Hiv Lifecycle

1. The life cycle of HIV
and HIV “disease”

Alan McCord
Director of Education

ed
Aue [email protected]
[email protected] a HIV Health InfoLine
415-558-8669 x230 INFORM 800-822-7422

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Z INFORM The life cycle of HIV and HIV disease December 2011

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Major points covered today

» Basics of the immune system.

» The life cycle of HIV, or its pathogenesis.
* HIV disease and the meds used to treat it.
+ Ways to address HIV disease.

3. Z INFORM © The life cycle of HIV and HIV disease December 2011

Immune system fundamentals

The immune system:

* protects the body from invaders.

+ is made up of dozens of types of immune cells.
* can distinguish between “self” from “non-self”.

Immune cells:

+ have specific roles.

* come in two main classes: B cells and T cells.
+ have a complex communication system.

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The life cycle of HIV and HIV disease

Parts of the immune system

+ Skin.

+ Bone marrow (B).
+ Lymph glands, vessels, lympr
+ Spleen.

* Thymus (T).

» Peyer' s Patches (GALT).
+ Appendix.

* Tonsils, adenoids.

December 2011

5. INFORM O The life cycle of HIV and HIV disease December 2011

HIV disease fundamentals

+ Pathogenesis is how something causes disease.

+ HIV can infect almost any type of body cell, and uses
them as a host to replicate, though it prefers immune
cells.

« Infected CD4s may die, produce more HIV, stop
functioning, or even become inactive (resting).

+ The immune system weakens over time. The body
may lose the ability to effectively fight off infections.

+ AIDS is the advanced stage of HIV disease,
and is defined by having specific conditions.

6. INFORM The life cycle of HIV and HIV disease December 2011

HIV life cycle

HIV illustration CD4 cell illustration

7. December 2011

“INFORM © The life cycle of HIV and HIV disease

HIV life cycle
1. ENTRY: (a) attachment, (b) binding, (c) fusion.
2. REVERSE TRANSCRIPTION: uses HIV enzyme
called
reverse transcriptase.
3. INTEGRATION: uses HIV enzyme called integrase.

4. TRANSCRIPTION: uses HIV enzyme called

protease.
5. MATURATION: (a) assembly, (b) budding, (c)

maturation.

8. The life cycle of HIV and HIV disease December 2011

4 Transcription: Cells infected

DNA makes proviral RNA. Protease
RS co-receptor enzyme cuts RNA strands.
Tb Attachment and binding:

HIV attaches first to a CD4 receptor, 5b Budding: immature virus

and then binds to a co-receptor, Und oppecpaia spot io push

either CCRS or OXCRA. ‘out of the cel, taking a piece
‘of membrane with it.

‘Ta Free virus

Te Fusion and
HIV fuses with CD4 membrane, and
then uncoats its contents into the cell,

2 Reverse transcription:
Single strands of HIV RNA are
Converted into DNA by the RT enzyme.

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INFORM © The life cycle of HIV and HIV disease December 2011

Current classes of HIV therapy

+ Els: entry inhibitors (prevents binding and
fusion).

+ NRTIs: nucleoside reverse transcriptase
inhibitors, or “nukes” (mimics nucleosides).

+ NNRTIs: non-nucleoside reverse transcriptase
inhibitors, or “non-nukes” (blocks nucleosides).

+ Ils: integrase inhibitors (newest class, jams
integration).

+ Pls: protease inhibitors (jams assembly at end).

« Mls: maturation inhibitors (not on market yet).

10. The life cycle of HIV and HIV disease

December 2011

The full HIV drug toolbox

NRTIs:
« Epivir (3TC, lamivudine) *

+ Emtriva (FTC,
emtricitabine)

+ Retrovir (AZT, zidovudine)

+ Videx (ddl, didanosine) *

Viread (TDF. tenofovir)
+ Zerit (d4T, stavudine) *
* Ziagen (ABV, abacavir)

NNRTIs:

- E RPV. rlpiviri

+ Intelence (etravirine:

+ Rescriptor (delavirdine) *
* Sustiva (EFV, efavirenz)
+ Viramune (nevirapine)

Fixed dose combos:
* Combivir (AZT+3TC)

ES
+ Epzicom (3TC+ABV)
+ Trizivir (AZT+3TC+ABV)

. +

+ Atripla (TDF+FTC+EFV
Entry inhibitors:

