PATHOLOGY, SECOND MBBS, MEDICAL COUNCIL OF INDIA, COMPETENCY BASED UNDERGRADUATE CURRICULUM FOR THE INDIAN MEDICAL GRADUATE, 2018

1. PA9.6
DEFINE & DESCRIBE THE
PATHOGENESIS & PATHOLOGY
OF HIV & AIDS
Dr IRA BHARADWAJ
MCI TEACHER ID: PAT 2300569
KUHS FACULTY ID: M21512

2. TEXT BOOK REFRENCES
• ROBBINS BASIC PATHOLOGY
• HARSH MOHAN TEXTBOOK OF PATHOLOGY
• DAVIDSON’S PRINCIPLES AND PRACTISE OF MEDICINE
• OTHER STANDARD REFRENCES

3. SLO
• GENERAL FEATURES OF IMMUNE DEFICIENCY DISEASES
• ETIOLOGY OF IMMUNE DEFICIENCY DISEASES
• ETIOLOGY OF SECONDARY IMMUNE DEFICIENCY
• ETIOLOGY OF AIDS
• PATHOGENESIS OF IMMUNE SYSTEM INFECTION
• IMMUNOLOGICAL DEFECTS IN HIV INFECTION

4. SLO
• PATHOGENESIS OF CNS INFECTION
• MORPHOLOGY OF HIV INFECTION
• CLINICAL FEATURES OF HIV INFECTION & AIDS
• LABORATORY DIAGNOSIS OF HIV & AIDS
• TREATMENT & PROGNOSIS OF HIV & AIDS
• QUESTIONS

5. IMMUNE DEFICIENCY DISEASES
GENERAL FEATURES
LEADS TO INCREASED SUSCEPTIBILITY TO INFECTIONS &
CERTAIN FORMS OF MALIGNANCY
• DEFECT IN B CELLS, COMPLEMENT, PHAGOCYTOSIS ---
PYOGENIC BACTERIAL INF
• DEFECT IN T CELLS --- VIRAL, FUNGAL,INTRACELLULAR
BACTERIAL INF, INCREASED INCIDENCE OF TUMORS

6. IMMUNE DEFICIENCY DISEASES
ETIOLOGY
•CONGENITAL (PRIMARY) IMMUNE DEFICIENCY,
uncommon
•SECONDARY/ACQUIRED IMMUNE DEFICIENCY,
commoner, especially HIV associated

7. SECONDARY/ACQUIRED IMMUNE DEFICIENCY
ETIOLOGY
• MALNUTRITION
• INFECTION (HIV)
• CANCER
• DIABETES MELLITUS
• RENAL DISEASE
• SARCOIDOSIS
• DRUGS

8. ACQUIRED IMMUNODEFICIENCY SYNDROME (
AIDS): ETIOLOGY
Infection by HIV-1 / HIV-2, a RNA retro virus
Important features regarding structure of virus
• Core – p24, p7/p9, 2 copies of RNA, enzymes – reverse
trancriptase, integrase , protease, other proteins
• Matrix protein – p17
• Envelope – gp 120 & 41,
• Genome – gag, pol, env genes + several others eg, tat, nef
Several subtypes are present, highly variable Ag structure

9. HIV
ROUTES OF TRANSMISSION
HORIZONTAL TRANSMISSION
• Sexual – male to male, male to female, female to male,
mucosal breach due to any cause eg other infections
increases the risk of HIV transmission
• Parenteral– shared needles, shaving blades, needle injury,
transfusion of blood & blood products
VERTICAL TRANSMISSION
• Mother to baby: in utero, intrapartum & postpartum

10. HIV
TARGET OF INFECTION
•IMMUNE SYSTEM
•CNS

11. HIV:PATHOGENESIS OF IMMUNE SYSTEM INFECTION
ENTRY OF VIRUS IN THE IMMUNE CELL
• CD4 +T lymphocytes, Dendritic Cells & macrophages have
receptor for gp120 which is present on the surface of the
virus
• Coreceptors- CCR5 (on macrophage), CXCR4 (on T L) are
coreceptors for gp 120 & gp41 [viral envelope]
• Virus binds to host cell membrane via gp120 & gp41 to
receptors & coreceptors on immunocompetent cells and is
internalized

