HIV, AIDS, immunology, virology, health, awareness

1. The journey from HIV infection to
AIDS
Aindrila Saha
Roll Number- 14110098

2. HIV
●
Retrovirus : A subgroup of Lentivirus (Retrovirideae family).
●
Human Immunodeficiency Virus : RNA virus.
●
Two types of HIV : HIV-1, which has high virulence, high infectivity,
a global prevalence and preferably originated from the
chimpanzees. HIV-2, which has comparatively lower virulence, low
infectivity, prevalent in Western Africa and originated from the Sooty
Magabey.
●
Mode of infection : Through transfer of blood, semen, vaginal fluid,
pre-ejaculate and breast milk (as free virus particlkes and host
immune cells infected with virus).
●
Entry into target cell --> ss RNA converted to dsDNA (reverse
transcriptase encrypted by ssRNA) --> viral DNA imported into host
nucleus and integrated into host genome (integrase + host
cofactors) --> Latent phase followed by lytic phase.

3. HIV structure
● Roughly spherical, 1/60 times the size of an RBC.
● Two copies of positive ssRNA (encodes for 9 viral genes)
+ canonical capsid (2000 copies of capsid protein p24) .
● The ssRNA is tightly bound to nucleocapsid proteins p7 and
enzymes for viral development such as reverse
transcriptase, protease, ribonuclease and integrase.
● Viral integrity maintained by matrix of viral protein p17 and
the viral envelope (lipids deriuved from human cells + viral
envelope proteins consisting of a cap made of 3
glycoproteins gp120 and a stem of 3 gp41 molecules +
proteins from host cell).

4. Fig: Structure of HIV virion

5. HIV Genome
● RNA genome has 7 structural landmarks (LTR, TAR,
RRE, PE, SLIP, CRS, INS) and 9 genes (gag, pol,
env, tat, rev, nef, vif, vpr, vpu and sometimes a 10th
tev).
● Gag, pol, env encode structural proteins for new virus
particles (eg, env encode gp160 which is cleaved into
envelope protein gp120 and gp41).
● tat, rev, nef, vif, vpr, vpu encode regulatory proteins
controlling various phases of viral relication and life
cycle in host including infection.

6. Fig: Structure of RNA genome of
HIV-1

7. Fig: Diagram of mature and
immature forms of HIV.

8. Tropism
● Viral Tropism : Cell types that a virus can infect.
● HIV can infect CD4+ T cells, macrophages, myeloid dendritic cells
and microglial cells.
● HIV-1 infects host cell through interaction with viral envelope
glycoprotein gp120 with CD4 receptors of target cells and
chemokine coreceptors CCR5 and CXCR4.
● M-tropic or non-syncitia-inducing strain (R5) of HIV-1 use CCR5
beta chemokine receptor along with CD4 receptors and can primarily
infect both Macrophages and Th cells.
● T-tropic or syncitia inducing strain (X4) of HIV-1 infect CD4
expressing T cells and alpha chemokine CXCR4 receptors in
macrophages to infect the host cell.
● Dual (R5X4) strains use both chemokine corecptors along with
CD4 receptors for host cell infection.

9. Viral Replication Cycle
1. Entry into Host cell:
● Adsorption of glycoproteins on viral envelope with host cell receptors,
CD4 and chemokine coreceptors.
● Interaction between trimeric envelope complex (gp160 spike containing
binding domains for host cell receptors) and CD4 + CXCR4/CCR5.
● Binding of gp120 with CD4 causes structural changes in envelope
complex expressing chemokine binding domains of gp120 and allowing
their interaction with chemokine coreceptors.
● Formation of stable two pronged attachment allows N-terminal fusion
peptide to fuse with the host cell membrane.
● Interaction between gp41, HR1 and HR2 causes collapse of extracellular
gp41 into a hairpin bringing viral and host membranes closer allowing
fusion and subsequent entry of viral genome into host cell.
● Other mechanisms: Infection of dendritic cells by mannose specific C-
type lectin receptors, Clathrin dependent endocytosis

10. Fig: Stages in the mechanism of
Viral Entry

11. Viral Replication Cycle (ctd.)
2. Replication and Transcription:
● ss(+)RNA is converted to cDNA by reverse transcriptase. (error prone
process leading to drug resistance and immune cell attacking).
● Degradation of ss(+)RNA by ribonuclease activity lof reverse transcriptase.
● Creation of sense DNA from anti-sense cDNA strand by DNA dependent
DNA polymerase.
● Formation of dsDNA and integration into host genome by integrase activity.
● Integrated DNA lie dormant in latent stage and require certain transcription
factor activators like NF-kB (expressed by activated T cells) to be present.
(Cells most likely to be killed by HIV are the ones fighting infection).
● Integrated DNA provirus transcribed into RNA --> RNA splicing to result in
mature mRNA --> exported into cytoplasm --> translation of viral regulatory
proteins Tet and Rev.
● Some of them bind to mature mRNA allowing them to serve as new viral
genome while some synthesize components of viral coatings and help in
packaging the genome into the capsid and envelope (gag-env).

