Introduction to HIV/AIDS Epidemiology Structural information of HIV Life cycle of HIV Symptoms & causes of AIDS due to HIV Pathophysiology Pharmacological Classification along with mechanism of action Novel targets for Anti-retroviral Drugs Summary References Vote of thanks

1. Title: CHEMOTHERAPY OF HIV/ AIDS INFECTION
Course Code: PC (540)
Date: 6th DECEMBER 2021 Slide No.1
Presented by: PRIYANSHA SINGH (PC2021- 14/226)
UJJAWAL SONI (PC2021- 14/237)
ANKIT KUMAR (PC2021-14/240)

2. CONTENTS
• INTRODUCTION TO HIV/ AIDS
• EPIDEMOLOGY OF HIV/ AIDS
• ABOUT HUMAN IMMUNODEFICIENCY VIRUS (HIV) & TRANSMISSION OF HIV/ AIDS
• PATHOPHYSIOLOGY OF ACQUIRED IMMUNODEFICIENCY SYNDROME (AIDS)
• PHARMACOLOGY OF DRUGS USED FOR HIV/AIDS
• NOVEL TARGETS FOR ANTI- HIV DRUGS
• REFERENCES
• VOTE OF THANKS
Slide No.2

3. INTRODUCTION TO HIV- AIDS
• Human immunodeficiency virus (HIV) is an infection that attacks the body’s immune system, specifically
the white blood cells called CD4 cells.
• HIV destroys these CD4 cells, weakening a person’s immunity against opportunistic infections, such as
tuberculosis and fungal infections, severe bacterial infections and some cancers.
• It is spread by contact with certain bodily fluids of a person with HIV, most commonly during unprotected
sex (sex without a condom or HIV medicine to prevent or treat HIV), or through sharing injection drug
equipment.
• If left untreated, HIV can lead to the disease AIDS (acquired immunodeficiency syndrome).
Slide No.3

4. • A person with HIV is considered to have progressed to AIDS when: the number of their CD4 cells falls below 200 cells per cubic
millimeter of blood (200 cells/mm3).
• In someone with a healthy immune system, CD4 counts are between 500 and 1,600 cells/mm3 OR they develop one or
more opportunistic infections regardless of their CD4 count.
• Without HIV medicine, people with AIDS typically survive about 3 years. Once someone has a dangerous opportunistic illness, life
expectancy without treatment falls to about 1 year.
• HIV medicine can still help people at this stage of HIV infection, and it can even be lifesaving. But people who start ART soon after
they get HIV experience more benefits—that’s why HIV testing is so important.
• However, by taking HIV medicine (called antiretroviral therapy or ART), people with HIV can live long and healthy lives and prevent
transmitting HIV to their sexual partners. In addition, there are effective methods to prevent getting HIV through sex or drug use,
including pre-exposure prophylaxis (PrEP) and post-exposure prophylaxis (PEP).
• First identified in 1981, HIV is the cause of one of humanity’s deadliest and most persistent epidemics.
INTRODUCTION TO HIV- AIDS contd….

5. EPIDEMOLOGY OF HIV/ AIDS
• The most recent global health observatory (GHO, 2014) data of HIV/AIDS published by WHO
proclaims that around 78 million people have been infected with the HIV virus and about 39
million people have died of HIV virus.
• In the current scenario around 35.0 million people are living with HIV globally.
• Nevertheless, the HIV burden may vary depending upon the geographical region, e.g. like Sub-
Saharan Africa is the most affected region which contributes nearly 70% of the global HIV
burden.
• The number of people dying from AIDS-related causes has been reduced with the increasing
availability of antiretroviral therapy in low and middle-income countries.
• This emphasizes the importance of treatment of HIV through antiretroviral therapy
Slide No. 4

6. HOW IS HIV TRANSMITTED
• You can only get HIV by coming into direct contact with certain body fluids
from a person with HIV who has a detectable viral load. These fluids are:
-Blood
-Semen
-Vaginal fluids
-Breast milk
• Receiving blood transfusions, blood products, or organ/tissue transplants
that are contaminated with HIV.

7. • For transmission to occur, the HIV in these fluids must get into the bloodstream of an HIV-
negative person through a mucous membrane (found in the rectum, vagina, mouth, or tip of the
penis); open cuts or sores; or by direct injection.
• Sharing injection drug equipment (“works”), such as needles, with someone who has HIV.
• From mother to child during pregnancy, birth, or breastfeeding.
• Getting stuck with an HIV-contaminated needle or other sharp object. This is a risk mainly for
health care workers. The risk is very low.
• Contact between broken skin, wounds, or mucous membranes and HIV-infected blood or blood-
contaminated body fluids.
TRANSMISSION OF HIV contd…

