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AIDS

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ACQUIRED
IMMUNODEFICIENCY
SYNDROME (AIDS)
▪Introduction
▪Epidemiology
▪Structure of HIV
▪Pathogenesis and life cycle of HIV
▪Clinical features
AIDS
▪ Caused by Human Immunodeficiency Virus(HIV) - Retrovirus
▪ Characterized by profound immunosuppression that leads to
opportunistic infections, secondary neoplasms and neurologic
manifestations
▪ 3 major routes of transmission
– Sexual contact
– Parenteral inoculation
– Passage of virus from infected mothers to their newborn
High risk categories
▪ Sexual transmission
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–
–
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Dominant mode of infection world wide
Homosexual transmission
Heterosexual transmission
Enhanced by coexisting sexually transmitted diseases
High risk categories
▪ Parenteral transmission
– IV drug abusers
– Recipients of blood transfusions
▪ Mother to infant transmission
– In utero by transplacental
– During delivery through infected birth canal – most common
– After birth by ingestion of breast milk
HIV Virus
▪ Lentivirus family
▪ Non transforming human retrovirus
▪ HIV – 1 and HIV-2 - genetically different but related forms
▪ HIV –1
– Most common type associated with AIDS in US,Europe and central africa
▪ HIV –2
– Principally in West Africa and India
Structure of HIV
▪ Spherical
▪ Cone shaped core
surrounded by lipid envelope
▪ Lipid envelope- derived
from host cell membrane
Structure of HIV
▪ Viral core contains
– Major capsid protein p24
– Nucelocapsid protein p7/p9
– Two copies of viral genomic RNA
▪ Contains gag,pol and env genestypical of retroviruses
– Three viral enzymes
– Proteae
– Reverse transcriptase
– integrase
Structure of HIV
▪ p24
– Most abundant viral antigen
– Detected by ELISA
▪ Viral core is surrounded by
matrix protein p17
▪ 2 glycoproteins in viral
envelope
– gp 120
– gp41
Pathogenesis of hiv infection
▪ The HIV virion expresses a cell surface
protein/antigen called gp120, that aids in the
binding of the virus to the target cells. Once
the virus enters the human body it attaches
itself to the target cell via the CD4 receptors
on the surface of the target cell and therefore
gains entry into the target cell. Gp120 is
responsible for tropism/attraction to CD4+
receptors. This function helps in entry of HIV
into the host cell.
▪ In addition gp120 also binds to two coreceptors CXCR4 and CCR5 on the host cell
surface. They too assist in the entry of HIV
into the host cell.
▪ The T-lymphocytes have surface CD4
receptors (CD4+ T lymphocytes) to which HIV
can attach to promote entry into the cell.
Human immunodeficiency virus is shown crossing the mucosa
of the genital tract to infect CD4+ T-lymphocytes. A
Langerhans cell in the epithelium is shown in red in this
diagram
NOTE: The probability of infection depends on both the number of
infective HIV virions in the body fluid which contacts the host as well
as the number of cells with CD4 receptors available at the site of
contact.
Pathogenesis of hiv infection
▪ Retroviruses are unable to replicate outside of living
host cells because they contain only RNA and do not
contain DNA. Therefore once HIV infects a cell, it
must use its reverse transcriptase enzyme to
transcribe/ convert its RNA to host cell proviral DNA
for replication.
▪ The enzyme, reverse transcriptase in the HIV
helps in the reverse transcription (i.e. conversion) of
RNA to proviral DNA. This HIV proviral DNA is then
inserted into host cell genomic DNA by the
integrase enzyme.
▪ Once the HIV proviral DNA is within the infected
cell's genome the HIV provirus is replicated by the
host cell to produce additional HIV virions which are
released by surface budding. Alternatively the
infected cells can undergo lysis with release of new
HIV virions which can then infect additional cells.
HIV viral particles are seen
adjacent to the cell surface in
this electron micrograph
HIV life cycle
Establishment of HIV Infection
▪ Macrophages and Langerhans cells are important both as reservoirs and vectors
for the spread of HIV in the body including the CNS. Both macrophages and
Langerhans cells can be HIV-infected but are not destroyed themselves. HIV can
then be carried elsewhere in the body.
▪ Once the infection extends to the lymph nodes, the HIV virions are trapped in the
processes of follicular dendritic cells (FDC's), where they provide a reservoir and
infect CD4+ T lymphocytes that are passing through the lymph node. The FDC's
themselves become infected, but are not destroyed.
▪ The target cells are: blood monocytes and tissue macrophages, T lymphocytes,
B lymphocytes, natural killer (NK) lymphocytes, dendritic cells (i.e. the
Langerhans cells of epithelia and follicular dendritic cells in lymph nodes),
hematopoietic stem cells, endothelial cells, microglial cells in brain, and
gastrointestinal epithelial cells.
