lecture 18 & 19: HIV and AIDS

gag

HIV gene that codes for structural proteins, including matrix capsid and nucleocapsid

pol

HIV gene that codes for enzymes, including protease, reverse transcriptase, and integrase

env

HIV gene that codes for for structural proteins and envelope proteins, including GP120 and GP41

tat

main HIV gene that codes for regulatory proteins

9

HIV genome contains _______ genes encoding 15 viral proteins

Tat

HIV virulence factor that is a transactivator of transcription

-enhances viral transcription and immune regulation

reverse transcriptase

HIV enzyme encoded by pol that •convert RNA genome into DNA to be integrated

integrase

HIV enzyme encoded by pol that integrates viral DNA into host DNA

protease

HIV enzyme encoded by pol that cleaves polyproteins into functional viral proteins

-primary infection 2-4 weeks with flu like symptoms

-latency with steady increase of anti-HIV ab and decrease of CD4 over 6-10 years

-full blown AIDs

clinical progression/timeline of HIV

gp160, also called Env gene

what is the viral attachment protein of HIV

receptor: CD4

coreceptor: CCR5 (on T cells, macs, DCs)

receptor and co-receptor of HIIV

CD4 T cells, macrophages, and DCs

target cells of HIV virus

1. gp120 binds CD4 and CCR5

2. conformational change exposes fusion peptide

3. capsid is released into cytoplasms and uncoated

4. The 2 ssRNA genomes are copied into 2 dsDNA molecules by reverse transcriptase that copies, then degrades, viral RNA

5. dsDNA is tranpsorted to nucleus and integrated into host cell by integrase

6/ proviral DNA is transcribed into genomiic RNA

7. viral proteinss are sysntehsized

8. viral particles are assembled and released by budding

steps of HIV-1 replication

gp120 and gp41 cmplex

protein on the HIV viral envelope that attaches to the CD4 cell

zidovudine

HIV med that competitively inhibits nucleotide binding to reverse transcriptase

Efanvirenz

HIV med that binds to and inhibits reverse transcriptase at different site than nucleotide reverse transcriptase inhibitors

indinavir

HIV med that prevents cleavage of the polypeptide products of HIV mRNAinto their functional parts--> prevents maturation of new viruses

Raltegravir

HIVI med that inhibits HIVI integration into host cell DNA

Enfuvirtide

HIV med that binds gp41--->inhibits viral entry into host cell

maraviroc

HIV med that binds CCR6---> inhibits initeraction with gp120--> prevents viral biniding

proofreading capability---> extremely high error rate during synthesis

-error rate leads to emergence of strains with changes in antigenicity--> drug resistance to ART

unlike other polymerases, reverse transcriptase lacks

Viral RT is error-prone (no proof-reading), high mutation rate leads to drug resistance to ART (anti-retroviral therapy).

what has led to the resistance to anti-retroviral therapy?

-→ reduced Th activity (esp. IL-2 and IFN-γ production), so reduced CD8 and mac function

the impact on immune system placed by loss of CD4 cells

<200 (TH1 most affected, TH2 predominant cytokine profile)

CD4 count diagnostis of AIDS

1.Flu-like (acute)

2.Feeling fine (latent)

3.Falling count

4.Final crisis

what are the 4 stages of untreated HIV iinfectioiin

CD4 >500

CD4 count associated with acute phase, peak of virus that declines, non-specific "flu-like" symptoms to asymptomatic

latent stage of HIV

no detectable viral DNA; in late stage, CD4 T cell count of 200-500 cells/u

– CD4 T cell count <200 cells/ul and appearance of at least 1 “indicator” disease (neoplasm, opportunistic infection, dementia

define criteria of full blownn AIDS

generation of viral diversity via mutation and recombination--> life long infection

how does HIV evade the immune system?

Step 1: Antibodies to gag and env proteins - immunoassay

Step 2: Confirm with detection of p24 core Antigen - acute and end-stage/AIDS

Step 3: NAAT (RT-PCR) for HIV RNA

steps to diagnosing HIV

antiretroviral therapy

reduces plasma viremia and reduces transmission

condoms, ART, less risky sexual practices

how to decrease risk of contracting HIV

take ART, avoid breastfeeding (delivery method depends on viral load)

•Also prophylaxis the baby

avoiding perinatal transmission of HIV via

-less likely to transmit HIV to partner

-fewer incidences of TB, severe bacterial infection

the benefits of early treatment of HIV

post-exposure prophylaxis

the taking of ART as son as suspected exposure occurred

-begin within 72 hours of exposure

2-3 antiretroviral meds taken for 28 days

what does PEP consist of?

