HIV Pathogenesis

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HIV Pathogenesis

• Jay Ravishankar M.D.
• jravishankar_at_downstate.edu
• 718 270 4180
• 10/14/08

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HIV pathogenesis

• Natural History of HIV infection
• Stages of HIV 1 infection
• Viral transmission, primary HIV infection,
  seroconversion, clinical latent period, early
  symptomatic infection, AIDS, Advanced HIV.
• Treatment

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Match the following

1. Window period
2. EIA / WB
3. Elite Controllers.
4. M tropic virus
5. CD4 lt 50

• A. HIV of 8-10yrs, CD4 gt 500, VL lt 50 no ART,
• B. CCR5 receptor
• C. CMV and atypical mycobacteria
• E. 6-12 weeks
• F. Detects antibodies

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Natural History of HIV Infection
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• Primary Infection

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Vaginal acquisition of
HIV infection.

• HIV most often enters thru the genital mucosa
• HIV has several targets including dendritic
  cells, macrophages, and CD4 T cells
• Clinical infection is more commonly mediated by
  macrophage (M tropic) rather than T cell tropic
  viruses
• The viral envelope protein gp 120 binds to the
  CD4 molecule on the dendritic cell

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Viral entry into the human
cell
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• CCR5 - Used by R5 HIV-1
• Macrophage tropic, NSI, slow replicating
• Transmitted, persists throughout infection
• CXCR4 - Used by X4 HIV-1
• T-cell line tropic, SI, Fast replication
• Associated with accelerated CD4 T cell lost

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HIV Tropism and Disease Progression
Courtesy GSK interactive CD "Exploring an
allosteric world CCR5 entry inhibitors and HIV"
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Primary HIV infection

• Within 2 days of exposure HIV is detectable in
  regional lymph nodes
• In plasma within 5 days
• Once virus enters the blood, there is widespread
  dissemination to organs such as the brain,
  spleen, and lymph nodes

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Human cells susceptible to HIV infection
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Target Cells in HIV Infection
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T cell dynamics in primary/acute infection

• One of the most notable immunologic defects in
  HIV-1 infection is the relatively weak or absent
  HIV-1-specific T helper cell function seen in
  most infected individuals
• HIV differs from other chronic viral infections
  in that the virus selectively targets and
  infects activated, expanding CD4 T cells
• During acute infection, viral replication occurs
  at an extremely rapid rate.
• Rapidly proliferating virus-specific TH become
  activated and expand in the presence of high
  viremia, resulting in subsequent infection and
  destruction of these cells.
• The progressive loss of CD4 cells is a hallmark
  of this disease

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Mechanisms of CD4 cell loss in HIV
infection
Syncytium
Virus mediated
Apoptosis
CTL induced
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Viral Dynamics/Kinetics

• High rates of viral replication
• 10 billion new HIV particles daily
• Rapid replication low fidelity of the
  replication process
• Allows HIV to mutate rapidly into a population of
  genetic variants called Quasi species.
• Allows evolution of HIV with increasing virulence
• Is the cornerstone of rapid development of
  resistance to antiretroviral drugs.
• Complete suppression of HIV replication may help
  to prevent disease progression.

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Biochemical markers in primary HIV infection

• Antibodies
• Viral load
• CD4

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Viral RNA
Envelope antibodies
P24
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Standard test for HIV

• Screening EIA (in pair) followed by confirmatory
  WB
• Neg no bands
• Positive gp120/160 and either P24 or gp41
• Indeterminate presence of any other bands
• Sensitivity and specificity gt99.5 in established
  disease
• Window Period-6-12 weeks

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Rapid HIV test
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HIV RNA Levels Viral Load Assays

• Viral load blood test measures
• copies HIV RNA particles / mL plasma
• Primary infection
• HIV RNA becomes detectable and rises to a peak,
  then
• Tapers to a stable level - virologic set
  point.
• Virologic set point is different in different
  individuals and its magnitude is predictive of
  the risk of disease progression.

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HIV RNA Levels Viral Load Assays (contd)

• F.D.A. approved for prognosis
• Determining the risk of progression of HIV
  disease to AIDS and death and therefore,
• Determining the need for antiretroviral therapy
  and
• Therapeutic monitoring of the effectiveness of
  antiretroviral therapy.
• Unacceptably high false-positive rate
• Not approved for diagnosis of HIV infection nor
  serologic surveillance.

