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Binds to gp41 gene, inhibits cell fusion
Fuzeon
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Binds to CCR5 and prevents cell fusion
Selzentry
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Anti-viral drugs: 1st line drugs
- Nucleoside and Nucleotide RT Inhibitors (NRTIs)
- Non-nucleoside RT Inhibitors (NNRTIs)
- Protease Inhibitors (PIs)
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Anti-HIV drugs: Back-ups
- Fusion inhibitor: blocks gp41-mediate fusion
- CCR5 antagonist
- Integrase inhibitor
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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
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Combination of anti-HIV drugs simplify dosing: Combivir
Lamivudine (NA) + Zidovudine (NA)
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Combinatons of anti-HIV drugs simplify dosing: Atripla
Atripla= Emtriva (NA) + Viread (NA) + Sustiva (NN)
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Structure of Nucleoside and Non-nucleoside analogues
R1-CO-NH-R2 peptide bond is present
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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?
NRTI
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
Protease Inhibitors
(Can't be used by themselves)
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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
Fuzeon
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Initiate HAART when pt. has
- AIDs-defining illness
- CD4 count <350 cells/mm
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HAART
Highly Active Anti-Retrovirus Therapy
- 2 NRTIs + 1 protease inhibitor OR
- 2 NRTIs + 1 NNRTI
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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
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Tx goals:
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.
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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)
Vorinostat
-
Vorinostat inhibits
histone deacetylase
-
HIV and Pregnancy:
HAART in USA
3rd world?
- 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)
- Hyperglycemia
-
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.
-
Elite Neutralizers
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
West Africa
-
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
- Leukemia/lymphoma
- 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
TSP/HAM
-
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
- IVDAs
-
HTLV-3 and -4
Seen in?
- 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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