12. Mechanism of HIV entry into the host cells.
Interactions with CD4 and CCR5 coreceptors are
illustrated.

13. HIV:PATHOGENESIS OF IMMUNE SYSTEM INFECTION
REPLICATION OF VIRUS IN THE IMMUNE CELLS
• v RNA by action of viral REVERSE TRANSCRIPTASE leads to
formation of complementary DNA (cDNA)
• In quiescent T cells HIV proviral cDNA persists in cytoplasm
in episomal, nondividing form
• In dividing T cells cDNA enters the nucleus and integrates
with the host DNA by action of viral integrase enzyme
• May remain latent for years or may divide to form virus
particle on activation of TL by antigens or cytokines.

14. Mechanism of viral entry & replication in cell
is illustrated

15. HIV:PATHOGENESIS OF IMMUNE SYSTEM INFECTION
TRANSPORT & SPREAD OF VIRUS
• Mucosal dendritic cells transport HIV to regional lymph
nodes
• Immune response which is activated, is inadequate to
eliminate the virus, it only partially controls the infection
• Virus spreads throughout body by macrophages, which
provide a safe vehicle for HIV to be transported to various
parts of the body including CNS

16. HIV:PATHOGENESIS OF IMMUNE SYSTEM INFECTION
PERSISTENCE OF VIRUS
• Infected cells persist [as immune response is inadequate] with
low rate of replication, resulting in slow death of CD4+ TL
• Follicular dendritic cells in germinal centers of lymph nodes acts
as reservoir for HIV
• Monocytes and macrophages also act as reservoir, because they
are relatively resistant to cytopathic effects of virus
• Macrophages are also important site of continued viral
replication in late stages of HIV infection when CD4 + T cell
numbers decline.

17. PATHOGENESIS
OF
HIV INFECTION

18. HIV:PATHOGENESIS OF IMMUNE SYSTEM INFECTION
ACTIVATION OF HIV REPLICATION & MECHANISM OF
LOSS OF CD4+TL
• Activation of TL by any cause eg any other infectious agent or
cytokines or activation of intracellular kinase (viral nef) is
followed by:
• Rapid proliferation of CD4+ TL & virus, leads to cytopathic
effects & virus specific immune response which cause death
of infected T lymphocytes.
• In addition activation of apoptosis leads to death of
uninfected T L.

19. HIV:PATHOGENESIS OF IMMUNE SYSTEM INFECTION
MECHANISM OF LOSS OF CD4+TL BY HIV

20. HIV:PATHOGENESIS OF IMMUNE SYSTEM INFECTION
DEFECTS IN IMMUNITY
• Total number of CD4+T lymphocytes is reduced
• Defective function of virus infected dendritic cells &
macrophages
• Decreased cytokines from TL leads to decrease in function of
B lymphocytes, natural killer cells, cytotoxic T lymphocytes,
macrophages & polymorphs.
• Non specific hyper gammaglobulinemia may be present

21. HIV:PATHOGENESIS OF IMMUNE SYSTEM INFECTION
MAJOR ABNORMALITIES OF IMMUNE FUNCTION
• LYMPHOPENIA: Predominantly due to selective loss of the
CD4+ helper-inducer T cell subset; inversion of CD4:CD8
ratio.
• DECREASED T-CELL FUNCTION IN VIVO:
- Preferential loss of memory T cells
- Susceptibility to opportunistic infections
- Susceptible to neoplasms
- Decreased delayed –type hypersensitivity

22. HIV:PATHOGENESIS OF IMMUNE SYSTEM INFECTION
MAJOR ABNORMALITIES OF IMMUNE FUNCTION
• ALTERED MONOCYTE OR MACROPHAGE FUNCTIONS:
- Decreased chemotaxsis and phagocytosis
- Decreased HLA class II antigen expression
- Diminished capacity to present antigen to T cells
- Increased spontaneous secretion of IL-1, TNF,IL-6

