HIV and AIDS

HIV-1 vs HIV-2

- HIV-1 is the MC worldwide and in the United States

- HIV-2 progresses slower, is milder, has lower viral load, and has slightly lower transmission risk

Origin of HIV-1 and it's unique characteristics

- Cross-species transfer from chimpanzees in Central Africa

- HIV-1 binds less preferentially during replication, hence it is more prone to mutations = HIGHER RESISTANCE

Origin of HIV-2

Cross-species transfer from sooty mangabeys in West Africa

Most common HIV clade in North America/Europe

Clade B

Most common HIV clade in Africa

Clade C

Family/genus of HIV

Retroviridae family, Lentivirus genus

The initial transmission of HIV is attributed to

- African logging camps + bushmeat trade

What type of virus is HIV

Enveloped, single-stranded RNA virus with a transcribed DNA intermediate (provirus integrates into host DNA)

Major HIV envelope glycoproteins

gp120 and gp41

What do gp120/gp41 do

- Mediate recognition of CD4 cells and chemokine co-receptors and allow fusion/entry

- Imagine they are like "grappling hooks" that grab onto CD4 cells

Key internal structural proteins/enzymes inside HIV virion

p24, p17, reverse transcriptase, integrase, protease

Key HIV characteristics

- Latency = but the virus is actively replicating (hence pt is contagious)

- Persistent viremia

- High affinity for CD4 cells

- Immune evasion via mutation and MHC-I downregulation = weakened host responses

Cells HIV can infect besides CD4 T cells

B cells, macrophages, monocytes, endothelial cells, CNS cells

Initial cell type HIV enters through at mucosal sites

Langerhans cells

What usually happens 2 days after being infected? What happens at day 5?

- Day 2 = Langerhans cells brings the virus to the lymph nodes

- Day 5 = The virus disseminates to the plasma

Major anatomic site for establishment/propagation of chronic HIV

- Lymphoid tissues/lymphoid organs -> the virus sets up shop in these tissues and steadily releases virus (complicates eradication)

What forms the persistent "proviral reservoir"

Persistently infected cells that steadily release virus and replenish latent proviral reservoir

Does HAART eradicate HIV

- No, it can decline the reservoir but eradication is not a realistic expectation

- Once the reservoir is set up, you're sorta screwed (this highlights the importance of PREP ASAP)

Proviral reservoir size relationship

- Directly correlates with viral load and inversely correlates with CD4 count

- High PROVIRAL RESERVOIR = LOW CD4

- High CD4 = LOW PROVIRAL RESERVOIR

What happens during the initial HIV plasma surge

Viral load becomes very high and CD4 count drops steeply

Seroconversion timing after infection

- Approximately 2-8 weeks (pt develops antibodies to HIV)

What causes the decrease in viral load after it's initial peak?

- HIV antibody + CD8 response (allows CD4 cells to rise up again, BUT NEVER TO BASELINE)

- CD4/CD8 ratio goes from high to low (physiologically we have more CD4, but w HIV it is inverse)

Why generalized lymphadenopathy occurs early

CD4 cells migrate to lymph nodes, become activated/proliferate, and become more susceptible to infection

How long does it take to establish chronic persistent infection?

- 10-11 years (without treatment)

Hallmark of HIV disease

Profound immunodeficiency from progressive quantitative and qualitative CD4 helper T-cell deficiency

Major cause of CD4 decline in HIV

- Increased apoptosis due to chronic immune activation + thymus dysfunction + direct viral destruction + syncytium formation

- Syncytium formation = unaffected CD4 cells clump together with an infected cell = giant multi-nucleated cell -> easier spread

HIV life cycle

1) Binding + entry

2) Reverse transcription

3) Integration

4) Replications

5) Maturation + budding

- Viron 1/2 life = 6 hours

HIV co-receptors

- CCR5 and CXCR4

- CCR5 deletion = increased resistance to infection or slower progression

How does HIV bind to CD4 and fuse?

