Life Cycle of HIV PLUS January 2013

The life cycle of HIVand HIV disease

Alan McCordDirector of Education

[email protected] x230

[email protected]

Major points covered today• Basics of the immune system.

• The life cycle of HIV, or pathogenesis.

• The benefits of HIV medications.

• Managing HIV disease over time.

The life cycle of HIV and HIV disease October 2012

Immune system fundamentalsThe 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.

The life cycle of HIV and HIV disease October 2012

Parts of the immune system• Skin.

• Bone marrow (B).

• Lymph glands, vessels, lymph.

• Spleen.

• Thymus (T).

• Peyer’s Patches (GALT).

• Appendix.

• Tonsils, adenoids.

The life cycle of HIV and HIV disease October 2012

Parts of the immune system

Innate immunity

• “born with” side

• Immediate response

• B cells (bone marrow)

• Macrophages, dendritic

cells, Langerhan cells

• Antibodies

• Others: monocytes, etc.

The life cycle of HIV and HIV disease October 2012

Acquired immunity

• “learned” side

• Delayed response

• T cells (thymus)

• CD4s: “manager” or “genera

l”

• CD8s: killer cells

• Others: CDs, T-helper, etc.

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 cells).

• 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.

• Billions of HIV particles can be produced every day.

The life cycle of HIV and HIV disease October 2012

HIV life cycle

HIV illustration CD4 cell illustration

The life cycle of HIV and HIV disease October 2012

HIV life cycle

actual HIV actual CD4, infected

The life cycle of HIV and HIV disease October 2012

HIV life cycle

The life cycle of HIV and HIV disease October 2012

HIV life cycle1. 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.

The life cycle of HIV and HIV disease October 2012

HIV life cycle

The life cycle of HIV and HIV disease October 2012

The life cycle of HIV and HIV disease October 2012

Current classes of HIV therapy• EIs: entry inhibitors (prevents attachment, binding and fusion).

• NRTIs: nucleoside reverse transcriptase inhibitors, or “nukes”

(mimics nucleosides).

• NNRTIs: non-nucleoside reverse transcriptase inhibitors, or

“non-nukes” (blocks nucleosides).

• IIs: integrase inhibitors (jams integration).

• PIs: protease inhibitors (jams assembly at end).

• MIs: maturation inhibitors (not yet, if at all).

The life cycle of HIV and HIV disease October 2012

The full HIV drug toolbox

NRTIs:• Epivir (3TC, lamivudine) *

• Emtriva (FTC, emtricitabine)

• Retrovir (AZT, zidovudine) *

• Videx (ddI, didanosine) *

• Viread (TDF, tenofovir)

• Zerit (d4T, stavudine) *

• Ziagen (ABV, abacavir)

NNRTIs:• Edurant (RPV, rilpivirine)

• Intelence (etravirine)

• Rescriptor (delavirdine) *

• Sustiva (EFV, efavirenz)

• Viramune (nevirapine)

Fixed dose combos:• Atripla (TDF+FTC+EFV)

• Combivir (AZT+3TC)

• Complera (RPV+FTC+TDF)

• Epzicom (3TC+ABV)

• Stribild (ELV+FTC+TDF)

• Trizivir (AZT+3TC+ABV) *

• Truvada (FTC+TDF)

Entry inhibitors:• Fuzeon (T20, enfuvirtide) *

• Selzentry (maraviroc)

Integrase inhibitors:• Isentress (raltegravir)

• elvitegravir (ELV)

Protease inhibitors:• Agenerase (amprenavir) *

• Aptivus (tipranavir) *

• Crixivan (indinavir) *

• Invirase (saquinavir) *

• Kaletra (lopinavir/r)

• Lexiva (fosamprenavir)

• Norvir (ritonavir)

• Prezista (darunavir)

• Reyataz (atazanavir)

• Viracept (nelfinavir) *

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

_ = newest drugs

The life cycle of HIV and HIV disease October 2012

Timeline of drug development

Strikethrough = discontinued in US.

The life cycle of HIV and HIV disease October 2012

Course of HIV disease to AIDS, untreated

The life cycle of HIV and HIV disease October 2012

Course of HIV disease, untreated

Nature Review | Immunology

The life cycle of HIV and HIV disease October 2012

Early infection, acute syndrome

• May or may not have symptoms.

• Burst of viral replication.

• 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.

The life cycle of HIV and HIV disease October 2012

Early intermediate

• Often without any symptoms.

• Fairly stable CD4s and HIV levels.

• 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.

The life cycle of HIV and HIV disease October 2012

Late intermediate

• Symptoms more variable.

• Difficulty with stabilizing CD4s and viral loads.

• Structure and function of lymph nodes begin to degrade due to high level of HIV activity.

• Immune system begins to erode.

• Minor conditions begin to worsen, such as herpes, genital warts, fungal infections, etc. Blood tests begin to show abnormalities.

The life cycle of HIV and HIV disease October 2012

Advanced disease, AIDS

• Uncontrolled HIV levels.

• Likely lower CD4 counts.

• Tenuous health, more frequent and more severe OIs. AIDS-related and non-AIDS-related events occurring more often. Hospital stays more likely.

• Perhaps collapse of immune system. HIV overwhelming the number and function of immune cells.

The life cycle of HIV and HIV disease October 2012

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.

The life cycle of HIV and HIV disease October 2012

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; more difficult to

fight off infections.

The life cycle of HIV and HIV disease October 2012

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.

• High: >100,000; low: <10,000.

• Keep as low as possible over time, preferably undetectable (<50

or <20 copies).

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

The life cycle of HIV and HIV disease October 2012

Monitoring HIV disease: CD4 cells• CD4 counts reflect the relative health of the immune system.

Keep as high as possible over time.

Federal Guidelines, revised March 2012

The life cycle of HIV and HIV disease October 2012

CD4 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.

• Consider CD4%, as well as CD8s, % and ratio.

The life cycle of HIV and HIV disease October 2012

Conditions increase urgency to start• CD4 count <200

• Loss of 100+ CD4s within past year

• Viral load >100,000

• AIDS-defining illness, certain OIs (crypto, TB, etc.)

• Pregnancy

• HIV-related kidney disease (HIVAN)

• Hepatitis B co-infection that requires treatment

• Hepatitis C co-infection

• Older age, >50 years

The life cycle of HIV and HIV disease October 2012

• 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 OIs/co-conditions appropriately.

• Consider disclosing HIV status.

• Find appropriate support groups, friend, advocate.

• Ask for help. There are many resources available.

Ways to address HIV disease

The life cycle of HIV and HIV disease October 2012

The life cycle of HIV and HIV disease October 2012