23. HIV:PATHOGENESIS OF IMMUNE SYSTEM INFECTION
MAJOR ABNORMALITIES OF IMMUNE FUNCTION
POLYCLONAL B CELL ACTIVATION:
• Gp 41 activates B lymphocytes directly
• Re-infection/ Reactivation of infection by cytomegalovirus
and EBV, both are polyclonal B L (lymphocyte) activators.
• HIV infected macrophages produce increased amounts of IL-
6, which stimulates proliferation of BL
• This leads to -
-Hypergammaglobulinemia and circulating immune
complexes
-Inability to mount de novo antibody response to a new
antigen or vaccine.

24. HIV:PATHOGENESIS OF IMMUNE SYSTEM INFECTION
EFFECTS OF DEFECTIVE INNATE, HUMORAL & CELL MEDIATED
IMMUNITY
• Decrease in macrophage & polymorph function decreases
innate immunity and increases susceptibility to opportunistic
organisms
• Impaired humoral immunity renders these patients prey to
disseminated infections by S pneumoniae and H influenzae,
both of which require antibodies for effective opsonization
and clearance.
• Impaired cell mediated immunity increases incidence of
infections by intracellular bacteria & viruses. There is
decreased immunosurveillance against tumors

25. HIV
PATHOGENESIS OF CNS INVOLVEMENT
• Macrophages and microglia cells in CNS (that belong to
Monocyte and macrophage Lineage) are Infected by HIV .
Neurologic deficit occurs due to :
• Viral products like soluble HIV gp 120 and induced nitric
oxide by gp 41, damage the neurons without infecting them
• Soluble factors (eg TNF) produced by infected microglia cells
also injure the neurons

26. HIV
MORPHOLOGY
No specific or diagnostic morphological changes are present
LYMPHNODE [Early lesions]
• Follicular hyperplasia ( BL area)
• Increased cellularity of sinuses due to B cells, plasma cells &
macrophages
• Special techniques show viral particles in follicular dendritic
cells and vDNA in macrophages & CD4+ TL

27. HIV
MORPHOLOGY
LYMPHNODE [Late lesions]
• Depletion of follicular cells & lymphocytes
• Follicles may become hyalinized
• Lymph nodes are atrophic
• Many opportunistic pathogens may be present

28. HIV
MORPHOLOGY
• SPLEEN & THYMUS – show changes similar to lymph nodes in
later stages
• CNS LESIONS - inflammation, demyelination, degeneration
OTHER MORPHOLOGICAL CHANGES MAY BE SEEN DUE TO
SECONDARY INFECTION & SECONDARY NEOPLASM
• The pathogens do not invoke appropriate immunological
response due to immune depletion, eg TB infection does not
show granulomas
• These microorganisms can be identified only by application of
special stains & techniques

29. HIV
CLINICAL FEATURES
• Presentation of HIV infection is dependent on the level of
immune suppression and its consequences
• Patient may remain asymptomatic or present with infection
affecting any part of the body, often by low virulence
organisms
• Depending on various factors, it is sub divided into various
stages, which often overlap, ending in AIDS [severe
immunodeficiency] & death

30. HIV:CLINICAL FEATURES
NATURAL HISTORY OF DISEASE

31. HIV
CLINICAL STAGING
• According to CDC it is classified as categories A,B & C for high
income countries
• According to WHO it is classified in 4 stages for low & middle
income countries [INDIA]
• Stage 1 [GROUP A] – asymptomatic / Persistent Generalized
Lymphadenopathy
• Stage 2 [GROUP B]- unexplained moderate weight loss, with
recurrent skin, oral & URT infections

32. HIV
CLINICAL STAGING
• Stage 3 [GROUP B] – severe weight loss, unexplained fever &
diarrhea, anemia, neutropenia, thrombocytopenia; oral
candidiasis/ hairy leukoplakia; tuberculosis & other severe
bacterial infections
• Stage 4 [GROUP C]– disseminated viral & fungal infections,
secondary neoplasms, CNS symptoms, cardiomyopathy,
nephropathy, & disseminated Leishmaniasis

