Micro Test 4: Anti-viral Therapy
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Binds to gp41 gene, inhibits cell fusion
Binds to CCR5 and prevents cell fusion
Anti-viral drugs: 1st line drugs
- Nucleoside and Nucleotide RT Inhibitors (NRTIs)
- Non-nucleoside RT Inhibitors (NNRTIs)
- Protease Inhibitors (PIs)
Anti-HIV drugs: Back-ups
- Fusion inhibitor: blocks gp41-mediate fusion
- CCR5 antagonist
- Integrase inhibitor
If you become resistant to one drug in an HIV class, you may become resistant to all of that class because they all work in the same manner
Combination of anti-HIV drugs simplify dosing: Combivir
Lamivudine (NA) + Zidovudine (NA)
Combinatons of anti-HIV drugs simplify dosing: Atripla
Atripla= Emtriva (NA) + Viread (NA) + Sustiva (NN)
Structure of Nucleoside and Non-nucleoside analogues
R1-CO-NH-R2 peptide bond is present
Act as DNA chain terminators
Cannot eliminate a latent HIV-1 infxn, but can control an ongoing infxn
Toxic!!! Adversely affect phosphorylation of normal nucleoside and inhibit mitochondrial DNA polymerase gamma
Nucleoside RT Inhibitors
NRTI: Can accidentally inhibit
Mitochondrial DNA Polymerase gamma
Which has a higher affinity for RT, NRTI or host DNA Pol?
NRTIs are active only on the triphosphate
Non-competitive inhibitors of RT that bind elsewhere than at the active site and block RT activity
Non-nucleoside RT Inhibitors
(Work synergistically with NRTIs)
Bind the active site of the viral protease and inhibit its activity.
Must be used along with NRTIs and/or NNRTIs
(Can't be used by themselves)
Approved for HIV+ pts who have tried other HIV-1 drugs but who can't control their viral RNA loads. Used in combination with other drugs
Fusion Inhibitors (Fuzeon)
Must be injected 2x daily
Initiate HAART when pt. has
- AIDs-defining illness
- CD4 count <350 cells/mm
Highly Active Anti-Retrovirus Therapy
- 2 NRTIs + 1 protease inhibitor OR
- 2 NRTIs + 1 NNRTI
Ppl who get HAART therapy
- Pregnant, HIV+ women
- Persons with HIV-associated nephropathy
- Persons co-infected with hepatitis B virus (HBV) when HBV tx is indicated
Pts. should show a 1 log decrease in HIV RNA in 8 wks and no detectable virus at 4-6 months.
4 Challenges to HIV Drug Tx
- NK cells act as reservoir
- Macrophages and microglial cells within CNS are protected by BBB
- Virus-infected macrophages and virus-coated FDCs are longer-lived than HIV-infected lymphocytes
- There is a pool of latently infected CD4+ cells within HIV+ pts.
Approaches to root out latent HIV-1
- Use IL-2 to reactive latently-infected cells
- Structured tx interruptions (STI) to ractivate latently-infected cells (whack-a-mole)
- Development of drugs that better pass the BBB
Inhibitor of histone deacetylase (HDAC)
HIV and Pregnancy:
HAART in USA
- Single dose of NNRTI during delivery
- C-sections for women with RNA levels >1000 copies
Prophylactic Options for HIV
- Vaginal cream containing tenofovirDaily, pre-exposure use of truvada
HAART-Associated Adverse Clinical Events
- Fat Maldistribution (Buffalo hump)
- Drug interactions (PIs and statins)
NO vaccine for HIV. Why?
Can make Abs against virus, but virus mutates.
Problem with HIV Live attenuated vaccine
Deletion of nef gene caused disease in young monkeys and some of the viruses were able to repair themselves.
Problem with HIV Inactivated Vaccine
Produces some protection, but does not protect from infxn. Decreases severity.
Problem with HIV Merck's T-cell vaccine
- Trivalen rAd5 vectors expressing clade B Gag, Pol, and Nef
- Vaccine failed to protect against infxn and those with Ad5 Abs showed an enhanced rate of HIV-1 infxn
Problems with HIV vaccines: Monomeric Env gp120 vaccine
No detectable protection in man even though it elicited type-specific binding Abs; failed to reduce broadly reactive neutralizing Abs
Problems with HIV Vaccines: DOD's RV144
Vaccination did not affect the degree of viremia or the CD4+ cell count in subjects who became HIV+
Blood in the US is screen by
- ELISA: anti-HIV-1; anti-HIV-2, HTLV-I and II
- PCR: HCV-RNA; HIV-1 RNA; WNV RNA
Long Term Non-Progressors
HIV+ individuals who have been disease free for > 15 years.
Generate neutralizing anti-HIV antibodies
How have LTNPs and ENs remained disease free?
- Infxn with Nef- or Vif-minus virus
- Defective in CCR5 or overproduce its ligand
- Generate a neutralizing primary antibody response
- Certain HLA haplotypes are linked to good control of the virus and a better prognosis
Where is HIV-2 mostly seen
Differences between HIV-1 and HIV-2
HIV-2 has a slower progression to AIDS, HIV-2 is more difficult to transmit because the viral burden is lower
1st human retrovirus to be isolated
Human T Cell Leukemia Virus (HTLV-1)
Infection with HTLV-1 leads to
- Tropical Spastic Paraparesis (TSP) or HTLV-1 Associated Myelopathy (HAM)
HTLV-1: Transmitted by free virus or virus-infected cells?
Virus infected cells
(Transmitted via the same routes as HIV-1)
HTLV-1 is endemic to
- Southern Japan
- Caribbean basin
HTLV-1 infxn does not invariably progress to illness.
1.2 million Japs are infected but only 700 new cases of ATL/ year
Slowly progressing degenerative disease that primarily affects the corticospinal tracts of the thoracic cord
No effective therapy for HTLV-1
HTLV-II infects humans but has not been linked to a specific illness. Endemic in? Prevalent among?
- North/South American-Indian tribes
HTLV-3 and -4
- Linked to no known disease
- Seen among native Africans, specifically bush meat hunters and those with close contact with primates
Animal Lentiviruses: Visna virus
Neurological defects in sheep
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