8. BASIC KNOWLEDGE OF HIV VIRUS
• BASIC VIROLOGY:-
• There are 2 types of HIV viruses
• HIV- 1: it is found worldwide & is the main cause of world wide pandemic.
• HIV- 2: it is found mainly in West Africa, Mozambique and Angola. It causes
a similar illness like HIV- 1. Its transmissibility is less efficient and is lesser
aggressive with slower disease progression.
• HIV- 1 has the most subtypes i.e.- A to K with A to E being the most
predominant subtypes

9. STRUCTURAL KNOWLEDGE OF HIV VIRUS
• It has an outer double lipid membrane (derived from the host
membrane).
• The lipid membrane is lined by a matrix protein.
• The lipid membrane is studded with the surface glycoprotein
(gp) 120 & the transmembrane gp 41 protein.
• These gp spikes surround the protein core.
• The gp120 & gp41 mediate the entry of virus into the host cell.
• The core (capsid) is made up of several proteins- P24.
• Within the capsid have 2 identical strands of RNA & viral
enzymes.

10. Fig. no. 1- Labelled diagram of HIV virus causing AIDS
Slide No. 5

11. LIFE CYCLE OF HIV VIRUS

12. Viral Enzymes in HIV required for its life cycle

13. EXPLANATION OF
HIV LIFE CYLE
ALONG WITH THE
DRUG TARGETS

14. Summary of enzymes in HIV life cycle

15. TIMELINE OF MULTIPLICATION OF HIV v/s
CD4 CELL COUNT IN AN HIV+ PERSON

16. SYMPTOMS OF AIDS
Slide No. 6

17. PHARMACOLOGICAL CLASSIFICATION OF
ANTIRETROVIRAL DRUGS
• HIV Virus is a retrovirus (RNA as its genetic material) and before its transformation into host cell DNA it undergoes
reverse transcription from RNA to DNA with the help of reverse transcriptase.
• Antiretroviral drugs have basically 3 ways to treat HIV infection
- Suppress HIV replication
- Reducing the emergence of resistance
- Prevent opportunistic infection
• Anti Retroviral Therapy (ART) & Highly Active ART (HAART) are required to achieve above mentioned 3 modes of
action.
• Synergistic action of all drugs under ART & HAART is a primary requirement for the effective treatment against
HIV/AIDS.

18. CLASSIFICATION OF ANTIRETROVIRAL DRUGS

19. MECHANISM OF ACTION OF
A FEW EXAMPLE OF DRUGS
UNDER CLASSIFICATION

20. Entry(fusion) inhibitors e.g.- Enfuvirtide
Enfuvirtide is an HIV derived synthetic
peptide
It acts by binds to HIV-1 envelope
transmembrane (GP41)
(GP41) is involved in fusion of viral and
cellular membrane
Fusion of two membrane is thus Prevented
and entry of the Virus is blocked

21. Mechanism of action of Enfuvirtide

22. CCR5 receptor inhibitor e.g.- Maraviroc
The globular gp120 of the HIV envelope
anchors to the CD4 site of the host cells by
binding to a cell membrane receptor, which
mostly is the CCR5 chemokine receptor
Maraviroc is a novel anti HIV drug
which targets the host cell CCR5
receptor and Blocks it

23. Mechanism of action of Maraviroc

24. Nucleotide Reverse Transcriptase Inhibitors
(NRTIs)
• These are prodrugs which are activated by host cell kinase to form
triphosphate
These drugs:-
1) Competitively inhibit reverse transcriptase
2) Also acts as chain terminators by incorporation into the DNA chain Eg:
Zidovudine
• It is a thymidine analogue which after phosphorylation in the host cell it
inhibits viral reverse transcriptase
Single
stranded
viral DNA
Double-
stranded
pro-viral
DNA
inhibited by
triphosphate

25. Mechanism of action of NRTIs

26. Non Nucleoside Reverse Transcriptase
Inhibitors (NNRTIs)
• These are nucleoside unrelated compound.
• They directly inhibit HIV reverse transcriptase without the need for
intracellular phosphorylation
• Note:- 1)Their locus of action on the enzyme is different that of NRTIs.
2) They are non competitive inhibitors

27. Mechanism of action of NNRTIs

28. Integrase Inhibitors
HIV integrase enzyme
enters the host cell
along with the genomic
RNA
After the HIV pro-viral
DNA is transcripted In
the cytoplasm of host
cells
This enzyme
translocates to the
nucleus along with the
proviral DNA
And cuts host
chromosomal DNA
Integrates the proviral
DNA with it and reseals
it
Thus the proviral DNA
becomes a part of the
chromosomal DNA, and
the cell gets permanent
infected
So integrase inhibitors
inhibit these enzyme
and it's further
functioning

29. Mechanism of action of Integrase Inhibitors

30. Retroviral Protease Inhibitors (aspartic
protease enzyme)
• Function of protease enzyme- It is involved in the production of
structural proteins and enzymes (including reverse transcriptase
and integrase) of the virus from the large viral polypeptide
synthesis in the infected cell.
• The polypeptide is broken into various functional components by
this protease enzyme.
• Protease inhibitors:-It acts on late step, so inhibitors of this
enzyme can be used to inhibits the post translational modification
of viral proteins

31. Mechanism of action of Protease Inhibitors

32. NOVEL TARGETS FOR
ANTI-HIV DRUG
DEVELOPMENT

33. NEED FOR NOVEL ANTI HIV DRUG TARGETS
Due to increase in existing drug resistance.
Due to absence of an effective vaccine.
Need for better tolerated, more convenient and less expensive
treatment.