Protease inhibitors:
. Agenerase (amprenavir)

+ Aptivus (tipranavir) *

+ Crixivan (indinavir) *

+ Invirase (saquinavir) *
+ Kaletra (lopinavir/r)

+ Lexiva (fosamprenavir)
+ Norvir (ritonavir)

+ i vil

+ Fuzeon (120, enfuvirtide) * Revataz (atazanavir)

u L ravi

Integrase inhibitors:
+ Isentress (raltegravir)

* Viracept (nelfinavir) *

* = older drugs, or not _
often used, or in special
cases

_ = newest drugs

11. The life cycle of HIV and HIV disease December 2011

Timeline of drug development

one-pil,
once-a-day
regimens

N

il Epzicom tri
Combo pills Combivir Trizivir E Atipla
Entry inhibitors Fuzeon Selzentry u
Integrase inhibitors Isentress dad pill
Crixivanı
Vrntept; | Kafetra; _ Invirase Aptivus
Proteinen 7 (Agnes Lexiva | Prezista
Sri Reyataz
‘Preveont
NATIs Retrovir MidexHivid- -Zeiit-Epivir | Ziagen gy gc Viread Emtriva

Rescriptot

NNRTIs Viramune Sustiva

Intelence Edurant

AAA ee ee ee ee ee el
1981 83 85 87 89 191 93 95 97 99 2001 03 05 07 09 2011

Strikethrough = discontinued in US.

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The life cycle of HIV and HIV disease December 2011

INFORM ©

Course of HIV disease to AIDS,

untreated

<5%

rapid
progressors

8-10 years

long-term
non-progressors

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Course of HIV disease over time,

(a A E | LATEINTERMEDIATE y ADVANCED DISEASE / AIDS
a , ‘
healthy HIV-positive possible minor symptoms ; ‘symptomatic HIV/AIDS.
1 1 1
HIV viral load 1 1
AIDS
i lood ! 1 death
§ 1 CDA cell count; 1
D 1 1
E 0 1 CD4
= 1 1 infection
> 1 y point
= 1 dt T
1 ' 1
1 1 N
1 1 1
! {Virus evolution !
(PE
1 1 1
1 i 1
i 1
1
1 i 1
— + » +
6-12 weeks 1-15 years, or more 2-3 years, or more

Nature Review | Immunology

14. INFORM The life cycle of HIV and HIV disease December 2011

Early infection, acute syndrome

» May or may not have symptoms.

“ele. Burst of viral replication.

Cb4cclls_ + Wide distribution of HIV throughout
the body.

* Seeding of HIV in lymph tissue.

+ Control of virus is probably not only
due to immune response but also
to “sequestration” of HIV in lymph
tissue.

HIV infection

—
6-12 weeks

15. INFORM The life cycle of HIV and HIV disease December 2011

— —

Early intermediate

» Often without any symptoms.
» Fairly stable CD4s and HIV levels.

Ces + HIV lies latent in lymph tissue.

* HIV uses lymph tissue as central
infection centers.

« CD4s and other immune cells
become infected when traveling
through lymph nodes.

+ HIV levels in lymph tissue are
generally much higher than blood.

md

1-15 years, or

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— —

Late intermediate

+ Symptoms more variable.
+ Difficulty with stabilizing CD4s and

viral loads.
SE + Structure and function of lymph
nodes begin to degrade due to high
Gans) level of HIV activity.

NS

Virus evolution
a.

+ Immune system begins to erode.
em » Minor conditions begin to worsen,

Eee such as herpes, genital warts,
[Mp a fungal infections, etc. Blood tests
Sr more begin to show abnormalities.

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— —

Advanced disease, AIDS

+ Uncontrolled HIV levels.
anddeatn * Likely lower CD4 counts.
* Tenuous health, more frequent and
more severe Ols. AIDS-related and
non-AlDS-related events occurring
more often. Hospital stays more
likely.
Perhaps collapse of immune
system. HIV overwhelming the
number and function of immune
cells.

CD4
infection
point

CDA cells

.

2-3 years, or more

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Wrap up on HIV disease ...

* Caused by human immunodeficiency virus
(HIV).

* CD4s are important immune cells, like generals.

« HIV reproduces constantly, infecting cells
throughout body.

+ HIV infects CD4s, and many other immune
cells.

« Disables immune system in many complex
ways.

