Page 572 - Clinical Immunology_ Principles and Practice ( PDFDrive )

CHaPTEr 39 HIV and Acquired Immunodeficiency Syndrome 549

CD4 T-cell count, and larger viral inoculum size are all associated After approximately 1 week, the virus becomes detectable in
with a greater risk of transmission. draining regional lymph nodes. Myeloid DCs are not infected
Sexual transmission is the most common mode of infection, with HIV; rather, HIV gp120 binds to DC-specific intercellular
responsible for 70–80% of worldwide infections. Besides the adhesion molecule–grabbing nonintegrin (DC-SIGN) in the cell
factors mentioned above, recipients in penetrative intercourse membrane. The resulting complex is internalized as a phagosome
are more likely to become infected. Anal intercourse carries the and then presented on the cell surface. As there is no fusion of
greatest risk, followed by vaginal intercourse, and oral intercourse the HIV Env with the DC membrane, infection does not occur.
is the least likely to spread the virus. The presence of other Plasmacytoid DCs, in contrast, express CD4 and the coreceptors
sexually transmitted diseases, especially ulcerative lesions, such CXCR4 and CCR5 and thus become infected by the virus. Infec-
as those seen in herpes simplex or syphilis infection, increases tion leads to expression of CCR7, which acts as a homing signal
the risk of transmission. for the lymph nodes; it is in lymph nodes that the virus infects
Parenteral transmission is the second most common route CD4 T cells, and significant viral replication occurs, resulting
of HIV infection, accounting for 8–15% of all HIV infections. in detectable viremia and dissemination through lymphoid tissues.
Examples include contaminated needles used by people who Of interest, the target cells for HIV infection, CD4 T cells and
are addicted to intravenous drug use (IDU), accidental needle monocyte/macrophage cells, are also reservoirs for the virus.
sticks occurring in health care workers, improperly sterilized HIV-infected cells carry a stable provirus integrated in the cell
hospital equipment, and contaminated blood products. Use of genome, which is transcriptionally silent until the cell is activated.
contaminated needles by people addicted to IDU is the largest risk These cells can reestablish HIV viremia even after prolonged
factor for parenteral transmission. In 2013, 7% of the estimated antiviral treatment, since viral reservoirs are unlikely to be soon
47 500 new HIV infections in the United States were attributed eradicated.
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to IDU. Although infection control efforts have greatly reduced
the risk, HIV transmission via transfusion of contaminated blood Gastrointestinal System: Early Target
products remains significant, particularly in resource-limited Within days of infection, 20% of CD4 T cells found in the GALT
settings where there is a dependence on replacement of blood are infected. Of these, up to 80% are killed, by lytic infection
by family member donors and paid blood donors and where and Fas-mediated apoptosis of both infected and noninfected
+
+
the infrastructure for routine blood screening is suboptimal. cells, mainly CD4 CCR5 memory T cells. By the time of peak
Perinatal transmission accounts for the majority of pediatric HIV viremia, 60% of the mucosal memory CD4 T cells are infected.
cases and for 5–10% of HIV infections in patients of all ages. The Because their destruction is less drastic, circulating CD4 T-cell
virus is capable of infecting the child in utero, during labor, and after counts do not reflect the magnitude of CD4 T-cell death taking
delivery through breastfeeding. Without preventive therapy, the risk place in the GALT. Following acute HIV infection, a massive
of a child contracting HIV from the mother during gestation or activation of the immune system occurs. Inadequate memory
during labor is about 15–40%. The majority of transmission events T-cell responses can lead to infection and inflammation of
occur during the passage of the fetus through the birth canal, by the entire bowel. The presence of immune activators over the
exposure of the baby to infected maternal blood, amniotic fluid, massive surface area of the bowel has been hypothesized to
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and/or cervical and vaginal secretions. Although breastfeeding result in the profound immune activation seen in HIV. Mucosal
increases the risk of transmission of the virus from mother to Th17 cells are a preferential target for HIV, further weakening
child by another 15–29%, breastfeeding is still recommended to mucosal immunity and favoring microbial infection. The viremia
prevent morbidity and mortality related to diarrheal diseases in decreases spontaneously from as high as 10 million copies of
settings where access to replacement feeding is limited. HIV RNA per milliliter during the acute illness phase to a
stable level many orders of magnitude lower called the viral
IMMUNOPATHOGENESIS set point. It is known that higher set points of viral load and
lower T-cell counts are loosely predictive of shorter periods of
The mechanisms of immunodeficiency induced by HIV are not clinical latency. Eventually, a prolonged period of homeostasis
limited to depletion of its main target cell, the CD4 T cell; HIV between the virus and the immune system collapses, and AIDS
infection ultimately leads directly or indirectly to the impairment ensues.
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of every arm of the immune system. The time of progression
from infection to the development of AIDS is not the same Chronic Immune Activation and Progression to AIDS
for all infected individuals, and several explanations have been After the acute stage, HIV infection induces a high degree of
proposed, including genetic resistance genes and the presence proliferation and turnover of CD4 and CD8 T cells. The massive
of low-virulence mutant viral particles. The study of long-term immune activation can be explained by the circulation of many
nonprogressor individuals has helped to define T-cell and antibody soluble factors, including TLR ligands. HIV infection appears
features associated with anti-HIV immunity in the search for to activate plasmacytoid DCs by stimulation of TLR7 to secrete
the optimal vaccine design, focusing on minimizing the escape interferon-α (IFN-) and proinflammatory cytokines, using both
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variants and inducing persistent specific viral neutralization or TLR8 and DC-SIGN to infect these cells. In turn, stimulated
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inhibition of replication. HIV researchers have also explored the DCs activate T cells, which are also being directly activated
role of chronic immune activation processes that are associated through TLR ligands. Bacterial products from the mucosa (e.g.,
with progression to AIDS, which also helps explain the diverse LPS) and HIV protein products, such as Nef, Env, Vif, and so
clinical impact of this viral infection in different individuals. on, are mediators of this immune activation. Other microbial
infections (viral, bacterial, or fungal) can stimulate the different
Mucosal Dendritic Cells: Myeloid Versus Plasmacytoid TLRs and result in CD4 and CD8 T-cell activation and apoptosis.
Following a mucosal inoculation of HIV, CD4 T cells are generally This rampant immune activation is thought to lead to the eventual
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infected by CCR5-tropic virus, also called R5 or M-tropic virus. collapse of the immune system.