HIV and Antiretroviral Tx Flashcards
Pneumocystis Pneumonia
Associated with severe immunosuppressed patients , possibility of cellular immmune dysfunction
Immunosuppressed patients
may have Pneumocystis and candidiasis
Kaposi’s Sarcoma
Malignancy described by a Hungarian physician in 1872
When and among who Kaposi’s Sarcoma observed?
Before AIDS, had been seen mainly in elderly Mediterranean men
% of Kaposi’s Sarcoma
Before ART occured in 20% of HIV-1 infected homosexual men, 2% of HIV-1 infected women and transfusion- infected HIV-1 patients
Which specific virus associated with Kaposi’s Sarcoma?
human herpesvirus 8
Death rate with AIDS-related death having peaked in 1995, but declined since 1995 due to
ART (antiretroviral therapy)
The first HIV cases reported in health homosexual man
Pneumocystis carinii* pneumonia and Kaposi’s sarcoma
Pneumocystis jiroveci
The first HIV cases reported in health homosexual man
Pneumocystis carinii* pneumonia and Kaposi’s sarcoma
Pneumocystis jiroveci
Transmission route(relationship ) of HIV
Heterosexual
Homosexual
Mother-child
Which treatment contribute to lower the death rate from HIV
antiretroviral therapy (ART).
Virus that cause AIDS?
retrovirus, the human immunodeficiency virus, HIV, present in Central Africa
How does HIV evolved in monkey and other apes?
HIV evolved from a lentivirus, simian immunodeficiency virus, SIV, in monkeys
SIV in apes led to which type of HIV?
HIV-1 in man,
with groups M,N, from chimpanzees,
and group P and perhaps group O from gorillas.
SIV in sooty mangabey monkeys led to?
the more indolent virus, HIV-2 in man
T/F
SIV viruses (40 different) are pathogenic in old world monkeys.
False
SIV viruses (40 different) are not pathogenic in old world monkeys.
SIVcpz and SIVgor infected
humans resulting in HIV-1, groups M,N.O, and P.
SIVcpz
was a recombinant virus from SIVmon and SIVrcm.
SIVsmm from a sooty mangabey infected
a human being, resulting in HIV-2
HIV evolved from?
a lentivirus, simian immunodeficiency virus (SIV)
SIV was transferred to
chimpanzees a few hundred years ago, with gorillas subsequently infected, and with man infected around 1920.
SIVcpz and SIVgor resulted in?
HIV-1, groups M,N,O, and P.
SIVsmm, from a sooty mangabey monkey,
infected a human being, resulting in HIV-2.
Prevalence of HIV
Worldwide by the end of 2020 there were 37.7 million people living with HIV, with 1.5 million new cases and 680,000 deaths that year.
Exam:
Home to ¾ of the people in the world with HIV?
Sub-Saharan Africa
Exam: Sub-Saharan Africa
Home to ¾ of the people in the world with HIV
Overall prevalence: 7% of the population has HIV, with prevalence rates over 25% in Botswana, Lesotho, and Swaziland
HIV is the primary cause of death in this region of the world
Most cases are from heterosexual transmission
Caribbean
Has the next highest prevalence of HIV, at 1.3% overall, 2.1% in Haiti, 3.3% in the Bahamas, with a 30% prevalence among MSM in Jamaica
Major route of Transmission of HIV
Sexual transmission, both homosexual and heterosexual
IVDU
Percutaneous needle-stick injuries and other body substance injuries
Transfusion-related transmission (blood products)
Mother-to-child transmission
IVDU
Currently feeding the epidemic in Central and Eastern Europe an some Asian countries
Prevalence among IV drug injectors is 12% in China, 16% in U.S, 37% in Russia
Exam: the highest Risk rate for acquisition of HIV by exposure
Blood transfusion (9/10)
HIV Exposure routes (3 categories)
Blood borne exposure
Sexual exposure
Other- Negligible
Stages of HIV infection
Viral transmission
Acute HIV infection
Early HIV infection
Chronic HIV infection without AIDS
AIDS
Advanced HIV infection
Viral transmission
Occurs through sexual intercourse, exposure to infected blood, perinatal transmission
Acute HIV infection
Signs and symptoms that occur just after transmission
Early HIV infection
6 month period following HIV acquisition
AIDS
CD4<200 cells/microL and/or AIDS defining condition
Advanced HIV infection
CD4<50 cells/microL
Acute HIV Infection aka
Also called the acute retroviral syndrome (if symptomatic)
When does Acute HIV infection occured?
