Page 571 - Clinical Immunology_ Principles and Practice ( PDFDrive )

548 ParT fOur Immunological Deficiencies

of these receptors compared with CD4 T cells. After the virus blood. They might produce very low levels of viral RNA and
is attached to the cell, the viral membrane fuses with the cell proteins and therefore might not be detected by immunosurveil-
membrane and viral RNA enters the cytoplasm. It is transcribed lance. HIV reservoirs are established during the acute phase of
by the viral reverse transcriptase into double-stranded DNA, the infection, hence the recommendation for early intensive
which is translocated to the cell nucleus, and the virus integrase treatment to reduce the population of latently infected CD4 T
enzyme mediates its integration into the cell genome. The viral cells (nonreplicating monocytes, astrocytes, and glial cells are
proteins Tat and Nef, in addition to T-cell activation factors, other latently infected cells). Molecular mechanisms that inhibit
induce active transcription and expression of viral RNA and HIV replication from viral DNA and maintain latent infection
proteins to produce new virus particles that exit the host cell to include histone deacetylases and methyl transferases with methyla-
infect other cells. CD4-independent viral entry has been demon- tion of viral genes, especially of the long-terminal promoter
strated in B cells, astrocytes, and kidney epithelial cells; however, repeat. These epigenetic modifications can be reversed by using
efficient viral replication is not likely to occur in these cells (see T-cell activation signals.
Treatment).
HIV Entry Through Mucosal Surfaces ANTI-HIV IMMUNITY
Using dilution techniques that can precisely determine unique Immunity against HIV depends mostly on specific cytotoxic
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virion genome sequences, it was found that about 80% of HIV CD8 T cells, which recognize and destroy infected cells. These
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infections via heterosexual transmission start with a single virion. antiviral cells are most efficient when certain combinations of
This is remarkable, considering the high rate of mutation and human leukocyte antigen (HLA) and virus strain occur in the
diversity of viral genome sequences found in infected individuals. host, such as the presence of a cell bearing the HLA-B27 allele
In contrast, HIV transmission occurring in MSM and in intra- and infected with clade B viral strain. However, HIV infection
venous drug users is caused by several viral variants, indicating almost always results in global T-cell destruction and exhaustion.
that the multilayered epithelia of the vaginal mucosa and the Antibody responses are initially directed against the gp41 portion
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cervical mucus are likely deterrents for lentiviral infection. of the Env protein. This response and subsequent anti-HIV
Regardless of the route of infection, the time to develop viremia antibodies become ineffective because of the rapid production
and immunological changes is similar to that of all forms of of escape mutants.
transmission. Viral replication can be detected in the germinal
center of lymph nodes within a week, and viremia is found HIV Vaccines: Basic Concepts
within 21 days of infection. The most active replication occurs Several efforts to develop an effective anti-HIV vaccine have
in the gut-associated lymphoid tissue (GALT), with massive attempted to address the genetic diversity of HIV that develops
depletion of CD4 T cells. Activation and destruction of CD4 T in the infected individual, by identifying epitopes that remain
cells are associated with an increase of serum cytokines, which relatively conserved and by inducing neutralizing antibodies as
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might explain the flu-like syndrome that patients might experience well as cell-mediated immunity. Broadly neutralizing antibodies,
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during acute HIV infection. Simultaneously, HIV reservoirs which target conserved Env epitopes from different strains and
become established with viral infection and integration of viral can prevent HIV from establishing infection, might develop in
DNA in resting cells. some individuals with chronic infection, offering hope for disease
prevention. Such antibodies are found to develop after approxi-
T-cell Depletion mately 2 years of infection, when many generations of escape
Progressive T-cell depletion in HIV infection is induced, in part, virions, inducing new antibody epitopes, allow the immune
by a state of chronic immune activation, which also contributes response to refine and select for best affinity. This concept suggests
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to noninfectious complications, such as cardiovascular disease. that several booster immunizations might reproduce the process
In individuals with HIV infection, immune activation is caused in shorter time. Current approaches involve viral vectors that
by increased microbial translocation in the gut, direct Toll-like drive the expression of HIV proteins in host tissue; an example
receptor (TLR) stimulation by HIV, and coinfection with other is a canary pox virus carrying the HIV env gene. No current
pathogens. This activated state results in increased levels of inflam- vaccines have been able to induce high titers of broadly neutral-
matory cytokines, such as interleukin-6 (IL-6). Also detected is an izing antibodies against HIV Env. Of note, an unexpected,
increase of lipopolysaccharide (LPS) in blood, which, in turn, can although modest, increased rate of HIV infection was observed
also activate the coagulation cascade and promote thrombosis. in individuals immunized with an adenovirus-based HIV vaccine
Low or normal levels of T regulatory cells (Tregs) are observed compared with nonimmunized individuals and was highest in
in long-term nonprogressors, suggesting their role in anti-HIV persons who had antiadenovirus antibodies before the trial. The
immunity, especially in modulating CD8 T-cell immunity. It mechanisms explaining this increased infection rate are not clear.
has also been suggested that Tregs may play a beneficial role by Results from the RV144 clinical trial conducted in Thailand
reducing chronic immune activation. 8 showing a 31% reduction of HIV transmission demonstrated
that vaccine protection may be a reality. New vector approaches,
HIV Latency and HIV Reservoirs improving T-cell responses and achieving high titers of broadly
The most difficult problem in the efforts toward achieving a neutralizing vaccines, are being investigated to increase vaccine
cure for HIV infection is the presence of HIV reservoirs, defined efficacy (see HIV preventive vaccines).
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as resting or nonreplicating cells infected with HIV. Anti HIV
drugs are able to efficiently suppress HIV replication; however, ROUTES OF INFECTION
when these drugs are stopped, activation of the resting cells
results in the production of new virus. Most viral DNA is detected HIV is transmitted through three routes of infection: sexual,
in memory CD4 T cells within lymphoid tissues and peripheral parenteral, and perinatal. In general, higher viral loads, lower