Establishment of HIV
Infection
▪ In addition HIV has the ability to
mutate easily. This high mutation
rate leads to the emergence of HIV
variants within the infected
person's cells that are more toxic
and can resist drug therapy. Over
time, different tissues of the body
may harbor differing HIV variants
Natural history
▪ 3 phase
– Acute retroviral syndrome
– Chronic phase
– Clinical AIDS
• Primary(acute)
infection
• Virus dissemination
• Development of host
immune responses
Acute Retroviral Syndrome
PRIMARY INFECTION
▪ Virus enters through mucosal epithelium
▪ Infects memory CD4+ T cells in mucosal lymphoid tissue
▪ Death of many infected cells
DISSEMINATION OF VIRUS
▪ DCs at sites of viral entry capture the virus and migrate into
the lymphnodes
▪ Pass HIV to CD4+ T cells – cell to cell contact
▪ Viral replication in lymph nodes
▪ Viremia
▪ Infects helper T cells ,macrophages and DCs in peripheral
lymphoid tissues
DEVELOPMENT OF HOST IMMUNE RESPONSE
▪ Humoral and cell mediated immune responses
▪ Seroconvertion and development of virus specific CD8+
cytotoxic T cells(3 – 7 weeks)
▪ Partially control the infection
▪ A drop in viremia to low but detectable levels(12 weeks)
Acute Retroviral Syndrome
▪ Clinical presentation of initial spread of the virus and host responses
▪ 40 – 90% of infected individuals
▪ Occurs 3-6 weeks after infection and resolves spontaneously in 2 -4
weeks
▪ Marked by nonspecific self limited acute illness with flu like symotoms
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Sorethroat
Myalgia
Fever
Weight loss
Fatigue
Rash,cervical adenopathy,diarrheas,vomiting
Chronic infection;Phase of
clinical latency
▪ Lymph nodes and spleen – continues viral replication and cell
destruction
▪ Few or no clinical manifestations- Clinical latency period
▪ Majority of peripheral blood T cell have no virus
▪ Destruction of CD4+ in lymphoid tissues and in blood continues –
number steadily declines
▪ May develop minor opportunistic infections- candidiasis,herpes
zoster,TB
AIDS
▪ Breakdown of host defense,increase in viral load,severe life
threatening clinical disease
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Long lasting (>1 month) fever
Fatigue
Weight loss
Diarrhea
Generalised LN enlargement
▪ Severe opportunistic infections,secondary neoplasm,neurologic
disease
▪ In the absence of treatment,most patients progress to AIDS after a
chronic phase of 7-10 years
▪ Exceptions
– Rapid proggressors- chronic phase 2-3 years after primary infection
– Long term non progressors- Untreated infected individuals who
remain asymoptomatic for 10 years or more, with stable CD4+ T
cell count and low viral load
– Elite controllers- 1% of infected individuals with have
undetectable plasma virus
Opportunitic Infections
Protozoal and
Helminthic Infections
▪ Cryptosporidium
(enteritis)
▪ Pneumocystis
(pneumonia or
disseminated infection)
▪ Toxoplasma (pneumonia
or CNS infection)
Fungal Infections
▪ Candida (esophageal,
tracheal, or pulmonary)
▪ Cryptococcus (CNS
infection)
▪ Coccidioides
(disseminated)
▪ Histoplasma
(disseminated)
Bacterial Infections
Viral Infections
▪ Mycobacterium
▪ Cytomegalovirus (pulmonary,
intestinal, retinitis, or CNS
infections)
– “atypical,” - Mycobacterium
aviumintracellulare(disseminated or
extrapulmonary)
– Mycobacterium
tuberculosis(pulmonary or
extrapulmonary)
▪ Herpes simplex virus
(localized or disseminated
infection)
▪ Nocardia (pneumonia,
meningitis, disseminated)
▪ Varicella-zoster virus
(localized or disseminated
infection)
▪ Salmonella infections,
disseminated
▪ Progressive multifocal
leukoencephalopathy
Neoplasms
Kaposi sarcoma
Primary lymphoma of brain
Invasive cancer of cervix
Kaposi sarcoma
most common neoplasm in patients with AIDS
caused by HHVS - KS herpesvirus with Cofactor HIV
proliferation of spindle cells with slitlike vascular spaces
express markers of both endothelial cells and smoothmuscles
Affects skin, G12, mucousmembrane CN and lungs.
Lymphomas
▪ Commonly it is B-cell Non Hodgkins Lymphoma.
▪ They are typically of a high grade and often in the brain.
▪ They are very aggressive and respond poorly to therapy.
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