- gp120 + gp41 binds to CD4 receptor causing conformational change -> then it complexes with CCR5 or CXCR4 -> allows for fusion w cell membrane -> virus enters the cell

Reverse transcriptase function

- Converts HIV RNA into double-stranded HIV DNA

- This process is ERROR PRONE -> high potential for mutations = can cause resistance

Integrase function

- Inserts HIV DNA into host cell DNA (forms provirus) -> the cell has now turned into an HIV protein factory (forever screwed)

Protease function

Cleaves precursor proteins to create mature infectious virions

How do new HIV virions exit the cell

Budding from the cell membrane -> they take pieces of the CD4 cell membrane with them to evade the immune system

Normal CD4 count range

~700-1600 cells/µL

Definition of AIDS by CD4 criteria

CD4 <200 cells/µL regardless of symptoms

Definition of AIDS by clinical criteria

Any AIDS-defining illness regardless of CD4 count

Acute retroviral infection timing

Typically 2-4 weeks after exposure

Acute retroviral infection presentation

- Flu-like or mononucleosis-like illness

- CD4 count drops BUT RARELY < 200

Common acute HIV symptoms

- Fever, night sweats, malaise, myalgias, headache, sore throat, cough, diarrhea, weight loss, generalized lymphadenopathy (due to hyperplasia of B cells in lymph nodes), maculopapular rash

- Pt might not present with any of this except LAD

- Prolonged s/s > 14 days is associated with faster progression to AIDS

Latency/asymptomatic stage key point

Patient is seropositive and virus is actively replicating despite no symptoms (except painless LAD)

Infectivity during latency/asymptomatic stage

Highly infective even if asymptomatic

Relationship between CD4 count and viral load

Higher CD4 generally corresponds to lower viral load

Early mild immune dysfunction signs ("B" symptoms group)

- Molluscum contagiosum and persistent hepatosplenomegaly

- Sign of immune system anergy -> infxs tend to be viral + fungal

Once a patient progresses past asymptomatic stage, can they return to stage 1

No, even if they later become asymptomatic

Untreated HIV mortality

>90% mortality within ~8-10 years (variable)

Main routes of HIV transmission

- Sexual transmission (MC) and parenteral exposure

- In the US, transmission is associated with homosexuals

- Worldwide, transmission is associated with heterosexuals

Can HIV be transmitted in a pt already (+)?

- Yes, different strains can be transmitted to already infected pts (they can pick up or spread more virulent forms of HIV)

Body fluids most relevant for HIV transmission

Semen, vaginal fluid, blood, body fluids (saliva has low titers and is not convincing as a transmission source) + breast milk + wound exudates

Strongest sexual risk behavior for HIV transmission

Receptive anal intercourse

Why receptive anal intercourse is highest risk

Thin/fragile rectal mucosa allows easier exposure to susceptible cells

Second highest risk sexual behavior

Vaginal intercourse

Male-to-female vs female-to-male efficiency

Male-to-female transmission is ~8x more efficient (transmission is easier bc of increased surface area)

What is the chief predictor of heterosexual transmission of HIV?

- Viral load (< 1500 copies = decreased risk)

- If pt is undetectable (< 200 copies) = every lower risk

Effect of consistent latex condom use

Significantly reduces HIV/STD transmission risk but not 100% effective (spermicidal condoms have no increased benefit)

How STDs affect HIV acquisition risk

- Gonorrhea/chlamydia increase risk (~3x), syphilis (~7x), HSV outbreak (~25x)

- Ulcer forming = higher rates of transmission

Female-to-female HIV transmission

- Very rare (few documented cases)

- Associated with sharing sex toys + menses + rough sex

Does casual contact or mosquito bites spread HIV

No evidence

Effect of lack of circumcision on HIV risk

- Associated with higher risk of HIV infection

- The foreskin can cause trauma and increase risk of ulcerative type STIs

Oral sex HIV risk compared to anal sex

Much less efficient for transmission (although it is still possible if pt has open sores + hard teethbrushing + receding gums)

Preferred PEP regimen

Tenofovir + emtricitabine (Truvada) + raltegravir or dolutegravir

When should PEP be started after exposure

Within 72 hours (earlier the better)

Indications for PrEP

HIV-negative patients at high risk (e.g., sex with HIV+ partner, high-risk MSM)

Recommended PrEP medication (classic)

Truvada (tenofovir + emtricitabine)