Occurs 2-3 weeks after HIV acquisition
Symptoms of Acute HIV
Fever, lymphadenopathy, sore throat, rash, myalgias, arthralgias, diarrhea, headache, weight loss are seen.
Painful mucocutaneous ulceration is quite distinctive
Aseptic meningitis, meningoencephalitis may be seen
T/F
Up to 60% of the time acute HIV infection is asymptomatic
True
When does Acute HIV progressed to AIDS?
If prolonged (>14 days), it is associated with a faster progression to AIDS
Early HIV Infection: Definition
Refers to the 6 month period following acquisition of HIV, with rapid viral replication and infection of CD4 cells
Early HIV infection: Lab results
Refers to the 6 month period following acquisition of HIV, with rapid viral replication and infection of CD4 cells
Viral load is usually high (>1,000,000 copies/ml)
CD4 can be transiently quite low
Early HIV infection may be associated with ( )
Opportunistic infections
can be occasionally seen, including oral or esophageal candidiasis; Pneumocystis pneumonia; CMV proctitis, colitis, or hepatitis; and severe cryptosporidiosis
Most patients seroconvert within the first several weeks after infection associated which stage of HIV?
Early HIV
By 6 months a steady state of viremia is reached
Early HIV
Chronic HIV Infection Without AIDS
Characterized by relative stability of viral load, with a slow progressive decline in CD4 count.
Chronic HIV Infection Without AIDS
the absence of ART, the average time to decline to a CD4 <200 cells/microL is 8-10 years.
1000 cells prior to seroconversion, with average of 1.19 years to 500 cells, then a decrease of 50 cells/year
Chronic HIV Infection Without AIDS
Involves high rate of HIV replication, CD4 cell death (109 cells/day), with CD4 cell replenishment.
The component of HIV virus (Exam!)
HIV has two identical copies of s.s. RNA, each within a nucleocapsid,
reverse transcriptase,
integrase,
protease all surrounded by a capsid then a matrix and then an envelope containing surface glycoprotein gp120 and transmembrane protein gp41.
Name of the glycoprotein receptor and transmembrane?
glycoprotein gp120(R)
transmembrane protein gp41.(TM)
Function of Gp 120?
Gp120 attaches to the CD4 receptor and a co-receptor, either CCR5 or CXCR4.
Reverse transcriptase function 1)
uses the viral RNA primer to form an RNA-DNA double helix in the host cell cytoplasm.
Reverse transcriptase function 2)
1) The ribonuclease site of the reverse transcriptase (RT) then degrades the viral RNA, and
2) the polymerase site of the RT synthesizes the complementary DNA strand to form viral double stranded DNA which then enters the nucleus.
In the nucleus, integrase of HIV,
allows the viral DNA to become part of the host cell genome.
What happened when gp120 binds to CD4?
This binding alters the gp120 to expose gp41 which penetrates the host cell and then folds to allow fusion of the virus envelope and the host cell, thereby allowing entry of the virus into the host cell cytoplasm.
what happened after the alteration of gp120 and 41?
his binding alters the gp120 to expose gp41 which penetrates the host cell and then folds to allow fusion of the virus envelope and the host cell, thereby allowing entry of the virus into the host cell cytoplasm.
The nucleocapsid disintegrates, with two naked strands of viral RNA in the cytoplasm along with the three enzymes,
1)reverse transcriptase,
2) integrase,
3) protease, all in the host cell cytoplasm.
Reverse transcriptase has two catalytic domains, names?
a ribonuclease active site and
a polymerase active site.
Reverse transcriptase mechanism?
uses the viral RNA primer to form an RNA-DNA double helix in the host cell cytoplasm.
The ribonuclease site of the reverse transcriptase (RT) do?
degrades the viral RNA,
The polymerase site of the RT do?
synthesizes the complementary DNA strand to form viral double stranded DNA which then enters the nucleus.
