Retro virus

2. African AIDS patient with slim disea
AIDS is a set of diseases due to
immunosuppression associated
with opportunistic infections and
malignant tumors, wasting, and
central nervous system (CNS)
degeneration.
CD4+ helper T cells,
macrophages, and
dendritic cells.

3. SID- AIDS
 Etiologic agent of AIDS- HIV
 AIDS was first reported in the United
States in 1981 in Los Angeles, New
York, and San Francisco.
 Discovered independently by Luc
Montagnier of France and Robert
Gallo of the US in 1983-84.
 Isolated from homosexual males-
 Attack the immune cells with CD4 co-
receptors
 T cell tropic virus
 Virus attack & destroy the CD4 T cells
which is essential for immune response
Nobel Prize in Physiology
or Medicine 2008
Phylogenetic analysis
of HIV sequences
suggest that HIV may
have been
initially transmitted to
humans around 1930.

4. HIV: Family Retroviridae
Based on the molecular & Antigenic diff.

5. In 2009 a new strain closely relating to gorilla simian
immunodeficiency virus was discovered in a Cameroonian
woman. It was designated HIV-1 group P
Sub type- A- world wide & most prevalent
Sub type- B- Americas & Europe
Subtype A,C,D- Africa
Subtype E,C, & B- Asia
Subtype E- Thailand
Subtype C- India & China
Subtype C- ETHIOPIA
Each group has evolved from independent
“cross-species transmission” events of
chimpanzee simian immunodeficiency virus
(SIVcpz) to humans. The group M strains,
responsible for global AIDS pandemic
M(main), O(outlier), and N(non-M, non-O).
Cameroon
Chimp Gorilla

6. HIV-1 consists of two identical strands of RNA and associated enzymes, including
reverse transcriptase, integrase, and protease, packaged in a cone-shaped core
composed of p24 capsid protein with a surrounding p17 protein matrix, all
surrounded by a phospholipid membrane envelope derived from the host cell.
Virally encoded membrane proteins (gp41 and gp120) are bound to the envelope

7. Antigenic variation & Diversity of HIV
 Highly mutable virus
 Antigenic variation – high in enveloped Proteins
 A region of the gp120 molecule, called the V3 loop,
is one of the most antigenically variable parts of the
virus
 This variability of HIV is may be due to the error
prone nature of Reverse Transcriptase enzyme
• Effect of mutation on HIV:
• Viral infectivity/pathogenicity increased or
decreased. ARV drug resistance
• Effect of mutation on Patient
• Escape from immune control.

8. A region of the gp120 molecule, called the V3 loop, is one of the most
antigenically variable parts of the virus

9. Routes of Transmission
Sexual Transmission
• Anal
• Vaginal
• Oral
• Homosexual (Gay) = 63%
• Heterosexual = 25%
Parenteral Transmission
Transfusions 8%
• Needle sharing <1%
Mother-to-Infant Transmission
Maternal-child <1%
• Transplacental
• Breast milk ingestion
sources of infection- blood, semen, genital
fluids, and breast milk
No transmission: Saliva,
Tears, Mucus, Urine,
Sweat, Feces, CSF

11. Pathogenesis
 Virus can attack any cell bearing CD4 & on the surface
Cytopathic effect (Destroy) on Th cells (CD4 cells); Impair the
functions of other immune cells that posses CD4 receptors
Suppress the function of infected
cell
Infected CD4 Th lymphocyte are
unable to release interleukin 2,
gamma interferon & other
lymphokines.
Primarily CD4 Th lymphocyte
macrophages
monocytes
B cells
Glial & microglial brain cells
intestinal cells
Follicular dendritic cells-
Langerhans cells
HIV→CD4+ cell→ CD4+ cell lysis → opportunistic infections and
neoplasms

12. a. HIV gp120 binds to CD4 on target cells (T helper cells
And Macrophages) at the site of infection.
b. HIV gp41 binds to a chemokine
receptor (CXCR4 or CCR5) and fuses
with the target cell membrane
c. Nucleocapsid containing viral
genome and enzymes enters cell
T-cell–tropic strains of HIV use the
coreceptor CXCR4
Macrophage-tropic strains use CCR5.

