HIV

ACQUIRED IMMUNODEFICIENCY
SYNDROME
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
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
 HIV
 TARGET OF INFECTION
 •IMMUNE SYSTEM
 • CNS
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
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.
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
 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
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.
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
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
 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
 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 IL6, 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.
 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 tumor
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
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
 LYMPHNODE [Late lesions]
 • Depletion of follicular cells & lymphocytes
 • Follicles may become hyalinized
 • Lymph nodes are atrophic
 • Many opportunistic pathogens may be present
 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
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
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
 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
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
 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”
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
MINOR HIV ASSOCIATED
DISORDERS
(CHRONIC
• It may merge withPHASE)
 ( STAGE
the latent phase with development of 2&3)
 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
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
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)
 • 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
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 )
AIDS: CNS LESIONS

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