1. Advances and Challenges in HIV Antiretroviral Therapy
Camille Angle, Meagan Bardan, Hanna Schimjawicz and Sean Tabarah
PHM Fall 2018
Instructor: Ms. Maya Latif
Coordinator: Dr. J. Henderson

2. HIV Attachment and Penetration
Wilen, C. B., Tilton, J. C., & Doms, R. W. D. (2012). HIV: Cell binding and entry. CSH Perspectives.

3. Genome Replication, Assembly, and Egress
•RNA undergoes RT yielding dsDNA
•Capsid disassembles and DNA enters the nucleus where it integrates into the host genome
•Host cell machinery continues to carry out transcription, transcribing essential viral genes
•Two copies of viral RNA, Gag and Env get sent to viral assembly sites
•Virus exits the cell, and is now able to infect new host immune cells
Adapted from:

4. Treating HIV: Anti-Retroviral Therapy (ART)
Combination of Antiretrovial Drugs (ARVs)
7 classes
Reduces viral load to undetectable levels in the blood
Immune system can recover
Prevents progression to AIDS
Improves health outcomes and reduces transmission
NOT a cure!

5. Drug Classes 7 drug classes First drug (NRTI) approved in 1987
Combination of these used in ART

7. Drug Classes: NRTIs/NNRTIs
NRTI = Nucleotide Reverse Trascriptase Inhibitor
NNRTI = Non- Nucleotide Reverse Transcriptase Inhibitor

8. NRTI competes with endogenous nucleosides
Missing -OH terminal required for addition of subsequent nucleosides
Terminates DNA chain
Incomplete DNA fragment is unable to integrate
NNRTI are noncompetitive inhibitors of RT
Induces conformational change in RT
Reduces RT activity

9. Challenges: Treatment but no cure
2 possible outcomes when virus infects a cell
Uses cell machinery to replicate
Remains in cell without replicating = latent cells
Form latent reservoir of HIV proviruses in resting CD4+ cells
Evades immune system and drug therapies
Requires lifelong medication
Expensive
Lifelong toxic side effects
Adherence difficulties
Fernández, Clara Rodríguez. Labiotech.eu, Labiotech UG, 22 Aug. 2018, labiotech.eu/medical/abivax-hiv- cure-viral-reservoir/.

10. Challenges: antiretroviral drug resistance
Nucleoside reverse transcriptase inhibitors
Virus replicates at high rate → ~1 mutation per replication cycle
Second type of mutation that increases RT selectivity for regular nucleotides
Mutation in RT
Chain terminating nucleotide is excised
Free 3’OH
Elongation Resumes

11. Challenges: antiretroviral drug resistance
Non-nucleoside reverse transcriptase inhibitors
2 mechanisms of drug resistance caused by mutation:
Loss/Change of interactions at NNRTI binding pocket
Steric hindrance

12. Dark blue and light blue = residues responsible for NRTI resistance
Red
= Residues responsible for NNRTI resistance
NRTI acts at the dNTP binding pocket
NNRTI acts allosterically
Nikolenko, G. N., et al. "Mechanisms of HIV-1 drug resistance to nucleoside and nonnucleoside reverse transcriptase inhibitors." Molecular biology 45.1 (2011): ,

13. Improvements in public health
Awareness for at-risk demographics
Better compliance
PrEP
Safe injection sites
Perinatal transmission prevention
ART during pregnancy
Precautions during labor
ART for child and mother postpartum

14. HIV therapy development

15. Biktarvy: Gilead’s latest regimen
Similar to Truvada®
Monthly PrEP was 1200$ in 2012, now at 2000$
Huge court decision in the UK last week
Smallest integrase-inhibitor based daily tablet
FDA approval this year
Phase 4 trials started May 2018
Being considered as PrEP
Improved cocktail
Bictegravir 50 mg – INSTI
Emtricitabine 200 mg – NRTI
Tenofovir alafenamide 25 mg – NRTI
Prodrug, lower dose than Truvada
Less bone and renal adverse events

