Download HIV-AIDS

Microbiology: Basic Properties of HIV
VIRAL ORIGIN:

Lentivirus: cause disease that requires a long time to develop (usually takes ~10 years after infection with HIV to
develop AIDS)

Types: share ~40% homology
HIV-I: most common form around the world
HIV-II: not as virulent and causes a disease that takes longer to develop and has a lower morbidity rate; common
in West Africa
GENERAL PROPERTIES:

Cellular Tropism:
Monocyte/Dendritic Cell/Macrophage: involved in initial infection
CD4+ T Cells: involved in initial and late infection (depletion results in immunodeficiency)
Microglia: infection occurs at later stages and affects neurons indirectly; results in neurological disorders (HIVassociated dementia)
HIV PATHOGENESIS:

3 Main Clinical Symptoms of AIDS:
CD4 T cell depletion
Neurological manifestations: 20-30% develop HAD
Neoplasms: Kaposi’s sarcoma, lymphoma (due to immunodeficiency)

Transmission:
Blood
Sexual transmission
Mother to infant (intrauterine or infection at birth; greatly decreased due to use of anti-retrovirals)

Clinical Course of AIDS:
Viremia:
o HIV replication occurs initially in mononuclear cells (ie. dendritic cells) and a few CD4 T cells present at
the site of entry
o After this, replication predominantly in CD4 T cells
o Initial spike in virus levels, followed by a decline during the persistent phase; levels will increase again
during the development of AIDS
Immune Response:
o Initial response: result of initial increase in CD8 T cells
o Sustained period: anti-gp120 Ab response; viremia kept in check during this time
o Other Basics:

Immunodeficiency: result of depletion of CD4+ T cells

Soon after infection: some people develop an influenza or mononucleosis-like infection

Persistent infection:
 Cells infected with HIV contain proviral DNA integrated into their own DNA (doesn’t
need to be expressed to be maintained by infected cell and passed onto progeny
cells)
 Only low amounts of virus produced in peripheral blood leukocytes (PBLs)
 High levels of virus produced in LNs
 Persistent stage can last for years and can be asymptomatic
 May cause peripheral generalized lymphadenopathy syndrome (PGL)

Eventually develop AIDS: wasting, opportunistic infections, neoplasms and CNS damage
 When CD4 count is less than 200 cells/uL
HIV REPLICATION:

Complex Genome: multiple spliced messages

Adsorption and Entry: binds both receptor and co-receptor
Receptor: CD4
o SU and the V3 Region of gp120: bind CD4

SU: composed of both variable and constant regions of aa
 V3: most important of these segments; immunodominant epitope recognized by
neutralizing Abs (however, highly susceptible to mutation and therefore evades the
immune response)
Co-receptor: CCR5 (macrophage) and CXCR4 (T cells)
o CCR5: beta-chemokine receptor; present mainly on monocytes and a few CD4 T cells
o CXCR4: alpha-chemokine receptor; present mainly on CD4 T cells
-
Important Point: “long-term progressers” (patients who are HIV positive but do not develop AIDS) are found to
have mutations in either of these co-receptors
o CCR5: overproduction of ligand, prevents HIV from binding (all spots take up by over produced ligand)
o CXCR4: mutation to molecule prevents HIV binding
Basic Binding Process:
o CD4 binds the HIV gp120 molecule first
o Results in conformational change so it can bind the co-receptor
o Another conformational change occurs that releases the TM protein from the hydrophobic pocket,
allowing it to attach to the cytoplasmic membrane

Viral Proteins:
Regulatory Proteins: essential for HIV replication
o Tat (transcriptional transactivator): transactivator of viral transcription allowing for high levels of viral
RNA to be transcribed (without it, there would be very little transcription)
o Rev (regulator of viral expression): regulates viral RNA transport of the following from the nucleus

Unspliced DNA packaged into virions as genomic RNA (used for translation of Gag-Pol
polypeptide precursor protein)

Single-spliced mRNA being transported to the cytoplasm as cell (encode envelope viral gp,
which is an important component of infectious virus particles)
Accessory Proteins: initially observed to be non-essential in vitro; may be important for pathogenesis in vivo
o Nef (negative factor): name is a misnomer; predominantly cytoplasmic

Downregulates CD4 and MHC class I: immune evasion

Prevents apoptosis of infected cell
o Vpr (viral protein R):

Role in ability to infect non-dividing cells (ie. macrophages): disrupts nuclear membrane to
allow transport of viral DNA into the nucleus

Arrests cellular proliferation: cells accumulate in G2 phase of the cell cycle
o Vif (viral infectivity factor):

Inhibits cellular protein that normally degrades reverse transcribed viral DNA
o Vpu (viral protein U):

Downregulates CD4 expression: immune evasion

Promotes virus budding: inhibition of cellular protein tetherin
THERAPY:

Highly Active Anti-Retroviral Therapy (HAART): combination drugs
Examples:
o 2 nucleoside reverse transcriptase inhibitors (NRTIs) + 1 non-nucleoside RTI (NNRTI)
o 2 NRTIs + 1 protease inhibitor

New Drug Targets:
TM viral protein
IN viral protein
CCR5

Vaccines: recombinant proteins (gp120, gag/pol/env)

New Treatments:
RNA interference
Recombinant viral DNA