34. OVERVIEW OF PRESENT TREATMENT
OPTIONS
All persons infected with HIV with a CD4 Lymphocytes count of
<350 cells per mm3,recommended regimen include a minimum of
three active drugs- starting regimens generally consist of a non-
nucleoside reverse transcriptase inhibitor(NNRTI) or HIV protease
inhibitor combined with two nucleoside or nucleotide reverse-
transcriptase inhibitors(NRTIs)

35. NOVEL ANTIRETROVIRAL TARGETS
(A)INTEGRASE
• The integrase inhibitor Raltegravir appears to be as potent as any
previously developed drug in terms of its short-term and 24 week
anti-HIV effects.
• It is expected to become a second-line therapy.
• A second integrase inhibitor , elvitegravir, is also in development.
• Advantage of this target  integrase is an essential and highly
conserved enzyme.
• Disadvantage resistance is moderate to high

36. NOVEL ANTIRETROVIRAL TARGETS
(B)CCR5
The CCR5 antagonist maraviroc has excellent short term anti-HIV
activity, and is associated with substantial efficacy after 24 weeks
of treatment with antiretroviral nucleosides in treatment when
combined –experienced patients.
Disadvantages 
 a. little or no activity against viruses that use CXCR4 as a co-
receptor , or have dual/mixed tropism.
b. toxicity to host cell protein might also be associated.

37. NOVEL ANTIRETROVIRAL TARGETS
(C) CXCR4
• CXCR4 antagonists have demonstrated anti-HIV activity in small
clinical studies.
• These antagonists(drugs) causes a transient elevation in
circulating neutrophils, lymphocyte and monocyte cell counts in
treated subjects, suggests a role for CXCR4 in peripheral trafficking
of these cells.
• DisadvantagesCXCR4 also play a critical role in central and
peripheral axon migration and nervous system development,
hence its long term inhibition may lead to neuropathy and also
may act as teratogenic, so it requires further study.

38. NOVEL ANTIRETROVIRAL TARGETS
(D)HIV REGULATORY PROTEINS
• Regulatory proteins of HIV exist to maximize replicative efficiency
and antagonizes the host defence ,e.g.- nef protein, which inhibits
apoptosis in infected cells.
• Hence these proteins represent potentially important drug
targets.
• Disadvantages a chemical nef antagonist s likely to quickly select
for resistance, as its target is non-essential, and might might not
produce detectable reduction in plasma HIV RNA to the same
extent as existing drugs

39. NOVEL ANTIRETROVIRAL TARGETS
(E)OTHER HOST PROTEINS
• For successful replication of HIV requires host proteins too, these
could become potential antiviral targets.
• Challenges as these proteins also essential for host, so targeting
selectively toxic to the virus may be difficult.
• Strategies most promising strategies to enhance naturally
occurring defences. For e.g. APOBEC3G, a cellular enzyme capable
of inactivating HIV RNA or DNA, but HIV vif protein degrade
APOBEC3G and counteracts its effect. Strategies could be either
neutralize vif or upregulate APOBEC3G expression.

40. SUMMARY
• HIV virus when present in blood at higher counts causes AIDS
• It is mainly spread through sexual contact or other fluids like blood,
milk etc.
• In AIDS, the HIV virus attacks CD4 cells primarily and reduces its count
to less than 200 cells/mm3.
• As the CD4 cells are drastically less therefore it paves way to
opportunistic infections which can never be cured.
• Due to AIDS patients' lives are reduced but with the discovery of ART
and HAART the lifetime of the patient can be increased.
• Many novel drug delivery systems with a targeted drug delivery
mechanisms are under study.

41. REFERENCES
• https://www.slideshare.net/ngogoyo/0102-biology-of-hiv
• https://hivinfo.nih.gov/understanding-hiv/fact-sheets/hiv-life-cycle
• https://www.niaid.nih.gov/diseases-conditions/hiv-replication-cycle
• https://pubmed.ncbi.nlm.nih.gov/11495453/#:~:text=HIV%20is%20a%20v
ery%20small,on%20the%20co%2Dreceptor%20specificity.
• Tripathi K.D., Essentials of Medical Pharmacology: 7th edition, Jaypee
Brothers Medical Publishers (2013), New Delhi.