12. Fig: Reverse transcription of HIV
genome from ssRNA to dsDNA.

13. Viral Replication Cycle (ctd.)
3. Recombination:
● Rapid recombination events (2-20 times per relication
cycle) between the two copies of ss(+) RNA of viral
genome.
● Copy-choice Recombination : During reverse transcription,
nascent cDNA can switch multiple imes between the two
RNA stands.
● Evolutionarily significant in developing resistance to anti-
retroviral therapy.
● Mechanism of recombination is an adaptive measure for
tackling damage caused due to reactive oxygen species
produced by ongoing infection.

14. Viral Replication Cycle (ctd.)
4. Assembly and Release:
● Assembly of HIV-1 virions occur in plasma membrane of host
cell.
● Env polypeptide assemly in Golgi-ER pathway, gp160 cleaved
into gp120 and gp41 by furin.
● Gp41 and gp120 transported to membrane where gp41 anchors
gp120 to the membrane.
● Gag(p55) and Gag-Pol(p160) proteins also associate with inner
membrane along with HIV genomic RNA (budding virus).
● Assemble of all virus components after cleavage of gag proteins
into structural components of matrix, capsid and envelope.
● Release of mature HIV after cellular lysis.

15. Fig: HIV assembling on the surface
of an infected Macrophage

16. Viral Replication Cycle (ctd.)
5. Spread within the Body:
● Hybrid spreading Mechanisms: Cell to cell spread and cell free
spread.
● Cell free spread: Virus particles from an infected cell bud out,
released into the body fluid, attack another healthy cell and infect
that new cell (involves a chance factor).
● Cell-to-cell spread: Two mechanisms – either by formation of
virological synapse between two closely packed cells, one of which
is infected or when an APC transmit HIV to T cell which involves
productive infection or capture and tansfer of virions in trans.
● Dual mechanisms (cell-to-cell spread more effective than cell free
spread) allow more stringent infection and evolution of species that
are resistant to the anti-retroviral drugs due to the vast diversity
generated.

17. Fig: Diagrammatic representation of
HIV Replication Cycle

18. Diagnosis
● Enzyme linked immuno sorbent assay (ELISA) to detect HIV-
1 antibodies. Non-reactive result --> HIV -ve.
● Reactive Result --> Duplicated.
● Confirmatory test by Western Blot or Immunofluorescence
assay.
● Modern day assays:
i) HIV-1(+) & HIV-2(-): HIV-1 antibodies detected.
ii) HIV-1(-) & HIV-2(+): HIV-2 antibodies detected.
Iii) HIV-1(+) &HIV-2(+): HIV antibodies detected.
iv) HIV-1(-) & HIV-2(- or indeterminate) : Nucleic acid test to
detect acute infection of HIV-1 or its absence.

19. Fig: Generalized graph of the relationship
between viral load and CD4 count over average
course of untreated HIV infection

20. Fig: HIV deaths in 2014 in different
countries other than US

21. Fig: Progress of HIV infection
through different stages

22. AIDS
● Acquired Immuno Deficiency Syndrome.
● Acute stage of HIV infection, symptoms arise 8-10
years after HIV infection.
● Due to destruction of CD4(+) T cells, the body is prone to
life threatening infections and cancers.
● Diagnosis of AIDS: AIDS defining condition and CD4
count below 200cells/mm3.
● Symptoms: HIV related encephalopathy,
Cytomegalovirus Retinopathy (associated with
blindness), Pneumocystis jeroviciae Pneumonia, Chronic
Intestinal Sporoidiosis, Invasive Cervical Cancer etc.

23. Fig: Schematic representation of
symptoms of AIDS.

24. Treatment
● Anti-retroviral Therapy
● No complete cure, reduced rate of onset of
AIDS, improved life style.
● Prevention and increase in awareness.

25. Fig: AIDS treatment options: What can be
done

26. Thank you!