HIV and the Immune System - njms.rutgers.edunjms.rutgers.edu/gsbs/olc/mci/prot/2009/HIV.pdfKumar et...
Transcript of HIV and the Immune System - njms.rutgers.edunjms.rutgers.edu/gsbs/olc/mci/prot/2009/HIV.pdfKumar et...
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HIV and the Immune System
May 13, 2009
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HIV/AIDS HISTORY• 1926-46 - HIV possibly spreads from monkeys to humans.
Newer data suggest viral ancestor appeared 1884-1924.• 1959 - First proven AIDS death.• 1981 - The Centers for Disease Control and Prevention (CDC)
notices high rate of otherwise rare cancer.• 1982 - The term AIDS is used for the first time.• 1983/84 - American and French scientists each claim discovery
of the virus that will later be called HIV.• 1985 - The FDA approves the first HIV antibody test for blood
supplies.• 1987 - AZT is the first anti-HIV drug approved by the FDA.• 1996 - FDA approves first protease inhibitors.• 2005 - >3 million deaths in one year world wide.• 2008 - Luc Montagnier wins Nobel Prize.
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Transmission of HIV infection requires contact with
BloodMilkSemenVaginal fluidWound exudates
from an infected individual.
Saliva, tears and sweat do not transmit HIV
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Structure of HIV-1
CD4 - CD4+ Tlymphocytes,monocytes, DCs,brain microglia
Modified from Abbas & Lichtman 20-3
CCR5 - mononuclearphagocytes, T cells(M-tropic) - 1st to beinfected
CXCR4 - naïve Tcells, B cells,monocytes (T-tropic)(2%) - 50% switch latein infection
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Pereyra et al. J. Infect. Dis. 197:563-571, 2008
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Analysis of viral isolates• Considerable variations in envelope
glycoproteins.• M (major group) >90% of all infections
– Clades (subtypes) A through K.
• O (outlier group) - restricted to west-central Africa
• N group - (“new”) extremely rare - discovered in Cameroon
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Mechanism of HIV entry into a cell
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Kumar et al: Robbins Basic Pathology 8e - www.studentconsult.com 5-32
Pathogenesisof HIV
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Kumar et al: Robbins BasicPathology 8e -www.studentconsult.com 5-32
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5-33
Mechanisms ofCD4 cell loss
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Normal CD4 =500-1600
Start antiretroviraltherapy when CD4<350*****
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Nonprogressors
I. Seroconvert - immune competence maintained - low levels of virus
II. Seronegative and disease-freeIII. CCR5 deficient (CCR5−�3232-
nucleotide deletion - 1% of the caucasian population
IV. HLA-B*27 and HLA-B*57 slow progression
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From Abbas 20-8
Immune Response to HIV Infection
Latently infected quiescent CD4+ T cells that contain non-integrated proviral DNA are important long-living reservoirs
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M.A. French. HIV Management 2008. The New York Course
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Moir & Fauci. Nat. Rev. Immunol. 9:235-245,2009
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Pugliese et al. Clin. Diag. Lab. Immunol. 12:889-895, 2005
Altered APC function, chemotaxis,and cytokine production
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MECHANISMS OF IMMUNE EVASION
High mutation rate - replication of retroviruses is prone to error - opportunity for accumulation of
undesirable mutations
Downregulation of class I MHC molecules
Preferential inhibition of CMI
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• Acute stage: HIVpreferentially replicates within activated, or recently activated memory, CD4+ T cells that express CCR5. Most CD4+ T cells in the intestine (particularly in the lamina propria) express this phenotype -favored target for virus.
• Chronic activation: disruption of organization of the immune system.
Grossman et al, Nature Medicine 12:289-295, 2006
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M.A. French. HIV Management 2008. The New York Course.
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Mehandru et al. J. Virol. 81:599-612, 2007
Gastrointestinal CD4+ T cellsharbor a greater viral burdenthan PB CD4+ T cells duringacute and early HIV-1infection.
Migration of T cells to GALT ismediated by α4ß7. gp120 binds to an activated form ofα4ß7.
Following HAART in pts withundetectable blood HIV RNA(>4 yrs), T cell numbers (sigmoid colon) increased.
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“tap-and-drain” model
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Possible causes of immune activation:
AIDS 22(4) 439-446, 2008
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Immune Reconstitution Disease (IRD)(Immune Reconstitution Inflammatory Syndrome (IRIS)
Immune reconstitution - reversal of HIV-related immune system decline to increase functional CD4+ T cells
Anti-retroviral treatment triggersinflammatory responses to pathogens -hypersensitivity reaction
Many cases resolve within a few weeks
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N. Cheonis. The Body. Winter 2004/2005
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Opportunistic Infections
• Protozoa– Cryptosporodium
• Bacteria– Toxoplasma, Mycobacterium avium, Nocardia,
Salmonella• Fungi
– Candida, Cryptococcus neoformans, Coccidioides immitis, Histoplasma capsulatum, Pneumocystis (carinii) jiroveci
• Viruses– Cytomegalovirus, herpes simplex, varicella-zoster
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Laboratory Diagnosis• Serology is the usual method for diagnosing HIV
infection. Serological tests can be divided into screening and confirmatory assays.
• Screening assays - ELISAs are the most frequently used screening assays. The sensitivity and specificity approaches 100% but false positive and negative reactions occur.
• Confirmatory assays - Western blot is regarded as the gold standard for serological diagnosis. However, its sensitivity is lower than screening ELISAs.
H. Fernandes
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Diagnosis in Children
• Positive HIV antibody test - not used in children <18 months because of the possibility of maternal antibodies - use PCR -treat with triple therapy.– Controversy - should HIV negative infants with
HIV-positive mothers be treated? Early treatment of asymptomatic infants prevents or delays progression of the disease
• Positive HIV antibody test in child >18 months usually indicates infection
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Treatment and Prevention of AIDS and Vaccine Development
Antiviral drugs used in combination (HAART)Nucleoside analogues - inhibit reverse transcriptase
activityViral protease inhibitors - block processing of precursor
proteins into mature viral capsid and core proteinsNewer reverse transcriptase inhibitors
NEW RECOMMENDATION: TREAT BEFORE HAART IS ABSOLUTELY NECESSARY
Inhibitors of viral entry - chemokine receptor antagonists andinhibitors of viral-cell membrane fusion
Integrase inhibitors - prevent integration of proviral DNA into hostDNA
Prevention - screening blood supply, public health awareness
Vaccine development
Antibiotics
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Barouch, D.H. Nature 455 (7213): 613-619, 2008
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Therapeutic Strategies to Modulate Expression of Chemokine Receptors
• Monoclonal abs to receptor• Chemokines that stay within the
cytoplasm are able to capture and bind to their corresponding receptor on the way to the cell surface.
• Short interfering RNA (siRNA) -selectively inactivate target genes