Page 14 - AIDSBK23C

Page 14

macropinosomes and destroyed, but some HIV becomes localized to intracellular vesicles,
escaping destruction and causing infection.[55]
In addition, peripheral blood monocytes and derivative macrophages express surface
integrins, which are cell adhesion receptors, consisting of noncovalently linked alpha and beta
subunits. Viruses use integrins to enter and exit cells. The alpha-V integrin of macrophages,
when activated, upregulates nuclear factor kappa-B and facilitates production of HIV within the
cell.[56]
Monocytes infected with HIV upregulate production of two cytokines that diminish the
inflammatory response of CD4 lymphocytes. Programmed death-1 (PD-1) is upregulated during
HIV infection when microbial products and the increased amounts of inflammatory cytokines in
the blood of HIV-infected individuals induce the upregulation of PD-1 on monocytes. Once PD-
1 is triggered, it upregulates production of the anti-inflammatory cytokine IL-10 by
monocytes.[57]
Dendritic cells play a key role in HIV infection. Two populations of dendritic cells have
been characterized. The conventional dendritic cells such as Langerhans cells are found in
epithelia and mark with CD11c. They become infected with HIV, and they can transport HIV
via lymph and blood to multiple sites within the body. They secrete interleukin-12 that induces
cytotoxic lymphocyte responses to infection. In contrast, plasmacytoid dendritic cells mainly
circulate in blood but can migrate to many tissue sites. They are CD123 positive and produce
type I interferons that can stimulate conventional dendritic cells. Dendritic cells circulating in
blood tend to decrease inversely in proportion to the increase in HIV viremia. This may be due
to apoptosis of HIV-infected dendritic cells, redistribution to lymphoid organs, or to decreased
production.[58]
Both conventional and plasmacytoid dendritic cells can activate NK cells, which provide
an innate immune response. However, the HIV nef gene encodes a protein that downregulates
HLA-A and B, but not C, expression of infected cells to evade cytotoxic lymphocyte responses
and killing by NK cells that recognize mainly HLA-C. Also, HIV reduces cytokines that activate
NK cells. Dendritic cells infected with HIV become resistant to NK cell destruction.[58]
The HIV envelope glycoprotein gp120 may affect the physiologic functions of NK cells.
The gp120 suppresses NK cell cytotoxicity, proliferation, and the ability to secrete IFN-gamma.
Extended exposure to HIV gp120 resulted in apoptosis of NK cells. These effects upon NK cells
aid in diminishing the innate immune response to HIV infection and make establishment of HIV
infection at the site of entry more likely.[59]
Within the lymph nodes, HIV virions are trapped in the processes of follicular dendritic
cells, where they reside in endosomal compartments formed from invaginations of cell surface
membrane. These compartmentalized virions in dendritic cells may infect CD4 lymphocytes that
are percolating through the node. Langerhans cells in the epithelia function similarly. The
dendritic cells themselves may become infected, but are not destroyed.[50] Stromal dendritic
cells can become infected via the chemokine receptor pathway, but also have a surface protein
called dendritic cell-specific ICAM3-grabbing non-integrin (DC-SIGN) that can capture HIV by
binding to the HIV envelope. DC-SIGN-bound HIV is more infectious and has a longer half-life
than free HIV.[55] Dendritic cells can migrate in lymph and blood to carry HIV throughout the
body.[60] The presence of gp120 of HIV appears to reduce the capacity of dendritic cells to
produce interleukin-12, suppressing cell-mediated immune responses.[61]
Within the cytoplasm of an infected cell, HIV reverse transcription begins in a reverse
transcription complex (RTC). The RTC complex migrates to the cell nucleus. Proviral DNA is