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LABORATORY MARKERS OF HIV INFECTION

• Markers of Immunologic Damage by HIV
• a. Subsets of T lymphocytes
• 1) measured by flow cytometry with
• 2) fluorescence-labeled monoclonal antibodies
  to
• 3) functional surface proteins (CD4 and CD8)
• 4) Normal Values
• Helper / CD4 cell count 400-1200
• Suppressor/ CD8 cell count 400-800

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Acute HIV Infection

• Many patients experience an acute syndrome within
  days to weeks of primary HIV infection.
• Often dismissed as self-limited viral syndrome
  resembling mononucleosis
• In one study, symptoms that occurred in more than
  ½ of patients presenting with acute HIV infection
  included Fever (88), Malaise (72), Myalgia
  (60), Morbilliform rash (58), Headache (55),
  Night sweats (50).
• One symptom that was a negative predictor of HIV
  infection, nasal congestion, occurred in 18 of
  patients with acute HIV infection compared with
  38 of patients without acute HIV infection (Daar
  ES, et al. Ann Intern Med 2001 13425-29)
• The take home message is that all patients with
  any risk factor for HIV infection should be
  offered testing whenever they present with the
  symptoms listed above.

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Clinical Latency
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CTL
CD4
Viral RNA
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Middle Stage of HIV infection (Clinical latency)

• Begins with establishment of the virologic set
  point (months after initial infection)
• Ends with signs of severe immune system
  compromise (years after initial infection)
• AIDS diagnosis- development of an opportunistic
  infection, or risk of opportunistic infection
  CD4 count lt200/cc)
• In absence of therapy, median duration is
  approximately 8-10 years, although there is wide
  variation in rate of progression.
• Destruction of lymphoid tissue may occur even at
  low viral loads
• Women appear to progress at lower HIV viral loads
  than men.
• Clinical manifestations are usually minimal early
  in this stage with the exception of
  lymphadenopathy, which in some patients,
  regresses as the disease progresses. (Clinical
  latency)

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Middle Stage of HIV Infection(Clinical Latency
contd)

• Episodic conditions that can occur include herpes
  zoster, oral or vaginal candidiasis, pneumonia
  and reactivation of tuberculosis.
• Serve as clinical clues to perform HIV testing if
  a person presents with these conditions and has
  not yet been tested for HIV.
• A common laboratory abnormality is
  hypergammaglobulinemia. Prior to 1985, this was
  a surrogate marker for HIV infection before an
  antibody test was developed.
• Hint, another indication to offer HIV testing,
  when this is the only lab abnormality found
  during a work-up.

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Likelihood of Developing AIDS in 3 Yrs
CD4 cells/µL
Percent progressing
gt30,000 10,000- 3,000- 501- lt500 30,000
10,000 3,000
Plasma HIV RNA (copies/mL)
Adapted from Mellors J et al. Ann Intern Med.
1997.
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Advanced HIV Disease

• CD4 count lt 200 cells/mm3, but no Opportunistic
  Infections
• In absence of prophylaxis, infections such as
  Pneumocystis carinii pneumonia (PCP), cerebral
  toxoplasmosis, and other infections can occur.
• Some patients remain asymptomatic (clinical
  latency).
• Without proactive counseling and testing
  programs, this is when most patients will present
  for care.

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Late Stage HIV Infection

• CD4 count lt 50 cells/mm3
• High risk of atypical Mycobacterial infections
  (Mycobacteria avium intracellulare, etc.),
  cytomegalovirus infection, PML can occur
• Secondary symptoms such as anorexia, diarrhea and
  wasting (Slim disease).
• High risk of death.