In the nucleus, integrase do?
allows the viral DNA to become part of the host cell genome.
The integrated viral DNA is called?
is called a provirus. It can remain latent or direct viral production.
Proviral DNA do?
can be transcribed into new viral RNA and viral mRNA, both of which migrate into the cytoplasm.
Ribosomes do?
allow the mRNA to direct the synthesis of viral polypeptides
Function of Protease?
Protease is needed to cut the precursor polypeptides into final viral proteins
Immature virus forms, containing ?
viral RNA, the three important viral enzymes, core proteins, and envelope glycoproteins then buds from the cell membrane, with protease needed for final viral maturation
Why Reverse Transcriptase is critical in HIV infection?
Important: Reverse transcriptase does not correct the errors it makes, with there being 5 errors for each genome and tremendous genetic instability, allowing for immune evasion through new antigen formation.
Attachment done by?
gp120, CD4 receptor, CCR5 or CXCR4 co-receptors
Fusion by?
gp41
Reverse Transcription by?
Reverse transcriptase
Reverse transcriptase has two catalytic domains, a ribonuclease active site and a polymerase active site.
Reverse transcriptase uses the viral RNA primer to form an RNA-DNA double helix in the host cell cytoplasm.
Integration by?
Integrase
Replication ? Transcription. Translation by?
Protease
Assembly –> Budding/ Maturation
Protease
Protease 3 functions?
Translation
Budding
Maturation
Targets of Antiretroviral Therapy- Attachment Inhibitors
May prevent attachment by binding to gp120
May interfere with the CCR5 co-receptor (useful only for R5 virus, and not useful if there is X4 virus that uses the CXCR4 co-receptor)
May work post-attachment by blocking attached virus from entering CD4 cells
Targets of Antiretroviral Therapy- Fusion inhibitor
Binds to gp41 and prevents fusion of the virus to the host cells
No activity against HIV-2
T/F
Targets of Antiretroviral Therapy- Fusion inhibitor is mostly used to treat HIV-2
False
No activity against HIV-2
Targets of Antiretroviral Therapy, intergrase inhibitors
Block integrase, the enzyme that inserts the viral genome into the DNA of the host cell
Targets of Antiretroviral Therapy- 8 mechanisms
1) Attachment Inhibitors
2) Fusion Inhibitor
3) Integrase Inhibitors
4) Protease inhibitors
5) Nucleoside and nucleotide reverse transcriptase Inhibitors (NRTIs)
6) Non-nucleoside reverse transcriptase inhibitors (NNRTIs)
7) Integrase Inhibitors
8) Protease inhibitors
Which antiretroviral therapy option mainly used for ART?
Integrase Inhibitors
Nucleoside and nucleotide reverse transcriptase Inhibitors (NRTIs)
Protease inhibitors
Targets of Antiretroviral Therapy-Protease inhibitors
Block the protease enzyme used to break down the precursor polypeptides into mature viral proteins
Currently play a vital role in ART
Attachment Inhibitors 3 mechanisms
1) Prevention of attachment by finding of gp 120
2) Prevention of attachment by interference with CCR5(antagonist)
3) Post-attachment inhibitor
Prevention of attachment by binding of gp120
Fostemsavir, a prodrug which must be converted to the active temsavir
Prevention of attachment by interference with CCR5 (antagonist)
Maraviroc (MVC), not useful if there is X4 tropic or mixed tropic virus
Tropism assay is needed to assess for potential efficacy
Post-attachment inhibitor
Blocks entry of virus into CD4 cells after attachment
Ibalizumab-uiyk, a monoclonal antibody given every 2 weeks
Fusion Inhibitor
Prevention of fusion by binding to gp41
Enfuvirtide, Fuzeon, (T-20)
36-amino acid peptide
Must be given by injection twice daily
Reverse Transcriptase Inhibitors: Names?
Vemlidy*
Nucleoside and Nucleotide
* Reverse Transcriptase Inhibitors
NRTIs are nucleoside analogues, faulty versions of the nucleotides used by reverse transcriptase to convert HIV viral RNA into viral DNA (competitive inhibition).