How effective is daily PrEP for sexual transmission

Reduces risk by >90%

How effective is PrEP for people who inject drugs

Reduces risk by >70%

Major parenteral transmission risks

- Needle sharing + contaminated syringes -> associated with tattoos + piercings

- Blood products (especially before 1985)

- IVF clinics

How long can HIV survive in syringes

Up to ~6 weeks

Can HIV be transmitted by saliva

No convincing evidence despite low titers detected

Can HIV be transmitted via tears/sweat/urine

No evidence of transmission

Can HIV be transmitted by human bite

Yes, can occur

Occupational exposure risk (needle-stick)

About 0.3% per needle-stick (way lower than hepatitis C and B)

Occupational exposure risk (mucous membrane)

About 0.09% (way lower than hepatitis C and B)

Factors that increase occupational HIV transmission risk

- Large quantity of blood

- Device visibly contaminated w blood

- Procedures requiring needle directly in vein/artery

- Prolonged contact

- High HIV titers

Most common cause of needle-stick injuries

Hypodermic injection needles (SQ + IM + IV)

What are the steps for needle sticks?

1) Wash off or irrigate

2) Document exposure

3) Test pt if they consent

Occupational follow-up HIV testing schedule

Baseline, then ~1 month, 3 months, and 6 months

Mother-to-child transmission timing

During pregnancy, delivery, or through breastfeeding

Transmission rates from mother to child without therapy

- Industrialized countries = 15-25%

- Developing countries = 25-35%

Factors associated w higher rates of transmission from mother to child

- High maternal viral load

- Low cd4

- Prolonged interval between membrane rupture + delivery

Effect of zidovudine in pregnancy

AZT starting in 2nd trimester + delivery + infant for 6 weeks reduces transmission rate to 5%

Mother-to-child transmission with HAART + C-section

Close to <1%

Why do we not use HIV antibody tests on newborns from an HIV (+) mother?

- Newborns are positive for <6 months (Maternal IgG is passed onto the fetus in utero)

How to diagnose HIV infection in newborns

PCR for proviral RNA/DNA at 14-21 days, 1-2 months, and 4-6 months

Breastfeeding and HIV risk

- Highest early in breastfeeding and increases with prolonged duration

- If mother decides to keep breastfeeding -> provide continual ART treatment to mother

Routine HIV screening model

Opt-out screening (test unless patient declines)

How often should high-risk MSM be screened

At least annually (consider every 3-6 months if increased risk)

HIV screening in pregnancy

Routine prenatal testing with opt-out; repeat in 3rd trimester in higher prevalence areas

What is the workaround if a pregnant HIV pt opts out of HIV testing?

- Newborns require mandatory tested for HIV in NY

What is the diagnostic procedure when it comes to HIV?

1) 4th generation HIV antigen/antibody test (tests for p24 + antibodies for HIV) (SCREENING TEST)

2) If screening test is (+) -> do HIV 1/2 differentiation assay (CONFIRMATORY)

3) If confirmatory test is (-) -> do PCR for HIV RNA

CD4 cell count is indicative of

- Pts risk of opportunistic infection + overall immune function

CD4 count interpretation

- >500 = essentially normal immune function (monitor trends with serial testing)

What viral load (Proviral RNA/DNA PCR) measures

- Viral replication activity and treatment response

- Also done in newborns to assess their HIV status

How often viral load is monitored after diagnosis

At time of diagnosis + every 3-4 months

High viral load and prognosis

Viral load >30,000 strongly associated with higher progression/death risk

Low-level viremia on therapy significance

Intermittent <400 copies is not usually considered virologic failure

Use of genotyping viral DNA/RNA

- Guides therapy + determines mutations/resistance patterns + optimizes drug regimens

Who can be told about a pts HIV status without their consent?

- People associated with medical care/records + public health authorities + insurance companies + funeral home + court order + legal guardian

- Law also requires reports contain names of sexual or needle sharing partners

AIDS pathophysiology core concept

- CD4 decline causes CD4/CD8 inversion, B-cell dysregulation, and impaired immune responses (anergy)

- CD4 count < 200 = AIDS

Estimated survival after developing AIDS

- 9 months to 2 years (untreated)

Why HIV patients still get OIs early after HAART begins

Persistently low CD4 counts keep risk high, especially first 6 months of HAART