33. ACUTE PHASE
• OCCURS 3-6-18wks AFTER INFECTION
• Mucosal DC (APC) migrate to LN & Dendritic Cells infect
CD4+TL & follicular dendritic cells in lymphnodes. Viral
replication takes place in LN
• Viremia (acute HIV syndrome) leads to spread of virus
throughout the body & self limited FLU LIKE SYMPTOMS

34. PRIMARY HIV INFECTION
(ACUTE PHASE)
• IT IS SELF LIMITED [there is partial control of infection and
acute symptoms regress] because Immune response is
activated – CTL & ANTI HIV Abs appear in 3-12 wks, this is
known as SEROCONVERSION;
• CD4+ TL count is more than 500 cells / uL
• The period when viral infection is present, but antibodies are
absent ie, before seroconversion, is known as “window
period”.

35. ASYMPTOMATIC INFECTION
(LATENT PHASE) ( STAGE 1)
• Immune response restricts the virus to LN & spleen
• Low level of viral proliferation & destruction of cells continues
in LN & spleen
• This is Clinically latent phase, it may merge with chronic
phase
• It may last for months to years (specially with therapy)
• CD4+TL count varies between 200-500 cells /uL
• Patient is asymptomatic, generalized lymphadenopathy may be
present

36. MINOR HIV ASSOCIATED DISORDERS
(CHRONIC PHASE) ( STAGE 2&3)
• It may merge with the latent phase with development of
symptoms intermittently, depending on variations in CD4+ TL
counts
• Common symptoms are – persistent generalized
lymphadenopathy, dysentery, diarrhea, candidiasis, fever,
weight loss, hematological cytopenias
• CD4+TL count varies between 200-500 cells/uL

37. FINAL PHASE OF AIDS
(STAGE 4)
FINAL CRISIS—AIDS (acquired immune deficiency syndrome )
• CD4+TL count is less than 200 cells /uL
There is evidence of the following in various combinations
• OPPORTUNISTIC INFECTIONS
• SECONDARY NEOPLASMS
• CNS SYMPTOMS

38. AIDS: OPPORTUNISTIC INFECTIONS
Opportunistic infections may show some geographical
variations, commonly encountered are
• LN- TB, (mycobacterium tuberculosis & atypical
mycobacterial infection), histoplasmosis & toxoplasmosis
• GIT – infections by - Candida, Clostridium, Salmonella,
Shigella, Entamoeba histolytica, Giardia, Cryptosporum,
Cytomegalovirus (CMV)

39. AIDS: OPPORTUNISTIC INFECTIONS
• RS- TB, Pneumocystis jirovecii, CMV, Histoplasma &
staphylococcal infections
• MUCOCUTANEOUS -Herpes, Varicella, human Papilloma
Virus (HPV),Epstein Barr Virus (EBV)
• BONE MARROW suppression & infection,
• CVS - cardiomyopathy
• KUB – nephropathy
• EYE- retinitis

40. AIDS: SECONDARY NEOPLASM
Commonly encountered neoplasms are :
• LN- B cell lymphoma
• SOFT TISSUE- Kaposi's sarcoma due to infection by Kaposi
sarcoma virus (KSHV) also known as human herpes virus 8
(HHP-8)
• BONE MARROW & CNS - Lymphoma
• FGT- Ca cervix due to infection by Human Papilloma Virus (
HPV )

41. AIDS: CNS LESIONS
CNS
• Infections
• Primary lymphoma (EBV)
• Aseptic meningitis,
• Vacuolar myelopathy,
• Peripheral neuropathy,
• Progressive encephalopathy (AIDS dementia complex)

42. HIV & AIDS
LABORATORY DIAGNOSIS: RATIONALE
• TESTS FOR ANTIBODY
• TESTS FOR ANTIGEN (P24 ) /c DNA/RNA
• TESTS FOR IMMUNITY (T4 L count)
• TESTS FOR OPPORTUNISTIC INFECTIONS & SECONDARY NEOPLASM