Toxicity of NRTIs
Didanosine and stavudine have mitochondrial toxicity and cause neuropathy and lipodystrophy and are rarely used.
The main toxicity of the NRTIs is mitochondrial, with the possibility of neuropathy, pancreatitis, lipoatrophy, and hepatic steatosis possible, along with lactic acidosis
Non-nucleoside Reverse Transcriptase Inhibitors
NNRTIs bind to and block reverse transcriptase directly. Not active against HIV-2.
Adverse Events Associated with NNRTIs
Efavirenz and rilpivirine can cause neurologic and psychiatric side effects and QT prolongation.
May see elevated LFTs with efavirenz.
Rash common with etravirine, but if mild usually resolves by week 4.
Nevirapine may cause hepatic necrosis, Stevens-Johnson, and is not recommended for treatment-naive patients. If CD4 at onset of Rx is over 250, there is a higher risk for hepatotoxicity.
Integrase Inhibitors
Integrase Inhibitors (INIs) block the action of integrase, the enzyme that inserts the viral genome into the DNA of the host cell.
Integrase strand transfer inhibitors (INSTIs) are in use
gravir -
Protease Inhibitors
PIs block the protease enzyme used to break down precursor polypeptides into the mature viral proteins.
-navir
Protease Inhibitors
PIs block the protease enzyme used to break down precursor polypeptides into the mature viral proteins.
Antiretroviral Regimen for the Treatment-Naive Patient
Two different nucleoside reverse transcriptase inhibitors,
1) NRTIs, and an 2) integrase strand transfer inhibitor, INSTI:
Antiretroviral Drug Resistance
Genotypic resistance assays detect the presence of specific drug resistance mutations in the genome coding for reverse transcriptase, protease, and integrase.
Antiretroviral Drug Resistance
Phenotypic resistance assays measure the extent to which an antiretroviral drug inhibits viral replication in vitro.
Pre-exposure Prophylaxis (PrEP) Against HIV Infection
Pre-exposure prophylaxis with tenofovir-emtricitabine can reduce HIV infection by over 90% in those at high risk of acquiring HIV.
Immunosuppressed patients
may have penumocytosis and candidiasis
SIVcpz
was a recombinant virus from SIVmon and SIVrcm.
T/F
Opportunistic infections can be occasionally seen in Early HIV infection
True
T/F
Oral or esophageal candidiasis; Pneumocystis pneumonia; CMV proctitis, colitis, or hepatitis; and severe cryptosporidiosis are see in acute HIV infection
False
Early HIV infection
HIV Infection 2022
ART must be taken indefinitely
● Drug resistance can occur
● The therapy is expensive
● There is presently no cure for HIV
● There is presently no vaccine
HIV controllers
HIV controllers have low or undetectable HIV RNA in the absence of ART.
If the patient has undetectable RNA, then is non-viremic, or “elite”.
1/300 HIV infected individuals are elite.
Positivity for HLA-B57 is often associated with being elite.
Note CCR5-delta 32 homozygotes have CD4 cells that hamper the entry of HIV.
Note cure for HIV would require eradication of latent virus in lymphoid tissue.
ART
Without treatment for HIV, survival once the CD4 is <200 is 38-40 months, and once the CD4 is <50 survival is 12-18 months.
Antiretroviral Therapy (ART)
ART
● Suppresses HIV RNA
● Increases the CD4 cell count
● Lowers HIV transmission
● Decreases the proinflammatory cytokines, chronic inflammation, and T-cell
activation, thereby lowering the risk for cardiovascular, renal, hepatic, and
neurologic diseases and malignancy
● Associated with an increase in CD4 cell count of 50-150 by year one, then an
increase of 50-100 per year until a steady state is reached
● A low pre-ART CD4 is associated with a poor immune recovery after initiation
of ART, stressing the need to treat HIV as early as possible
● Early therapy is associated with a near-normal life span
Opportunistic Illnesses seen with AIDS- CD4 count
In general opportunistic illnesses related to HIV develop
when the CD4 count is below 200 cells/microL,
usually within 12-18 months once the CD4 is < 200.
