Download ACQUIRED (SECONDARY) IMMUNODEFICIENCIES

 Anergy is called a generalized deficiency in DTH responses after lymphoma
(Hodgkin's disease)
 Viruses other than HIV are known to impair immune responses; include the
measles virus and human T cell lymphotropic virus 1 (HTLV-l)
Aquered Immunodeficiency syndrome (AIDS)
 Associated opportunistic infections and malignant tumors, wasting, and central
nervous system (CNS) degeneration
 HIV infects a variety of cells of the immune system, including CD4+ helper T cells,
macrophages, and dendritic cells
 HIV epidemic was first identified only in the 1980s
 HIV has infected 50 to 60 million people and has caused the death of over 22
million adults and children
 Approximately, 70% are in Africa and 20% in Asia, and almost 3 million die of the
disease every year
 Approximately, 14,000 new infections every day, and by the year 2010, 50 to 75
million infected people will be added
 Approximately, 5 million new cases every year occur in young adults (15-24 years
old)
Molecular and Biologic Features of HIV
 HIV, retroviruses, is a member of the lentivirus family of animal and long-term
latent infection of cells and short-term cytopathic effects
 Two closely related types of HIV (HIV-1 and HIV-2), have been identified
 HIV-1 is by far the most common cause of AIDS, but HIV-2, which differs in genomic
structure and antigenicity, causes a similar clinical syndrome
HIV Structure and Genes
 Consists of two identical strands of RNA packaged and surrounded by a
phospholipid bilayer envelope derived from the host cell membrane
 Long terminal repeats (LTRs) at each end of the genome regulate viral gene
expression, viral integration into the host genome, and viral replication
 gag sequences encode core structural proteins
 env sequences encode the envelope glycoproteins gp120 and gp41, which are
required for infection of cells
 pol sequences encode reverse transcriptase, integrase, and viral protease
enzymes required for viral replication
 Also, HIV-1 includes six other regulatory genes, namely, the tat, rev, vif, nef, vpr,
and vpu genes, whose products regulate viral reproduction in various ways
Viral Life Cycle
 Most important chemokine receptors that act as coreceptors for HIV are
CXCR4 and CCR5
 More than seven different chemokine receptors are coreceptors for HIV entry
into cells as the leukotriene B4 receptor
 Macrophage-tropic (M-tropic), T-tropic and both T cell lines and macrophages
(dual-tropic virus)HIV virus
 Macrophage-tropic virus isolates express a gp120 that binds to CCR5, which is
expressed on macrophages (and some memory T cells)
 Whereas, T cell-tropic viruses bind to CXCR4,which is expressed on T cell lines
 T-tropic strains tend to be more virulent, presumably because they infect and
deplete T cells more than do M-tropic strains
 Naive T cells are resistant to HIV infection because these cells contain an active
form of an enzyme that introduces mutations in the HIV genome
 This enzyme has been called APOBEC3G (apolipoprotein B mRNA-editing
enzyme catalytic polypeptide-like editing complex 3)
Pathogenesis of HIV Infection and AIDS
 HIV disease begins with acute infection, which is only partly controlled by the
adaptive immune response, and advances to chronic progressive infection of
peripheral lymphoid tissues
 Acute (early) infection is characterized by infection of memory CD4+ T cells
(which express CCR5) in mucosal lymphoid tissues, and death of many
infected cells
 Transition from acute phase to a chronic of infection is characterized by
dissemination of the virus, viremia, and development of host immune
responses
 Dendritic cells in epithelia capture the virus and pass HIV on to CD4+ T cells
through direct cell-cell contact
 In the next, chronic phase of the disease, lymph nodes and the spleen are sites
of continuous HIV replication and cell destruction
 Clinical latency period
 It is estimated that HIV destroys up to 1 to 2* 109 CD4+ T cells every day
Progression of HIV infection
Clinical course of HIV disease
Mechanisms of Immunodeficiency Caused by HIV
 An important cause is the direct cytopathic effect
 Chronic activation of the T cells may predispose the cells to apoptosis
 HIV-specific CTL can kill infected CD4+T cells
 HIV-infected CD4+T cells and target the cells for antibody-dependent cellmediated cytotoxicity (ADCC)
 Defective maturation of CD4+ T cells in the thymus
 Functional defects in the immune system include a decrease in T cell responses
to antigens and weak humoral immune responses
 Proportion of IL-2 and IFN-γ-secreting (Th1) T cells decreases and the
proportion of IL-4 and IL-10 secreting (TH2-like) T cells increases
 Increased numbers of CD4+ CD25+ regulatory T cells
 Macrophages, dendritic cells, and follicular dendritic cells also play important
roles in HIV infection and the progression of immunodeficiency
Transmission of HIV
 Sexual contact is the most frequent
 Mother- to-child
 Inoculation of a recipient with infected blood or blood products
 Major groups at risk for the development of AIDS in the United States include
homosexual or bisexual males, intravenous drug abusers, heterosexual partners
of members of other risk groups, and babies born of infected mothers
Clinical Features of HIV Disease
Immune Responses to HIV
 HIV-specific humoral and cell-mediated immune responses, but imited
protection
 Initial adaptive immune response CD8+ T cells specific for HIV peptides
 Antibody responses to a variety of HIV antigens are detectable within 6 to 9
weeks after infection (Neutralizing antibodies against gp120)
Mechanisms of Immune Evasion by HIV
 Extremely high mutation rate because of error-prone reverse transcription
 Evade CTLs through down-regulation of class I MHC
 Inhibit cell-mediated immunity
Treatment and Prevention of AIDS and
Vaccine Development
 Three classes of antiviral drugs, used in combination
 First type of drug to be widely used consists of nucleoside analogues that
inhibit reverse-transcriptase activity, as ‘-azido-3' -deoxythymidine (AZT)
 Viral protease inhibitors have been developed that block the processing of
precursor proteins into mature viral capsid and core proteins
 New triple-drug therapy, HAART (highly active anti-retroviral therapy)
 Such vaccines include nonvirulent recombinant hybrid viruses composed of
part SIV and part HIV sequences or viruses that have been attenuated by
deletions in one or more parts of the viral genome, such as the nef gene
 live –attenuated virus vaccines
 CTL-mediated immunity is the use of live recombinant non-HIV viral vectors
carrying HIV genes
 DNA vaccines are composed of combinations of structural and regulatory
genes of SIV or HIV packaged in mammalian DNA expression vectors
 Recombinant protein or peptide subunit vaccines that elicit antibodies