16. Summary
ARVs reduce viral load in HIV positive individuals and significantly improve health outcomes
7 classes of ARVs that exert effects at different stages of the HIV life cycle
NRTIs and NNRTIs are most commonly used classes
Both act on Reverse Transcriptase to prevent transcription of viral DNA from viral RNA
NRTI completes with nt when RT is extending viral DNA chain → missing OH group causes termination of DNA chain→ Incomplete DNA fragment is unable to integrate
NNRTIs bind and inhibit the activity of RT directly so no viral DNA is transcribed
HIV infection of inactive T-cells leads to latent cells that cannot be targeted by drugs → therefore unable to completely eradicate virus and requires lifelong treatment
Mutations in RT confers resistance to antiretrovirals
Mutations can decrease selectivity for drug or allow it to excise chain terminating nucleotides (NRTIs) and decrease the affinity between the drug and the enzyme (NNRTI)
Resistance mechanisms slowed partially by combination therapy and varying drug targets
Some routes of infection can be controlled with the right programs in place
PrEP
Perinatal care
Clean needle distribution

17. References
Wilen CB, Tilton J.C, Doms RWD. HIV: Cell binding and entry. CSH Perspectives. 2012;2:a006866
HIV Egress [Internet]. Vimeo.com [cited 24 September 2018]. Adapted from:
HIV/AIDS: The Basics Understanding HIV/AIDS [Internet]. AIDSinfo [cited 23 September 2018]. Available from:
HIV treatment [Internet]. Unaids.org [cited 23 September 2018]. Available from:
Richman D. HIV chemotherapy. Nature. 2001;410(6831):
Tsibiris A, Hirsch M Antiretroviral Therapy for Human Immunodeficiency Virus Infection. In: Mandell G, Douglas R, Bennett J, Dolin R, Blaser M, ed. by. 8th ed. Philadelphia, Pa: Elsevier, Saunders; 2018.
Xing S, Siliciano RF. Targeting HIV latency: pharmacologic strategies toward eradication. Drug discovery today Jun 1;18(11-12):
Wilen CB, Tilton J.C, Doms RWD. HIV: Cell binding and entry. CSH Perspectives. 2012;2:a006866
HIV Egress [Internet]. Vimeo.com [cited 24 September 2018]. Adapted from:

18. References
7. Aguilera LU, Rodríguez-González J. Studying HIV latency by modeling the interaction between HIV proteins and the innate immune response. Journal of theoretical biology Nov 7;360:67-77.
8. Nikolenko GN, Kotelkin AT, Oreshkova SF, Ilyichev AA. Mechanisms of HIV-1 drug resistance to nucleoside and nonnucleoside reverse transcriptase inhibitors. Molecular biology Feb 1;45(1):
9. Singh K, Marchand B, Kirby KA, Michailidis E, Sarafianos SG. Structural aspects of drug resistance and inhibition of HIV-1 reverse transcriptase. Viruses Feb 11;2(2):
10. Andrew Hill, A. (2018). Tenofovir alafenamide versus tenofovir disoproxil fumarate: is there a true difference in efficacy and safety?. [online] PubMed Central (PMC). Available at: [Accessed 24 Sep. 2018].
11. Fitzaimons T. Following court ruling, generic Truvada could soon be available in U.K. [Internet]. NBC Universal News Group. Available at: [accessed 25 Sep. 2018].

19. NRTIs/NNRTIs NRTIs Action NRTI Result: NNRTI Action: NNRTI Result:
Competes with nucleosides in growing viral DNA chain
NRTI Result:
Incomplete DNA chain
Cannot integrate
NNRTI Action:
Binds and reduces reverse transcriptase (RT) activity
NNRTI Result:
No viral DNA is transcribed
NRTIs/NNRTIs
Removed slide but still relevant information