43. HIV & AIDS
LABORATORY DIAGNOSIS
Pre & post test counseling is mandatory
• TESTS FOR ANTIBODY : are negative in window period
before seroconversion
• TESTS FOR ANTIGEN (P24 ) /c DNA/RNA are positive in all
phases & very specific, especially before seroconversion
• VIRAL LOAD : PCR for HIV RNA is crucial for monitoring
response to antiretroviral therapy (ART)

44. HIV & AIDS
LABORATORY DIAGNOSIS
TESTS FOR IMMUNITY (T4 L count)
• Done by flow cytometery
• Useful indicator of degree of immune suppression.
• There is 20% day to day variation in CD4+TL counts,
therefore single values are not very useful.
• CD4+TL count below 200 cell/ul, suggests severe
immunosuppression & is an indication for use of prophylactic
antibiotic therapy

45. HIV & AIDS
LABORATORY DIAGNOSIS
TESTS FOR OPPORTUNISTIC INFECTIONS
• The pathogens do not invoke immunological response due to
immune depletion, therefore the morphology may be
different from those of normal cases; eg TB infection may
not show granuloma formation
• Identification of these microorganisms may require special
stains & techniques
• TESTS FOR SECONDARY NEOPLASM vary from case to case

46. HIV & AIDS
TREATMENT & PROGNOSIS
RATIONALE OF ANTIRETROVIRAL
THERAPY [RED ARROWS]
PROGNOSIS
OTHER FACTORS
• ANTI RETROVIRAL TREATMENT HAS
CONSIDERABLY IMPROVED THE
PROGNOSIS
• OTHER SUPPORTIVE TREATMENT
AS REQUIRED IMPROVES THE
QUALITY OF LIFE
• PREVENTION OF INFECTION
STRATEGIES ARE ESSENTIAL IN
CONTROLLING PERSON TO PERSON
SPREAD OF HIV INFECTION

47. ESSAY
• Define AIDS. Describe the etiopathogenesis and lab diagnosis
of the same
• Discuss routes of transmission, pathogenesis, major and
minor signs, pathologic changes and laboratory diagnosis of
acquired immunodeficiency syndrome

48. SHORT ESSAY – CLINICAL CASE
A 24 yr old male c/o fever, diarrhea and weight loss for one
month. O/E there is generalized lymphadenopathy and oral
candidiasis.
Answer the following questions:
• What is your diagnosis?
• What is the pathogenesis of this condition?
• What investigations will you advice?

49. SHORT ESSAY –CLINICAL CASE
A 30yr old male truck driver presented with h/o fever& cough
since 3 weeks, progressive fatigue & wt loss of about 10kg
during the last six months. O/E he had generalized
lymphadenopathy, warts on hands & genitals. CNS – neck
stiffness+, kerning's sign positive. RS – crepitations +nt. He
died after 2 days. Answer the following:
• What is your diagnosis?
• Explain the etiopathogenesis of this condition?
• What is the probable cause of death ?

50. MCQ
Human Immunodeficiency Virus Attaches To Receptors On
a)T4 Lymphocytes
b)Neutrophils
c)Lymphocytes
d)Natural Killer Cells

51. MCQ
What Is “Window” Period
a)Infection Is Absent
b)Infection Is Present But Symptoms Are Absent
c) Infection Is Present But Antibodies Are Absent
d)Infection Is Absent & Antibodies Are Absent
•

52. MCQ
HIV Spreads To CNS via
a) Neutrophils
b) Macrophages
c) T Cells
d) B Cells

53. MCQ
AIDS Is Associated With
a)CD 4 Count 500 - 1000 Cells/Ul
b)CD 4 Count 200 – 400 Cell/Ul
c)CD 4 Count 10 - 100 Cells/Ul
d)CD 4 Count 300 – 500 Cells/Ul

54. MCQ
Loss Of CD4 T Cells In HIV Infection Occurs Due To
a)Cytopathic Effect Of Virus
b) Apoptosis
c)Killing Of Infected Cells By Cytotoxic T Lymphocytes
d)All Of The Above