Page 11 - AIDSBK23C

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HIV-1 can upregulate pro-inflammatory cytokine production by genital epithelial cells, including
tumour necrosis factor (TNF)-α that impaires the tight junction barrier, allowing HIV-1 and
luminal bacteria to translocate across the epithelium.[39]
Endothelium may also harbor HIV virions following parenteral transmission and during
HIV viremia following infection. Endothelial cells express surface syndecans that mediate
adsorption of HIV by binding of viral gp120 to heparan sulfate chains of syndecan. Although
syndecan does not substitute for HIV entry receptors, it enhances infectivity and preserves virus
infectivity for a week, whereas unbound virus loses its infectivity in less than a day. In addition,
the ligand for E-selection (CD62L) is incorporated into the virion during budding and can
enhance virion attachment to endothelial cells and accelerate transfer of HIV to CD4 cells.[40]
HIV primarily infects cells that have CD4 cell-surface receptor molecules, using these
receptors to gain entry. Many cell types share common receptor epitopes, though CD4
lymphocytes play a crucial role. Cells with CD4 receptors susceptible to HIV infection may
include cells of the mononuclear phagocyte system, principally blood monocytes and tissue
macrophages, as well as T lymphocytes, natural killer (NK) lymphocytes, dendritic cells
(epithelial Langerhans cells and follicular dendritic cells in lymph nodes), hematopoietic stromal
cells, and microglial cells in brain. Galactosylceramide expressed by human monocyte derived
immature dendritic cells as well as dendritic cells isolated from blood and mucosal tissue and in
situ on mucosal tissue can act as a mucosal epithelial receptor for gp41 on HIV.[22,41,42]
In addition to the CD4 receptor, a coreceptor known as a chemokine is required for HIV
to infect cells. Chemokines are cell surface membrane-bound fusion-mediating molecules found
on many cells. A diagrammatic representation of the relationship of the chemokine receptor to
the CD4 receptor is shown below.

HIV entry into a host cell begins with gp120 binding to CD4 receptor, which induces a
conformational change in gp120, exposing coreceptor binding sites. The V3 loop region of
gp120 determines whether the host cell CCR5 or CXCR4 chemokine coreceptor will be engaged.
After the chemokine coreceptor is engaged, the gp41 on the HIV surface undergoes a
conformational change. The gp41 transmembrane coreceptor consists of HR1 and HR2 helical
regions along with a fusion peptide. Conformational change in gp41 through HR1 and HR2
interaction leads to formation of a stable structure that allows fusion of HIV and host cell
membranes, with a fusion pore through which the viral core enters the host cell. These cores can
utilize host cell microtubules to move toward the cell nucleus.[43,44]
The chemokine coreceptors include the CXC family (CXCR1 to CXCR5) and the CC
family (CCR1 to CCR9). Their presence on cells can aid binding of the HIV envelope
glycoprotein gp120, promoting infection. Initial binding of HIV to the CD4 receptor is mediated