13. Chemokine receptor
CD4 and chemokine receptors on the
host cell surface function as HIV-1
CXCR4 and CCR5
More than 7
diiferent
coreceptors
for HIV entry in
to the cell
M-tropic, virus
CCR5
T-tropic virus
CXCR4

14. Multiplication of HIV
in Th cells.

15. Integrated Viral genome
Latent Lytic
Long incubation period
for months or years
Infect other CD4 cells
Antibodies (and T Cells)
cannot detect provirus or
latent virions
integrated HIV DNA is called
the provirus.

16. Viral particles may remain within host cell
vacuoles – latent virions

18. 1) PRIMARY INFECTION
2) LYMPHOID INFECTION
3) ACUTE SYNDROME
4) IMMUNE RESPONSE
(Ab & CD4 and CD cells)
5) LATENCY
6) AIDS
109 virions are released every day
continually infect and destroy additional host
T cells.

19. HIV induces strong cellular and humoral immune responses
CTL-cytotoxic T lymphocytes (CD8 killer T cells)

20.  High mutation rate of HIV
 HIV latency
 Compromised immune function, primarily through the loss
of CD4 T helper cells
Why is HIV not cleared by the immune system?

21. CD4 T cells are depleted in the course of HIV infection

23. 23
Phases of HIV/AIDS
1. Acute or primary Infection
2. Window period
3. Sero-conversion
4. Asymptomatic period
5.HIV/AIDS - related illness
6. AIDS

24. 1. Acute HIV infection
Within 3-10 weeks of Infection, 50-70% of
victims experience
No detectable
anti-HIV
antibodies
Virus can be
detected by RT-
PCR
CD4 count- ~ 400- 600
Viral load- 106

25. 25
2. Window period (Pre- seroconversion)
sero negative period
Time period between infection & first appearance
of Antiviral Ab
Duration: approximately 3 months
No symptoms or signs of illness
Virus is multiplying rapidly - viral load is high
Person is very infectious
HIV test is negative for ELISA (Seronegative)
Virus can be detected by RT-PCR

26. 26
3. Sero-conversion
Happens about 3 months after infection
Body starts making antibodies to HIV (eg. Anti Gp 120
& Anti P24) (P24Major capsid protein)
HIV ELISA test becomes positive
Person may have a mild flu-like illness,
(Lymphadenopathy, Pneumonitis, gastrointestinal &
CNS involvement) lasting a week or two & recover
rapidily

27. Immune responses in HIV infection (Seroconversion period)

28. 28
4. Asymptomatic period
Time period between seroconversion and onset of
HIV/AIDS-related illness
Duration variable: < 1 year to > 15 years
Minimum 8 yrs
Most people remain healthy (asymptomatic) for
about three years
gradual decline in CD4 T cells
The CD4 count is above 500 cells/µl

29. 29
5. HIV/AIDS-related illness
Duration is variable: average
about 5 years
Illnesses initially mild, with
gradual increase in frequency and
severity
CD4 count is between 500 & 200
cells/µl
Opportunistic infections may
begin to appear (Kaposi’s
sarcoma, oral/genital candidiasis,
herpes zoster, etc.).

30. 30
6. AIDS
Final phase of HIV/AIDS
CD4 count is below 200 cells/µl
Duration:
 without antiretroviral drugs, less than 2 years
 with antiretrovirals, potentially many years
Viral loads are high & the person is very infectious
A CD4 T- lymphocyte count below 200 cells per mm3
is defined as AIDS

31. 31
CD4 counts
CD4 count reflects phase of disease &
measurement of immune system damage
CD4 count: (Cell/µl)
 500 – 1200: Normal
 200 – 500: Beginning of HIV
illness
 < 200: AIDS

32. Opportunistic infections
 Approximately 80% of deaths
in AID patients are due to
Opportunistic pathogens.
 VIRAL INFECTIONS
(cytomegalovirus)
 FUNGAL INFECTIONS (candida,
Pnuemocystis carinii)
 BACTERIAL INFECTIONS
(mycobacteria)
 PROTOZOAL (toxoplasmosis)

36. Innate responses against HIV
• Production of antimicrobial
peptides (defensins), and
activation of NK cells,
dendritic cells and the
complement system
• Macrophage Internalize and
process the virus & present
to T cells to initiate the
adaptive response
HIV counter-attack
• The virus can infect cells
(Macrophage) of the innate
immune system
• Innate cells can act as depot
and effectively transmit virus
Innate immune system vs HIV
.

