical Latency - the period folllowing Acute infection

A

Virus load decreases to a new level ‘set point’ (which can vary by on avg 30,000 ml)

Pt usually asymptomatic during this period, which without treatment lasts on avg 7 - 10 yrs

Virus load remains relatively constant, while CD4 levels slowly decline
- gradually the levels of CD4+ T cells fall to the point where immune system cant combat opportunistic infection

Key point - virus load is best lab marker to predict rate of disease progression

Keep point - lack of symptoms mean many HIV infx are not detected until the pt presents with AIDS which delays treatment and helps spread the disease

50
Q

What predicts progression to aids?

A

HIV RNA levels (set point)

After acute infection, th amt of circulating virus falls to some level - this level can vary widely between pt, but for any given pt virus load remains relatively stable for years until pt progress to AIDS

Pt with high virus loads progress to AIDS more quickly than those with low virus

51
Q

Wide variation in the rate or progression to AIDS

A

Exposed- uninfected

  • some people remain HIV- despite repeated exposure to virus
  • CC4r5 polymorphism acts for only a very small number of these individuals

Rapid progressors: some people progress to AIDS very quickly within just 1 - 3 years

Long term nonprogressors: some ppl have been HIV+ for a very long time and have not progressed to AIDS. Perhaps 5% of infected people are in this category and they have low virus loads

Elite controllers: subset of long term nonprogressors who have virus loads below the limits of detection (less than 50 copies per ml)

52
Q

Antiviral therapy

A

4 classes of antiretroviral drugs. RT and protease inhibitors were the first to be developed, are the most common and form the backbone of antiretroviral therapy

Integrase inhibitors and entry inhibitors are used less frequently

Entry inhibitors

  • receptor binding: one CCR5 antagonist is now in widespread clinical use
  • membrane fusion, one drug: enfuvirtide

RT inhibitors

  • RT was first target for antiviral drugs
  • nucleoside inhibitors and nonnucleoside inhibitors

Integrase inhibitors

Protease inhibitors - protease was discussed earlier and its activity is needed for the virus to mature and to become infectious, 8 different protease

53
Q

Different Kinds of reverse Transcriptase (RT) inhibitors

A

Nucleoside Reverse Transcriptase Inhibitors (NRTI)

  • look like nucleotides - RT tries to incorporate them into viral DNA which stops chain elongation
  • referred to as NUCS

Nonnucleoside RTIs (NNRTI) bind to RT at a site that is different from NRTIs.

  • viruses resistant to NRTIs are sensitive to NNRTIs and vice versa
  • Non-NUCS
  • allosteric inhibitors that when bound induce a change in conformation in RT that prevents it from functioning

Because NRTIs and NNRTIs bind to different sites on RT and work by different mechanisms, they are typically used in combination

54
Q

Protease inhibitors: prevent virus maturation

A

Protease inhibitors you have heard about target this protease domain in gag and prevent it from working as a result the virus cant mature

Once virus has formed, protease clips the gag protein, generating the matrix, nucleocapsid and capsid proteins

  • this is needed for virus to mature and become infectious
  • in this presence of a PI, virus infects cells normally and new virus particles are produced, but these viruses fail to mature and so are noninfectious
55
Q

FDA approved Drugs for HIV Therapy

A

Coformulated drugs

Recommended regimens for initial therapy

Integrase inhibitor + two NRTIs

NNRTI + two NRTIs

Protease and entry inhibitors are spared: used for pt who fail initial therapy

Many drugs now coformulated; single pill = 2 or3 drugs

56
Q

What happens when HAART is started?

A

Virus load constant during clinical latency

Virus production must equal virus destroyed each day

Administration of HAART causes virus load to fall 2 logs within a day or two

This reveals the underlying dynamics of HIV infx

Also makes clinical trials much easier- if a new drug does not result in a rapid decline in virus, the trial can be stopped

Rapid decay upon HAART treatment, about 80% of the time HAART therapy reduces VL to below the limit of detection

57
Q

Why does HAART not work sometimes?

A

Patient miss doses, drug levels fall

Allows virus to replicate

Replication= mutation

Resistance progressively arises

Key to HIV therapy to suppress replication forever

15% of new HIV infx in North America are being caused by drug resistant virus strains which is why you do a genotype test before you offer treatment

58
Q

HIV drug resistance

A

Acquisition of drug resistance is a step wise process
- 4 - 6 mutations needed for HIV to achieve maximal resistance to any single drug

Some of these mutations directly affect binding site of drug
- while these mutations do prevent drug from binding, they als oresult in a nonfunctional enzyme so some mutations are selected for that are compensatory in nature - dont really make RT or protease resistant to drug, but enable an enzyme that has resistance-conferring mutations to work more efficiently - compensatory mutations

59
Q

What does genotypic analysis of plasma HIV tell you

A

Drug resistance!

By about 3 weeks after initiation of therapy, position 82 in protease gene was sometime sa valine and sometimes an alanine

By 8 weeks, position 82 was alanine, and positions also different at 54 and 71

Step wise accumulation of mutations - some enhance drug resistance while some are compensatory mutations- they improve protease function
- by about 32 weeks, essentially all of the virus has 5 mutations in protease that make it highly drug resistant

60
Q

HIV genotyping is highly predictive of phenotype!