+ Immune system gradually weakens over time;

Pm a |

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Other factors in HIV disease may further
weaken the immune system:

Co-infections and other conditions.
+ STIs and others (hep B & C); diabetes, hypertension, kidney disease.

Lifestyle issues.
* Street drugs, smoking, poor sleeping habits, lack of exercise, etc.

Stress.
+ Released chemicals work against immune system.

Poor nutrition.

+ Affects immune system, contributes to weight and bone loss and
fatigue.

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Monitoring HIV disease: Viral load

« Viral load tests reflect the current activity of HIV
in the blood. They do not reflect the amount of
HIV in other parts of the body, like semen,
vaginal fluids, breast milk, etc.

» Keep as low as possible over time, preferably
undetectable (<50 copies).

« Viral load is generally about the same in men
and women.

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RM O The life cycle of HIV and HIV disease December 2011

Monitoring HIV disease: CD4 cell counts

» CD4 counts reflect the relative health of the
immune system. Keep as high as possible over

o 200 350 500 600 1000
| 1 ñ ñ 1
|

|

|

|

|

CO

Low CD4: Below normal CD4: “Normal” CD4: Normal CD4:

ls common Ols uncommon Healthy individuals
Should be on therapy Shouldbeon therapy Should be ontherapy Consider therapy HIV-negative people

Federal Guidelines, revised January 2011

22. The life cycle of HIV and HIV disease December 2011

Possible benefits of starting at 350-500

+ An increasing number of observational results and early clinical studies suggest lower rates of
AIDS and other health-related conditions and death.

+ Current first line regimens are more effective and easier to take and tolerate, which helps
improve adherence.

+ People who start above 350 are better able to achieve and maintain higher CD4s over time
than those who start below 350.

+ People with better overall health tend to have an easier time tolerating medicines.
+ Starting in this range reduces the risk of early damage to the immune system.
+ Starting in this range reduces, though does not eliminate, inflammation.

+ Untreated HIV, even at higher CD4s, may contribute to heart, liver, kidney, brain and other
organ diseases and cancers.

+ Starting in this range reduces the transmission of HIV, based on several studies of mixed HIV
status, heterosexual couples.

+ Early treatment may decrease overall cost of health care by avoiding more serious conditions.

23. The life cycle of HIV and HIV disease December 2011

Possible risks of starting at 350-500

+ Randomized studies have not been done, providing more solid evidence of an added benefit.

+ ART-CC and NA-ACCORD studies included many people who were taking regimens used less
often today and did not assess the impact of long-term side effects, adherence or drug resistance.

+ Some studies show a higher risk of heart disease with continued use of certain NRTIs and Pls;
higher rates of bone loss are linked to longer time on treatment.

+ Some long-term side effects of newer HIV meds are not known and may not appear until after
10 or more years of use.

+ Possible side effects may decrease the quality of life for otherwise healthy people.

+ Starting in this range increases risk of earlier resistance, which may lead to running out of options.
+ Current pipeline of experimental HIV meds is thin and may not produce many more drugs soon.

« Starting in this range may add 2-3 more years of total time on treatment.

+ Starting in this range increases the risk of treatment fatigue, which could lead to poor adherence.

+ May increase the collective cost of health care over time, and the current economy may make it
difficult for some people to access public programs like ADAP to cover the cost of their meds and
blood work.

+ Results from START study will not be available until around 2014.

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CDA cell counts and viral load tests

« Establish a baseline as soon after diagnosis as
possible ... two sets of tests about 6 weeks
apart.

« Trends are more informative than single result,
every 6 months, or more often for symptoms.

* CD4s: >500. Viral load: <50 (undetectable)

+ If you can, take tests at same time of the day
each time, using same lab each time.

+ Active infections, vaccines can affect results.

« Testing errors can affect results.
. i O, 0,

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Ways to address HIV disease
« How we treat HIV disease today is very different
than it was in the 80s and 90s.

» HIV therapy works. Newer drugs are less toxic
than earlier generations. Easier to take and
tolerate.

+ Ask questions until they’ re answered.

« Find HIV-experienced health providers.

« Screen and treat Ols/co-conditions
appropriately.

+ Consider disclosing HIV status.

26. “INFORM The life cycle of HIV and HIV disease

INFORM

HIV HEALTH INFOLINE

1-866-HIV-INFO

www.projectinform.org/HlVhealth

December 2011