37. CD8 T cells responses against HIV
• initial adaptive immune
response to HIV infection is
characterized by expansion of
CD8+ T cells specific for HIV
peptides
• 10% or more of circulating CD8+
T cells may be specific for HIV
during acute infection.
• These CTLs control infection in
the early phase
CD8 T cells vs HIV
HIV-infected cells may evade CTLs through
stoping the expression of class I MHC
HIV counter-attack
• Virus mutates (Ag) and
escapes
• Lack of CD4 T cells:
a. Insufficient signals to
activate more killer cells
a. Defective memory
b. Impaired function

38. CD4 T cells responses against HIV
• Activated by innate immune
system
• Facilitate CD8 T cell (killer) and
B cell activation
• CD4+ T cells mediate cytolytic
responses against HIV-infected cells,
perhaps using Fas ligand to target
Fas on infected CD4+ T cells.
HIV counter-attack
• Infects CD4 T cells
• Causes depletion of the CD4
T cell population
• Uses surviving CD4 T cells
as a reservoir (latent HIV)
CD4 T cells vs HIV

39. B cell responses against HIV
• Directed by CD4 T cell to
make antibodies against HIV
• Antibodies neutralize the
virus to prevent spread
HIV counter-attack
• Virus mutates at a very high
rate
• Loss of CD4 T cells results in:
– Increase in numbers of
immature B cells
– Exhaustion
– Decreased memory
B cells vs HIV
anti-gp120 and anti-gp41 antibodies
antibodies to p24, reverse transcriptase
Broadly neutralizing antibodies (Few
years after infection). These antibodies
bind to a site on a viral protein that the
virus are unable to mutate ( CD4
binding site of gp140.)

40. HIV has an extremely high mutation rate because of error-prone reverse
transcription and this may evade detection by antibodies or T cells generated in
response to viral proteins.
It has been estimated that in an infected person, every possible point mutation
in the viral genome occurs every day.
A region of the gp120
molecule, called the
V3 loop, is one of the
most antigenically
variable parts of the
virus

41. LAB DIAGNOSIS
Immunological Test
Specific Test for HIV detection

42. Immunological Test
Lymphocyte count usually Below 2000/mm3
CD4 T cell count will be usually less than
200/mm3
Platelet count will show thrombocytopenia
Low level of Ig M
Lymph node biopsy showing profound
abnormality

43. Specific Test for HIV
Virus Isolation- can be isolated from
Blood, Lymphocytes, Cell free plasma,
Semen, saliva, Tears, urine & milk
Viral RNA- detected by RT-PCR
Ab detection – ELISA & WESTERN BLOT
Ag detection- P24 Ag capture assay
(ELISA)

44. Treatment
Highly active anti-retroviral drug
Combination of antiviral drugs are admin,
first introduced in 1996
Goal of HAART are
Suppress the viral multiplication
Restore the immune function
8 million people are on antiretroviral
therapy (UNAIDS, 2012)

46. Bone marrow transplant led to the first HIV cure
• Timothy ray Brown, also known as the Berlin patient, became the first person ever to
be “cured” of HIV without the use of antiretroviral therapy.

47. Defectives copies of the gene knock out
CCR5 receptor protein production – and
with nothing to grab onto, HIV is thwarted
from entering CD4+ cells. Mr. Brown’s
donor had these mutations. By bone
marrow replacement of Mr. Brown’s
CD4+ cells with ones resistant to HIV entry,
the virus was no longer able to infect its
target cells and cause disease in Timothy
How it worked:
Mutations in both copies of the CCR5 gene
Absent
HIV cannot infect cells if there is no
CCR5 on the surface.
Cysteine-cysteine chemokine receptor 5 (CCR5)

48. Various approaches for HIV vaccine development

49. Vaccines under clinical trial