A

Collect blood from a patient and sent it to a lab where the viral genome is sequenced—> tells you sensitivity to drug

61
Q

When to treat

A

HAART recommended for alll HIV+ individuals provided that they will take drugs regardless of VL or CD4 count

Order a genotype test- make sure pt not infected with a drug resistant virus

Initiate therapy with integrase + two NRTIs or NNRTI + two NRTIs. Many variations depending on age, VL, coinfection, HLA, etc. But always 3 drugs used

Monitor virus load

If sustained VL rebound, repeat genotype test

62
Q

How do you deal with needle sticks?

A

Less severe injury (small needle, no obvious blood on it)

  • pt has low virus load, the recommendation is to take two drug post exposure prophylaxis (PrEP)
  • pt has high virus load—> 3 drug PEP

More severe (large bore needles, deep injury, obvious blood on device, needle used in pt artery or vein)

  • HIV+, low VL: 3 drug PEP
  • HIV+, hi VL: 3 drug PEP

Mucosal exposure (small volume)

  • HIV + low VL, 2 drug PEP
  • high VL - 2 drug PEP
Mucosal exposure (large volume)
- 2 drug PEP if low VL and 3 drug PEP if high VL

If pt has unknown HIV status- consider 2 drug PEP if risk factors

63
Q

HIV and pregnancy

A

HIV+ mothers can transmit virus to baby during pregnancy, vaginal delivery, and via breast milk, total chance of transmission is 20 - 45%

All pregnant women should be screened for HIV as early as possible during each pregnancy

Number of HIV + women giving birth in the US has been increasing each year, now around 9,000 per year

Women who receive HIV medication during pregnancy reduce the risk of transmitting the virus to their babies to less than 1%

64
Q

Dynamics of HIV1 replication in pats on antiretroviral therapy - Can HIV be eradicated from an infected person?

A

No HIV eradicated due to

Viral reservoirs

  • memory T lymphocytes are infected with HIV
  • as long as memory cell is resting the infection is nonproductive (viral proteins not being made) so cell is invisible to the immune system
  • cell is latently infected but this process is reversible should the cell become activated virus can be produced

Low level of ongoing replication

65
Q

Frequency of LAtently infected CD4+ T cells as a function of time on HAART

A

Constant, doesnt decline

66
Q

Viral reservoir

A

Latent reservoir for HIV guarantees lifetime persistence in the vast majority of pt on current HAART regiments

Viral reservoir represents an archive of all virus types that have ever circulated in patient: once a pt fails a drug, resistant viruses likely resides in the pt, every years after so you ca

67
Q

What is the scale of HIV-1 genetic variation

A
  • tons of genetic diversity of HIV even from a single patient- equivalent to genetic variation in circulating influenza strains throughout the world

Flu vaccine is changed every year

68
Q

HIV says one step ahead of the humoral response

A

Collect virus at different times after the infection and collect serum at different times after the infection

You have serum Ab to the previous version of the virus - Ab in any given serum sample could neutralize HIV isolated from a patient 6 mo previous but not virus collected at the same time—> humoral immune response is working- neutralizing ab indeed made but the virus evolves resistance to these ab by mutating the viral Env protein, one step ahead of immune esponse

69
Q

New stuff: vaccine nad reservoirs

A

One vaccine trial has shown effectiveness but vaccines unlikely to work because of genetic diversity and mutation
Immunize patients with canary pox vector with HIV gagpol and ENv genes, live attenuated vector that would elicit cellular and humoral immunity and then boost patients with recombinant HIV env to get higher levels of Ab

Kick and kill clinical trials are under way
- latent reservoir means existing therapy isnt curative but if you could activate latently infected cells this would cause cells to die and drugs to prevent new cells from being infected

70
Q

NEw stuff: Prexposure prophylaxis (PrEP) with ARVs

A

PrEP for HIV- individuals who are at ongoing high risk for infection

  • sex, MSM, infected partner
  • IV drug

If taken every year, reduces infx risk > 90%

PrEP should be part of a comprehensive prevention plan

FDA approved PrEP: Truvada (single pill with two NUCS)

Should be followed every 3 months; test for infx since 3 drug Tx not sufficient to control infx

71
Q

Worlds 1st cure

A

Berlin pt, infected with HIV, also leukemia

Give him BMT with donor homozygous CCR5 polymorphism—> HIV eradicated
HIV+ male with HAART

Leukemia

Treated with chemo and relapsed

Hematopoietic stem cell transplant with chemo— CCR5 homozygous donor

Virus undetectable in the abscence of antiretroviral therapy (ART) ~ 6 yrs post transplant

72
Q

HTLV1

A

Human T cell leukemia Virus

Monoclonal malignancy

Transmission thought to occcur by cell to cell contact and not by free virus during the intimate exchange of body fluids: perinatal transmission via milk lymphocytes during breast feeding, lymphocytes contained in semen during sexual intercourse, unscreened blood transfusions and sharing of blood contaminated needles by intravenous drug users,, incubation several decades long

Microbiology (10 decks)

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