Spatial Aspects of HIV Infection - Mathematical Methods and Models in Biomedicine - page 6

of infection, as these cells tend to be spatially dispersed in the cervical mucosa
(see [ 43 ] and references therein). During simian immunodeficiency virus (SIV)
infection of the genital mucosa of macaques only a very small fraction of the viral
inoculum establishes infection and the infection is initially established in a highly
focal manner [ 81 ]. Furthermore, in many cases infection is established by a single
transmitted founder virus [ 56 ]. These observations indicate the blocking effect of
the epithelial barrier and the need for a close proximity of susceptible target cells
next to the portal of entry. Continuous viral production and sufficient expansion
of the founder population of infected cells are crucial for the establishment of
a systemic infection by SIV and HIV [ 42 , 81 ]. The local influx of inflammatory
cells into the sites of infection and the activation of nearby resting CD4 + T cell
populations create new target cells for the virus [ 43 , 47 ] allowing the infection to
get established. Furthermore, productively infected CD4 + T cells and stromal
dendritic cells or Langerhans cells harboring virions can emigrate into the draining
lymphatic system and spread the infection to different anatomical compartments
such as lymph nodes [ 47 ].
Once an infection is established, the dynamics of the cell populations involved
varies between different compartments within a host. While the CD4 + T cell
population in mucosal tissue is massively depleted during the first weeks of infection
[ 107 ], this loss is not reflected in the peripheral-blood CD4 + T cell count [ 40 ].
In SIV and HIV, several studies have estimated different clearance rates of the virus
in different compartments [ 27 , 85 , 127 , 128 ]. Furthermore, some cell populations
such as follicular dendritic cells in secondary lymphoid organs can act as a reservoir
for HIV and maintain the infection even in the presence of host immune defenses
and antiretroviral therapy [ 46 , 48 - 50 , 115 ].
The way by which HIV spreads inside a specific organ or tissue can also
affect the infection dynamics. Besides the infection of cells by freely diffusing
viral particles, HIV, as do several other viruses, has the ability to spread by cell-
to-cell transmission [ 43 , 114 ]. While free virus transmission allows the virus to
spread rapidly through the blood and lymph and to infect distant tissues, the virus
is vulnerable to antibody-mediated neutralization, opsonization, and phagocytosis.
Besides antibodies other plasma components, such as complement, may also interact
with free virions and reduce their infectivity or hasten their destruction. In contrast,
cell-to-cell transmission of viral particles allows the virus to avoid exposure to
plasma components, such as antibody and complement, and phagocytic cells.
However, cell-to-cell transmission only allows the infection of nearby target cells,
making the spread of infection dependent on the local availability of target cells.
This could lead to the establishment of foci of infected cells [ 81 ] and can cause
the infection to move like a traveling wave through the tissue [ 7 ]. In vitro HIV
transmission has been observed to occur during direct cell-cell contact via so-
called “virological synapses” between target T cells and infected cells [ 52 , 53 , 72 ]
or via long-ranging nanotubes between T cells [ 118 ]. Because multiple viruses or
viral genomes can be transmitted by these processes, cell-to-cell transmission has
been estimated to be much more efficient than transmission via free viral particles,
with estimates ranging between 10-fold and up to 18,000-fold [ 22 , 70 , 113 , 117 ].