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then transcribed. Proviral DNA is detectable within hours in infected CD4 lymphocytes, but
may require 36 to 48 hours to appear within macrophages. Integration of HIV into host cellular
DNA can occur without mitosis.[55]
Most HIV infections likely begin from a single virus—a "founder" virus, from which
subsequent clones develop. The initial infectious process is inefficient because the virus persists
poorly in the environment and must find a host cell quickly, so most virions perish. Host cells
elaborate an antiviral apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like-3G
(APOBEC3G) with cytidine deaminase activity that leads to defective viral replication. In
addition, the HIV gene for reverse transcriptase has a high mutation rate and a high rate of error
for reverse transcription. Thus, most initial HIV interactions with host cells do not result in
established infections.[62]
After initial entry of HIV into host cells and establishment of infection, HIV virions are
released from infected cells, may then enter the systemic circulation, and are carried to
widespread sites within the body. Cells of the mononuclear phagocyte system, including those in
lymph nodes, spleen, liver, and bone marrow can then become infected with HIV. Besides
lymph nodes, the gut associated lymphoid tissue in gastrointestinal submucosa provides a
substantial reservoir for HIV. Primary HIV infection is followed by a burst of viremia in which
virus is easily detected in peripheral blood in mononuclear cells and plasma. In the period of
clinical latency of HIV infection, there is little detectable virus in peripheral blood, but viral
replication actively continues in lymphoid tissues.[54]
Infection of the central nervous system by HIV requires that HIV-infected peripheral
blood mononuclear cells cross the blood-brain barrier. Then infection of macrophages and
microglial cells can occur. The immune activation leads to release of neurotoxic factors that
further stimulate microglial activation along with neuronal apoptosis.[55]
Once the HIV proviral DNA is within the infected cell's genome, it cannot be eliminated
or destroyed except by destroying the cell itself. The HIV proviral DNA then directs its
replication by infected host cells. This replication may first occur within inflammatory cells at
the site of infection or within peripheral blood mononuclear cells (CD4 lymphocytes and
monocytes) but then the major site of replication quickly shifts to lymphoid tissues of the body
(lymph nodes and gastrointestinal tract). The initial burst of viral replication that follows
infection is followed by replication at a lower level, which accounts for the clinically apparent
latency of infection. However, viral replication is stimulated by a variety of cytokines such as
interleukins and tumor necrosis factor, which activate CD4 lymphocytes and make them more
susceptible to HIV infection.[32,51]
Activation of viral synthesis leads to release of new infective particles from the host cell
surface by budding. Replication may also cause cell lysis with release of additional infective
viral particles. Host cell death may be mediated via several diverse mechanisms: direct viral
cytopathic effects, fusion to multinucleated giant cells (syncytia formation), cytotoxic immune
response by other lymphocytes (CD8+ cytotoxic T-lymphocytes), autoimmune mechanisms,
disruptive interaction of HIV envelope proteins with the cell membrane, immune clearance from
alteration of antigenicity of the host cell, activation of apoptosis (programmed cell death), or
toxic accumulation of viral DNA, RNA, or proteins.[21,22,32,51]
Apoptosis plays a key role in the decline in T cell numbers during HIV infection. Acute
HIV infection results in immune activation with apoptosis of infected lymphocytes. Expression
of tumor necrosis factor (TNF) related apoptosis-inducing ligand (TRAIL) and FAS ligand
increase and have a paracrine effect to promote further apoptosis of bystander cells.[62]