Page 18 - AIDSBK23C

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Memory T lymphocytes play a role in maintenance of HIV infection. Resting memory
cells are long-lived. Memory CD4 cells that become infected with HIV constitute a significant
reservoir for transcriptionally silent provirus. They remain unaffected by antiretroviral treatment
and provide a source for continuing infection.[80] In addition, CD4+ CCR5+ memory T cells in
GALT become infected in high numbers, while induction with activation of remaining
uninfected CD4+ cells leads to their apoptosis, quickly depleting CD4 lymphocyte numbers.[62]
The magnitude of HIV-1 production in infected persons is enormous. The numbers of
"productively infected cells" (those cells with 20 or more copies of HIV-1 RNA) are initially
quite high. Within 3 to 4 weeks following initial HIV infection, a peak viremia occurs. The
HIV-1 RNA level at this peak is often in the range of 1,000,000 copies/mL. CD4 cell numbers,
in contrast, are falling at peak viremia.[62]
When primary HIV-1 infection occurs, most of the productively infected cells are CD4
lymphocytes, accounting for about 80% of all infected cells at the site(s) of mucosal inoculation
and 90% of infected cells in lymphoid tissues. However, follicular dendritic cells (FDCs) within
the lymphoid tissues provide the greatest reservoir in well-established HIV-1 infections,
particularly throughout the clinically latent period before the onset of AIDS, harboring an
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estimated 10 copies of HIV-1 RNA. The pool of 10 to 10 productively infected CD4 cells
within the body, averaging 50 - 100 copies per cell, gradually diminishes over time, eventually
leading to immune failure and the onset of AIDS. The total virion production per day in an
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10
infected person averages greater than 10 to 10 copies. Additional reservoirs of HIV-infected
cells may be present in the central nervous system, lung, and liver.[81,82]
Since the HIV provirus becomes part of the infected host's cellular DNA, the host's cells
may be infectious even in the absence of a demonstrable HIV serum viremia or detectable HIV
antibodies.[51] However, antibodies formed against HIV are not protective, and a viremic state
can persist despite the presence of even high antibody titers. HIV has the additional ability to
mutate easily, in large part due to the error rate in production of the reverse transcriptase enzyme,
which introduces a mutation approximately once per 2000 incorporated nucleotides. This high
mutation rate leads to the emergence of HIV variants within the infected person's cells that can
then resist immune attack, exhibit greater cytotoxicity, generate syncytia more readily, or can
impart drug resistance. Over time, various tissues of the infected host’s body may harbor
differing HIV variants.[21,22,29,83]
Moreover, the primary target of HIV is the immune system itself, which is gradually
destroyed. Viral replication actively continues following initial HIV infection, and the rate of
CD4 lymphocyte destruction is progressive. Clinically, HIV infection may appear "latent" for
years during this period of ongoing immune system destruction. During this time, enough of the
immune system remains intact to provide immune surveillance and prevent most infections.
Eventually, when a significant number of CD4 lymphocytes have been destroyed and when
production of new CD4 cells cannot match destruction, then failure of the immune system leads
to the appearance of clinical AIDS.[22,29]
HIV infection is sustained through continuous viral replication with reinfection of
additional host cells. Both HIV in host plasma and HIV-infected host cells appears to have a
short lifespan, and late in the course of AIDS, the half-life of plasma HIV is only about 2 days.
Thus, the persistent viremia requires continuous reinfection of new CD4 lymphocytes followed
by viral replication and cell turnover. This rapid turnover of HIV and CD4 lymphocytes
promotes the origin of new strains of HIV because of the continuing mutation of HIV. Presence
or emergence of different HIV subtypes may also account for the appearance of antiretroviral