•For HIV- & at high risk for infection

ex: ongoing relationoship with infected partner, not mutually monogomous, MSM, STD in last 6 months, IVDU in last 6 months

pts indicated to take PrEP

every 3 months

how often are pts who take PrEP tested for HIV

tenofovir & emtricitabine

the two meds in PrEP

•Acute mononucleosis-like symptoms correlates to virus disseminating through lymphoid tissue

•Generalized lymphadenopathy, fever, fatigue, rash, pharyngitis, HA, arthralgia, myalgia

primary sympptoms of HIV infection

8-10 years

Avg time from acquisition to a CD4 <200 cells/μL is approximately

•Majority asymptomatic, but will often have generalized lymphadenopathy

symptoms of latent stage of HIV

thrush, vaginal candidiasis, oral hairy leukopplakia, herpes zoster , const. symptoms for more than one month

symptomatic illnesses associated with chronic HIV infection without AIDS

•HIV + & CD4 count < 200/μL or HIV+ w/ certain infections

definition of AIDs

grade A

screen ages 15-65 for HIV at least once in their lifetime or more

-screen all pregnant women

-if risk factors, test annually

USPSTF recommendation fo HIV screening

every 3-6 months

how often to screen gay and bisexual men for HHIV

•screen with a highly sensitive initial test and confirm reactive results with a different test that is both sensitive and highly specific

what is the general principle of HIV testing

IgG-sensitive HIV-1/2 antibody differentiation supplemental assay

-shortest window period of positivity

confirm initial Ag/Ab test with this test for HIV

•2 step testing (EIA + Confirmatory IgG sensitive assay) is sensitive 99.5 % and specificity of 99.9%. If ELISA (EIA) negative, then HIV is neg unless acute infection.

define the 4th generation testing of HIV and its efficacy

between 2 - 6 weeks; median window is 18 days after exposure with 99% of HIV-infected persons detectable within 44 days of exposure

-can due 4th gen testing

when is HIV detectable (outside window period)

4th generation tests

•Detect both HIV antibodies and the HIV-1 p24 antigen, but do not differentiate between them.

5th generation tests

•Detect both HIV antibodies and the HIV-1 p24 antigen, and provide separate results for each. Can differentiate between HIV-1 and HIV-2 antibodies. Detects the same biomarkers as 4th, but it is about being able to independently confirm each one separately

-HIV drug resistance testing

-may defer ART initiation til after this tests results, unless early infection or pregnant

initial testing in confirmed HIV + pt

pregnancy test

test in women before initiating ART

DTG based regimen

is one of the recommended options for persons of childbearing potential initiating ART

nucleoside, nucleotide, and non nucleoside inhibitors

what are the 3 types of reverse transcriptase inhibitors?

integrase inhibitors

suffix -gravir indicates this HIV drug

protease inhibitors

-exception: lenacapavir is a capsid inhibitor

suffix -avir indicates this HIV drug

•Zidovudine

•Stavudine

•Lamivudine

•Emtricitabine

VUDINE

list the pyrimidine analogs of NRTI

•Didanosine

•Abacavir

•Tenofovir

list the purine analogs of NRTI

darunavir

what is the most commonly used protease inhibitor

protease inhibitors

HIV drug class that renders the virus immature and noninfectious

Lenacapavir (capsid inhibitor)

indication: for adult patients living with HIV-1 in whom other available treatments have been unsuccessful due to resistance, intolerance, or safety considerations.

capsid inhibitor

-Capsid inhibitors are a class of drugs that interfere with HIV capsid, a protein shell that protects HIV's genetic material and enzymes needed for replication. Capsid inhibitors can disrupt HIV capsid during multiple stages of the viral life cycle

MOA of lenacapavir

4 hours post dose

-ppeak plasma concentrations of lenacapavir happen when?

Binds to the HIV integrase active site and blocks the strand transfer step of retroviral DNA integration which is essential for HIV replication

MOA of integrase strand transfer inhibitors (--gravir)

Maraviroc

A CCR5 inhibitor always used in combination with other HIV medicines

-tropism test must be performed prior to use

•Selectively binds to the human CCR5 chemokine co-receptor present on the cell membrane which prevents the interaction of HIV-1 gp120 and CCR5 for HIV to enter CD4 cells.

