Clinical Overview of HIV Disease
Section 2: Basics of HIV Virology and Immunology
Virology
HIV-1 and the less common HIV-2 belong to the family of retroviruses. HIV-1
contains a single-stranded RNA genome that is 9 kilobases in length and contains
9 genes that encode 15 different proteins.( 40,41 ) The major viral proteins
(some of which contain >1 protein subunit) are classified as structural proteins
(Gag, Pol, and Env), regulatory proteins (Tat and Rev), and accessory proteins (Vpu,
Vpr, Vif, and Nef).
Three major classes of HIV-1 have emerged: M (main), N (new), and O (outlier).
Among M group viruses, which account for >90% of HIV infections worldwide, there
are 9 subtypes, called clades, designated by the letters A-D, F-H, J, and K, as
well as many recombinant forms.( 303,304 ) Variation between one clade and
another in the amino acid sequences of the envelope protein may exceed 30%.
Clade B, the most common subtype in the Americas and Western Europe, differs
considerably from those clades found in Asia and Africa, where the majority of
HIV-infected individuals reside (see
Figure 1 ). Viral diversity is greatest in sub-Saharan Africa. To date, most
HIV drug development has targeted clade B. As HIV treatment is extended into
regions where non-B clades predominate, issues of differential drug response,
drug mutation patterns, and reliability of viral testing (ie, viral loads and
resistance testing) may emerge.( 305,306 ) Sequence diversity among various
clades also needs to be considered in vaccine development, as most HIV-specific
neutralizing antibodies ( 307 ) and some cytotoxic T-lymphocyte (CTL) responses
( 308 ) are type specific.
HIV infection of a host cell begins with the binding of the virus particle (virion)
to the host cell. This process is initiated when the surface envelope protein (Env,
which consists of 3 copies each of the 2 subunit proteins gp120 and gp41)
engages its primary receptor, the CD4 molecule on the surface of the target
cell.( 42 ) Initial binding to CD4 exposes another portion of the Env trimer,
which then binds to a coreceptor, usually the chemokine receptor CXCR4 (in the
case of T-cell-tropic, or syncytium-inducing strains of HIV) or the chemokine
receptor CCR5 (in the case of macrophage-tropic, or nonsyncytium-inducing
strains).( 43 ) This coreceptor binding causes the gp41 trimer portion of the
envelope molecule to spring open and "harpoon" the lipid bilayer of the target
cell membrane. The "hairpin" domains of gp41 then fold together to pull the
virus and host cell membranes together, allowing fusion to occur.( 44 ) The
viral contents, including copies of the viral genetic material and the Pol
protein (reverse transcriptase, or RT) thus enter the cytoplasm of the host
cell. Reverse transcription, that is, the copying of the viral genetic material
from RNA into DNA can then occur.
The preintegration complex (PIC), composed of the copied DNA (cDNA) and a number
of viral and host proteins, then enters the cell nucleus, where the viral enzyme
integrase mediates the insertion of the viral cDNA into the host chromosomal
DNA.( 45 ) The resulting integrated DNA virus (also called a provirus, to
distinguish it from the virion form) may remain latent for hours to years before
becoming active through transcription (copying of DNA into RNA).( 46 )
Transcription of the viral genome is under complex control of a number of
proteins, including Tat and cellular DNA transcription factors.( 47 ) Transport
of the transcribed viral RNA out of the nucleus also depends on a number of host
and viral factors, including Rev.( 48 ) The transcribed viral RNA may be
transported out of the nucleus in its full-length form to serve as genetic
material for new virions, or it may be partially or fully spliced. The unspliced,
partially spliced, and fully spliced versions of viral RNA direct the synthesis
of different viral proteins by the cell ribosomes. New viral particles are
assembled at the plasma membrane and incorporate Gag subunits, Pol, Nef, Env,
Vpr, and viral genomic RNA.( 53 ) The HIV viral protease enzyme acts following
virion assembly to cleave viral proteins into functional structural and
enzymatic components. Gag then functions in the budding of mature virions from
the plasma membrane.( 54 ) The Nef protein acts on the cellular environment to
promote replication by inhibiting the host immunologic response to HIV ( 49-51 )
and inhibiting death of infected cells by apoptosis.( 52 )
Current HIV therapies inhibit the viral replication process at the binding and
entry stage (fusion inhibitors), the reverse transcription stage (nucleoside and
nonnucleoside reverse transcriptase inhibitors [NRTIs and NNRTIs,
respectively]), or the protein cleavage stage (PIs). Inhibitors of coreceptor
binding, integration, and maturation are in clinical trials.
Immunology
Individuals infected with HIV show both cellular and humoral (antibody)
immune responses to the virus, but these responses are unable to prevent the
ultimate progression of disease in the great majority of infected individuals.
Cellular responses are mediated by CTLs (CD8 cells) and helper T lymphocytes
(CD4 cells). CTLs inhibit HIV replication both directly, by recognizing and
killing infected cells, and indirectly, by producing soluble chemokine antiviral
factors.( 55,56 )
CTL-mediated killing of virally infected host cells occurs through direct
contact, whereby the T-cell receptor on the surface of the CTL recognizes a
fragment (epitope) of an HIV protein bound to a major histocompatibility complex
(MHC) class I molecule on the surface of the infected host cell. After this
interaction, the CTL releases enzymes that kill the infected cell. CTL responses
directed against certain epitopes of the Gag protein have been associated with
slower HIV disease progression than CTL responses against other epitopes.( 57 )
CTLs also exert effects through soluble factors such as RANTES, macrophage
inflammatory protein (MIP)-1-alpha, and MIP-1-beta, which inhibit HIV from
infecting new cells by blocking HIV coreceptors.( 58 )
CD4 responses to HIV are important in viral control, and strong HIV-specific CD4
responses are associated with lower HIV viral loads.( 59 ) CD4 cells respond to
HIV antigens presented in conjunction with MHC class II molecules on the surface
of infected cells. The fact that HIV infects CD4 cells themselves is an
evolutionary strategy with a number of consequences. Because productive HIV
infection occurs in activated CD4 cells, infection and killing of CD4 cells that
are responding to HIV infection itself may cause a selective decrease in the
number of HIV-specific CD4 cells. (HIV can also exist in nonactivated CD4 cells
in a preintegrated form, which can become integrated if activation occurs within
a few days.[ 60 ]) Additionally, as some of the activated, infected CD4 cells
differentiate into resting memory CD4 cells, they may carry copies of the HIV
genome in a postintegrated form that can persist for decades.( 61 ) Current
antiretroviral medications cannot efficiently eliminate the virus from cells in
the resting state, leading to persistence of infection even in the presence of
suppressive therapy.( 61 ) Moreover, HIV continues to evolve under the selection
pressure of the immune response that occurs in each infected individual, and
mutations in the viral epitopes recognized by the immune system may enable the
virus to escape the control of even broad and robust CD4 and CD8 HIV-specific
responses.( 62 )
Depletion of CD4 lymphocytes is the hallmark of HIV infection, and predicts an
individual's risk for infection with opportunistic pathogens as well as other
complications of HIV disease. Evidence has shown that both increased peripheral
destruction and decreased production of CD4 cells likely play a role in this
decline.( 63-67 )
Humoral immunity appears to be less effective in controlling viremia than
cellular responses, as HIV is remarkably effective at evading host antibody
responses, and broadly neutralizing antibodies are rare.( 68,69 ) The difficulty
in eliciting broadly neutralizing antibody responses against HIV has posed a
particularly difficult challenge to the development of a protective HIV vaccine.
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