Transcript Immunopathogenesis of HIV Disease

ImmunoPathogenesis
of HIV Disease
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Overview of HIV Epidemic
Basic biology of HIV-1
Stages of HIV Disease
Viral and Cellular Dynamics after HAART
HIV Therapy and Future Directions in
Pathogenesis Research
Overview of HIV Epidemic
• Origin of virus
• Scope of worldwide Epidemic
• Brief History of Epidemic
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Immunodeficiency syndrome identified (GRID) in late 1970’s
Identification of virus and development of serological test - 1984
Introduction of first antiretroviral drug (AZT) – 1987
Identification of three stages of disease – early 1990’s
Competitive RT-PCR to measure viral RNA in plasma – 1993
combination antiretroviral drugs (protease inhibitors & RTI) – 1995
Introduction of ART to Africa – 2001
Epidemic still expanding – 2006
Death rates in persons aged 25-44 years in the United States
A global view of HIV infection
38.6 million people [33.4‒46.0 million] living with HIV, 2005
Life cycle of HIV
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Viral Entry - CD4 and co-receptors
Reverse Transcription
Integration into host chromatin
Transcriptional activation of integrated provirus
Production of viral proteins, particle assembly and
maturation
Chemokine Co-receptors for HIV
• Two co-receptors - CXCR4 and CCR5 with distinct viral
isolates
• CXCR4 - T tropic - syncytium inducing - present in late
stage disease
• CCR5 - M tropic - non- syncytium inducing - dominant
in early infection
• Natural ligands - SDF-1/CXCR4 & MIP-1a, MIP-1b, &
RANTES/CCR5
• Protection from infection in CCR5 D32 homozygotes
HIV Latent Infection
• Pre-integration latency
– After reverse transcription, before integration
– Due to lability of unintegrated DNA, this pool is dependent on
continual de novo infection
• Integrated latency
– Integrated provirus with low or absent transcription of viral
genes (no expression  no clearance)
– Likely the major reason for eradication failure
– Controversy about origin, role of defective viral genomes,
chromatin integration sites, and clearance rate
High viral mutation rate
• Reverse Transcriptase is fairly sloppy and cellular RNA
polymerases are not high fidelity enzymes
• Estimated to be around 1000 different sequence variants in
a single individual at one time
• Rapid evolution of drug resistance, if there is continued de
novo infection
• In general, inverse relationship of “viral fitness” in vivo
growth rate and drug resistant phenotype. Wild type virus
grows out when drugs withdrawn.
• Partial drug mediated inhibition of growth is recipe for
resistance
Diagnosis of HIV Infection
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Signs & Symptoms of Primary Infection
HIV Ab measurement (EIA  Western Blot)
HIV viral RNA in plasma
Response to suspected exposure (needle stick)
Post-exposure prophylactic ART
Laboratory Testing for AIDS
• Antibody testing —to diagnose HIV infection.
• p24 protein testing —may be used to detect early HIV infection, to monitor
HIV therapy and HIV progression, and to screen blood for HIV.
• Viral load testing —to decide when to start therapy and to monitor therapy
and HIV progression.
– In chronic phase, the extent of viremia (as measured by HIV-1 RNA) can predict
disease progression
• CD4 testing —to decide when to start therapy and to monitor therapy, HIV
progression, and the status of the immune system.
– >500 asymptomatic
– 200-499 early symptoms
– <200 severe immunosuppression
• Genotypic resistance testing —to determine if a particular strain of HIV is
resistant to the therapy you are on and if the therapy should be switched.
Occupational Exposure to HIV
• Concept of Universal precautions
– Any human bodily fluids could be contaminated with
infectious agents transmitted by parenteral exposure.
• In case of possible exposure, immedately report to
HIV response team (at UAB 4-3675) or ER.
• Early Treatment with antiretroviral drugs have very
substantial benefit
– Time after infection is critical.
– Excellent results if ART started within several days.
Three Phases of HIV Disease
• Acute Infection Syndrome
– “flu-like” clinical illness
– high viral load that resolves coincident with development of
effective CD8 T cell response
• Clinical “Latent” Disease
– Widely variable viral load correlated with rate of disease
progression (loss of CD4 T cells)
– Lymphadenopathy and constitutional symptoms
• End Stage Disease (AIDS)
– CD4 T cells < 200; often increase in viral load
– development of opportunistic infections
AIDS-Defining Opportunistic Infections and
Neoplasms in HIV Infection
Infections
PROTOZOAL AND HELMINTHIC INFECTIONS
Cryptosporidiosis or isosporidiosis (enteritis)
Pneumocystosis (pneumonia or disseminated infection)
Toxoplasmosis (pneumonia or CNS infection)
FUNGAL INFECTIONS
Candidiasis (esophageal, tracheal, or pulmonary)
Cryptococcosis (CNS infection)
Coccidioidomycosis (disseminated)
Histoplasmosis (disseminated)
BACTERIAL INFECTIONS
Mycobacteriosis ("atypical," e.g., Mycobacterium aviumintracellulare, disseminated or extrapulmonary; M.
tuberculosis, pulmonary or extrapulmonary)
Nocardiosis (pneumonia, meningitis, disseminated)
Salmonella infections, disseminated
VIRAL INFECTIONS
Cytogegalovirus (pulmonary, intestinal, retinitis, or CNS
infections)
Herpes simplex virus (localized or disseminated)
Varicella-zoster virus (localized or disseminated)
Progressive multifocal leukoencephalopathy
Neoplasms
Kaposi sacroma
Non-Hodgkin lymphomas (Burkitt, immunoblastic)
Primary lymphoma of brain
Invasive cancer of uterine cervix
Viral Dynamics after HAART
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Log Plasma vRNA
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HAART
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t½  1 day
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Time
Initial Rate
Independent of
Absolute vRNA
Dynamics of HAART Induction
• Rapid fall in viral RNA in plasma
– First phase is very rapid (t½ = 1-1.5 days) and fairly
consistent among individuals, second phase slower.
• Rapid Increase in CD4 T cells in Blood
– Redistribution of lymphocytes from inflammed tissue is
primary mechanism - previously thought to be change in
CD4 T cell growth
• Significant Immune Reconstitution
– Decreased incidence of OIs and death
Status of HIV Dynamics on HAART
• Despite initial optimism, infection not eradicated
• Concept of Reservoir
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- residual viable virus during HAART
Latently infected CD4 T cells
Sequestered Anatomic site - CNS, ?others
Persistent rounds of de novo infection
Intermittent Non-adherence
Both Latent infection and persistent vRNA+ cells - Tissue and Blood
• Slow evolution of viral quasispecies sequences
Goals in Medical Management of HIV Disease
• Pharmacological suppression of viral Replication
– Multiple drugs available – low replication  low mutations
– Monitoring status – viral load and CD4 count
• Eradication - complete elimination of viable virus
– Problems - HAART alone does not result in Eradication.
 Regimen
is difficult - Intermittent regimen Non-Adherence
 Development of Drug Resistance
 Persistent population of latently infected CD4 T cells
• Induction of Immune Control
– Increase efficiency of immune response to viral antigen to maintain
control of replication at very low viral load
– Low viral load = Lack of disease progression
– Normal “successful” outcome of chronic viral infection