Page 19 - AIDSBK23C

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drug resistance as well as the variability in pathologic lesions as different cell types are targeted
or different cytopathic effects are elicited during the course of infection.[22,84,85]
Active replication of HIV occurs at all stages of the infection. However, a month after
initial infection and peak viremia occur, equilibrium begins to be established between HIV
replication and control of HIV by the host immune system. In general, clearance rates of HIV
are similar among persons, but the rate of HIV production determines the viral load in the steady
state. This marks the clinically latent phase of HIV infection. The presence of viremia, as
detected by serum HIV-1 RNA, suggests that the immune system is less able to contain the virus.
Increasing levels of serum HIV-1 RNA suggest a loss of the equilibrium and emergence from
latency to a more rapid progression to AIDS. The absence of a detectable serum HIV-1 RNA
suggests a slower progression to clinical AIDS. Greater HIV-1 RNA levels in patients with
symptomatic acute HIV infection suggest that such persons may progress more rapidly to
AIDS.[86] As the number of CD4 cells diminishes in the late stages of AIDS, macrophages still
serve as key sites for continuing viral replication.[55]
Cytokine activation of CD4 lymphocytes can increase the production of HIV by infected
cells. Activated T cells increase intracellular nuclear factor kappa B (NF-kB) levels, which
enhances proviral transcription to generate new virions. Proinflammatory cytokines that
stimulate virion production include tumor necrosis factor alpha (TNF-α), interleukin 1 (IL-2),
and interleukin 6 (IL-6).[87]
Innate immune responses may play a role in HIV replication. A population of T
lymphocytes in the gut mucosa, known as gamma delta T cells, is a first line of defense against
intestinal pathogens. They have been shown to produce TH1 and TH2 types of cytokines, as
well as viral suppressive factors including RANTES. Alpha and beta interferons produced in
response to viral infection can promote a TH1 response and help prevent T lymphocyte
apoptosis. The CC cytokines produced by activation of macrophages, dendritic cells, T cells,
NK cells, and gamma delta lymphocytes can block CCR5 coreceptors of HIV. Apolipoprotein B
mRNA-editing, enzyme-catalytic polypeptide-like-3G, or APOBEC3G, is an intracellular anti-
viral factor that can inhibit HIV. However, HIV can produce compounds that counter these
innate immune mechanisms.[34,88]
Virally infected cells that produce interferons may diminish HIV replication via protein
products upregulated by the interferons. One such protein is tetherin, a transmembrane cell
protein. Tetherin forms a membrane anchor to entrap enveloped virions and prevent their release
from the cell. Reduction in release of virions will diminish viremia.[89]
Genetic variability in HIV also leads to differences in biological phenotypic
characteristics of viral pathogenic effects. HIV can be divided into three groups: (1) non-
syncytium-inducing (NSI) variants that have a low replicative capacity; (2) non-syncytium-
inducing variants with a high replicative capacity; and (3) syncytium-inducing (SI) variants.
From 30 to 60% of HIV-infected persons may eventually develop such variants. The SI variants
appear to evolve from NSI variants, with a change in surface gp120, during the course of HIV
infection, usually at a time marked by a peripheral blood CD4 lymphocyte count between 400
and 500/µL. SI variants use the CCR5 chemokine receptor for cell entry, while NSI strains use
CXCR4 receptors. The appearance of SI variants is associated with CD4+ cell tropism, rapid
CD4+ cell decline, higher HIV-1 RNA plasma levels, symptomatic HIV disease, male sex, and
rapid progression of HIV infection. However, only about half of patients with AIDS have the SI
variants, and NSI variants can also be seen with disease progression.[86,90]