MOA of maraviroc

•increased liver enzymes, muscle/joint pain, cough

side effects of maraviroc

Enfuviritide

entry inhibitor inndicated inn pts whose infection is not well controlled by ongoing treatment with other HIV meds

Binds to the gp41 glycoprotein subunit of the viral envelope to prevent conformational changes needed for fusion of viral and cellular membranes and entry of HIV into CD4 cells.

MOA of enfuvirtide, a entry inhibitor

-2 NRTIs + (NNRTI or integrasae inhibitor or protease inhibitor) + PK enhancer (cobicistat + ritonavir)

-3 ARV + 2 booster

initial combination antiretroviral regimen for people with HIV

-tenofovir alafennamide OR tenofovir fumarate

-emtricitabine

-a --gravir

what are the 3 drugs initiated for most naive HIV + pts

HIV-infected women on cART with HIV RNA ≤ 1000 copies/mL late in pregnancy/near delivery date

IV zidovudine is not required for this woman late in pregnancy/near delivery date

HIV RNA >1000

HIV RNA number necessitating mother get IV zidovudine near delivery

at onset of labor or 3 hours piror to scheduled C-section until delivery of infant

at what point of pregnancy should IV zidovudine be administered?

-zidovudine syrup given as soon as possible (6-12 hours of delivery) until 6 weeks of age

-can lessen to 4 weeks if mother consistently on cART during pregnancy with suppressed viral load and reliable adherence

management of newborn baby whose mother has received HAART during pregnancy

add nevirapine suspension to zidovudine syrup regimen

management of newborn baby whos mother has not received HAART during pregnancy

38%

___% of people living with HIV are still not accessing ART

set as targets that by 2020, 90% of all people with HIV will know their HIV status, 90% of all people who know their status will be on ART, and 90% of all people receiving ART will have viral suppression

what is UNAIDS 90-90-90 goal?

immune reconstitution inflammatory syndrome

•Inflammatory disorders associated with paradoxical worsening of preexisting infectious processes following the initiation of highly active antiretroviral therapy (HAART) in HIV-infected individuals.

-unmasked by host's regained capacity to mount an inflammatory response

continue ART, treat opportunistic infections mostly with steroids

management of immune reconstitution inflammatory synndrome

coronary artery disease due too increased cholesterols due to ART

HIV pts are at risk for this heart disease

HCV, HBV

pts with HIV have an increased risk for cirrhosis esp with co-infection oof

HIV-associated neurocognitive disorder (HAND)

HIV associated CNS disorder characterized by memory and psychomotor impairment, depressive symptoms, movement disorders

-can progress to AIDS demention

10%

HIV wasting syndrome is a condition that occurs when a person with HIV loses more than ___% of their body weight, along with experiencing diarrrhea, weakness, or fever for at least 30 days

-ART, appetite stimulatnts, cytokine inhibitors, anabolic agents, human growth hormone (effectss don't last long)

-nutrition, exercise

treatments of HIV wasting syndrome innclude

cervical cancer, anal cancer

cancer to test for yearly in pts with HIV

breast, colon prostate

cancers that have normal screening recommendations for pts with HIV

200

avoid giving live virus vaccines if CD4 is below

herpes zoster

TB

opportunistic infection associated with CD4 over 500

mucocutaneous

______ infections tend to present first in pts with HIV

•unicellular fungus Pneumocystis jiroveci

-previously called pneumocystis carinii

pneumocystis pneumonia is caused by

airborne

transmission of pneumocystis pneumonia

-subacute progressive dyspnea

-hypoxemia and rales on PE

signs of pneumocystis pneumonia

pneumocystis pneumonia

CXR shows •diffuse, bilateral, symmetrical interstitial infiltrates emanating from the hila in a butterfly pattern

-CT shows patchy areas of ground glass attenuation

•Tx: TMP-SMX + steroids (if hypoxemic) x 21 days

•Prevention: TMP-SMX daily for CD4 < 200

tx and prevention of pneumocystis pneumonia

pneumatoceles

air-filled cysts that may form abcesses; associated with pneumocystis pneumonia

Pneumocystis jiroveci

found on silver stain