Opportunistic Illnesses seen with AIDS- organisms
Pneumocystis pneumonia, esophageal candidiasis, Kaposi’s sarcoma, disseminated Mycobacterium avium-intracellulare,
disseminated cryptococcal infection, and cytomegalovirus disease* are most common
(* seen with CD4 < 50 cells/microL, advanced HIV infection)
Disease seen with CD4 < 50 cells/microL, advanced HIV infection
avium-intracellulare,
disseminated cryptococcal infection and cytomegalovirus disease are most common
Opportunistic Illnesses seen with AIDS
Without treatment for HIV, survival once the CD4 is <200 is 38-40 months, and once the CD4 is <50 survival is 12-18 months.
Chronic HIV Infection Without AIDS mostly associate with which area of cell or tissue?
Most HIV is in the lymphoid tissue, on the surface of dendritic cells and inside lymphocytes in a latent form
Symptoms of Chronic HIV Infection without AIDS
Most patients have no symptoms, but some have fatigue, sweats, weight loss, generalized lymphadenopathy.
Chronic inflammation may accelerate appearance of cardiovascular disease, cognitive decline, osteoporosis, and malignancies.
Other symptoms with Chronic HIV infection without AIDS
Hairy leukoplakia, seborrheic dermatitis, bacterial folliculitis may be seen.
When they occur, VZV, herpes and human papillomavirus infections are more severe than normal.
Acquired Immunodeficiency Syndrome (AIDS)
AIDS is present once the CD4 cell count is <200 cells/microL or if an AIDS defining condition is present.
Progression of AIDS
Progression to AIDS once HIV infection is present typically occurs over 5-10 years in the absence of ART, but patients can progress to AIDS over 1 to greater than 10 years.
Viral load and CD4 in AIDS
The viral load and CD4 count are independent predictors of HIV progression
HIV-1 vs HIV-2
HIV-2 (seen mostly in West Africa, Portugal, Spain, Goa, India) progresses slower than does
HIV-1, the cause of most infections worldwide
Predictive of faster evolution to AIDS:
advanced age at time of infection, HIV M subtype D, use of coreceptor CXCR4 vs CCR5, lower number of CD8 cells, co-infection with M. tb, fungi, helminths, or T. pallidum.
Slower progression of AIDS?
The presence of the HLA-B57 allele and the CCR5-delta 32 mutation each are associated with slower progression of disease.
Malignancies associated with AIDS
Cervical cancer, invasive
Kaposi sarcoma
Lymphoma, Burkitt
Lymphoma, immunoblastic
Lymphoma, primary brain
Other conditions associated with AIDS
HIV encephalopathy
HIV wasting syndrome
ART?
Antiretroviral Therapy
ART purpose
Suppresses HIV RNA
Increases the CD4 cell count
Lowers HIV transmission
Decreases the proinflammatory cytokines,
chronic inflammation, and T-cell activation,
thereby lowering the risk for cardiovascular, renal, hepatic, and neurologic diseases and malignancy
Associated with an increase in CD4 cell count of 50-150 by year one, then an increase of 50-100 per year until a steady state is reached
A low pre-ART CD4 is associated with a poor immune recovery after initiation of ART, stressing the need to treat HIV as early as possible
Early therapy is associated with a near-normal life span
The integrated viral DNA is called
provirus. It can remain latent or direct viral production.
In the nucleus, integrase of HIV,
allows the viral DNA to become part of the host cell genome.
Adverse Effects of Protease Inhibitors
Hyperglycemia, diabetes, hyperlipidemia, lipodystrophy, hepatotoxicity, PR prolongation.
Atazanavir can cause renal injury
Darunavir has a sulfonamide moiety
Adverse reactions Integrase Inhibitors
Weight gain, insomnia, diazziness, neural-tube defects
T/F
Early HIV, viral load is transiently low but CD4 is usually high
False Viral load is usually high (>1,000,00
T/F
Early HIV, CD4 can be transiently quite low
True
ART use:
Nucleoside and nucleotide reverse transcriptase Inhibitors (NRTIs)
Integrase Inhibitors
Protease inhibitors
Have no activity against HIV-2.
Non-nucleoside reverse transcriptase inhibitors (NNRTIs)
Fusion Inhibitor