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Factors Affecting HIV Disease Progression

• Age people older than 35 yrs progress to AIDS
  faster than 16-24 yrs 6 15 (Am J of epidemiology
  1992)
• Pts who have symptomatic primary infection tend
  to progress rapidly than asymptomatic at
  seroconversion.
• Replicative capacity of the virus
• CCR5 co receptor usage VS CXCR4
• CCR5 ? 32 heterozygosity associated with
  decreased risk of progression

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Risk of progression

• Co infection with other pathogens
• Herpes
• Syphilis
• Super infection with HIV
• TB
• Impact of treatment

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CD4gt500 HIVgt13yrs No HAART Also called
controllers VLlt50 elite controllers
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Interval summary

• HIV pathogenesisDepletion of CD4 T cells.
• Biochemical markers ( antibodies, VL, CD4) of HIV
  infection
• Symptoms of primary infection
• Clinical latency period
• Advanced disease

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Interventions

• Prophylaxis against Opportunistic Infections
• Antimicrobials used to prevent infections caused
  by pneumocystis carinii, atypical mycobacterial
  infections,
• Treatment of HIV infection

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Antiretroviral Drug Approval1987 - 2008
RAL MVC
ENF ATV FTC FPV
ETR
Pre HAART ERA Monotherapy Sequential
adding Resistance
TPV
DRV
TDF
EFV ABC
LPV/r
APV
RTV IDV NVP
NFV DLV
3TC SQV
d4T
ddC
AZT
ddI
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FDA-Approved Antiretroviral Agents
Intelence
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• A 40 yr male was diagnosed with HIV infection 2
  weeks ago. His CD4 is 247 and VL 55,000.
• He is willing to be engaged in medical care.
• What do you do?

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• When to start treatment?
• Eradication of HIV Infection is not possible

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ART Goals Tools to Achieve Them

• Improved quality of life
• Reduction of HIV-related morbidity and mortality
• Restoration and/or preservation of immunologic
  function
• Maximal and durable suppression of viral load
• Prevention of vertical transmission
• Prevention of transmission to sexual partners

• Selection of ARV regimen
• Preservation of future treatment options
• Rational sequencing of therapy
• Maximizing adherence
• Use of resistance testing in selected clinical
  settings

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• Resistance is the consequence of mutations that
  emerge in the viral proteins targeted by
  antiretroviral agents.
• Genotype and Phenotype are 2 types of resistance
  testing

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Who needs resistance testing ?

• Newly diagnosed patients
• Chronic HIV infection-Treatment naive
• Pregnant women
• First HAART failure
• Salvage situation

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Initial Treatment Preferred Components
NNRTI Option
NRTI Options¹
EFV

• ABC 3TC²
• TDF FTC³

OR

PI Options
ATV RTV FPV RTV (BID) LPV/RTV (BID)

• Avoid in pregnant women and women with
  significant pregnancy potential
• ¹ FTC can be used in place of 3TC and vice versa
• ² For patients who have tested negative for
  HLA-B5701
• ³ TDF FTC or 3TC is preferred in patients with
  HIV/HBV coinfection

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Week 48 HIV RNA lt 50 c/mL (NNRTI vs PI vs BPI vs
NRTI)
The DHHS Guidelines Work
Bartlett J. et al., 12th CROI, Boston 2005, 586
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Immune reconstitution disease

• Case Definition
• A paradoxical deterioration in clinical status
  after initiating highly active antiretroviral
  therapy (HAART) attributable to the recovery of
  the immune response to latent or subclinical
  infectious or non-infectious processes
• Other Nomenclature
• Immune reconstitution inflammatory syndrome
  (IRIS)
• Immune restoration/restitution/recovery disease
• immune rebound illness

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• A 50 yr male was started on HAART 6 weeks ago.
  His Cd4 at the beginning of treatment was 53 and
  VL was 72K.
• He now presents with fatigue, anemia and a
  swelling in the neck

MAC accounts for1/3rd of all reported IRS Usually
happens in the first 8 weeks Starting CD4 usually
low ( lt 100) Robust response to HAART
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Immune Reconstitution

• For many OIs, an inflammatory reaction may occur
  when treatment for those OIs is started
  concurrently with ART.
• Initiation of ART also has been associated with
  inflammatory reactions in patients harboring
  subclinical infection that becomes clinical in an
  atypical manner several weeks after ART is
  started.

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Risk factors for IRIS
MAI TB Cryptococcus PCP Herpes
Host susceptibility
Microbial antigens
CD4lt 50
Adapted from French et al, 2004
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Management of IRIS

• Diagnostic Dilemmas
• Immune Reconstitution Syndrome
• Relapse
• Drug Toxicity
• New Disease Process

• Therapeutic Dilemmas
• Stop or continue ART
• Stop or change OI therapy
• Add immunosuppressives

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Summary-II

• When to start treatment
• Resistance testing
• Preferred regimens
• IRIS