Immunotherapy for Infectious Diseases

154 Fox
receptor binding by the V3 loop is the next key step, which confers infectious tropism
depending on the host receptor that the virus is able to utilize. Early in HIV infection,
the infecting strains are typically best able to bind to the receptor CCR5 and are
macrophage-tropic (13–17). With disease progression, more pathogenic strains arise that
are able to bind to CXCR4 (18). These strains are able to replicate in transformed T-cell
lines that express CXCR4, but not CCR5, and they induce syncytium formation. Other
chemokine receptors have also been identified that HIV strains are able to utilize.
Resistance to HIV infection has been linked to production of high levels of the natural
ligands for these receptors, competing for binding with HIV (19,20), and with
mutations in the genes coding for the receptors, yielding a poor match for HIV binding
(21–23). Following binding by gp120 to both primary and secondary receptors,
gp41 binding leads to fusion of viral and host cell membranes, uncoating of the HIV
genomic RNA and its associated proteins, and its entry into the cell. HIV reverse transcriptase
then makes a double-stranded DNA copy of the viral RNA, which is transported
to the nucleus and integrated into the host cell chromosome by the viral integrase
enzyme. The relative infidelity of the reverse transcriptase enzyme to the RNA template
leads to a high mutation rate. Transcription of the integrated provirus is dependent
on host cell activation and DNA-dependent RNA-polymerase activity. Initially,
double-spliced viral mRNA is produced, coding for viral proteins. Later, as a result of
the action of the HIV rev gene product, single-spliced and full-length HIV genomic
RNA is produced and transported to the cytoplasm, where it is encapsulated in viral
proteins. The virion buds from the host cell membrane and then matures into an infectious
virus particle after cleavage of immature viral proteins by HIV protease. Each
step of this complex life cycle presents opportunities for intervention with antiviral
agents.
PATHOLOGIC MANIFESTATIONS
Host Response
HIV disease is characterized by immune activation, which becomes chronic owing
to its failure to clear the infection. This eventually leads to exhaustion of immunologic
resistance and vulnerability to opportunistic disease. The unremitting inflammatory
immune response also results in tissue damage, contributing to wasting, renal disease,
cardiac disease, dementia, and neuropathy. Proinflammatory cytokines have been
shown to stimulate HIV replication; therefore this response, which is elicited by HIV
antigens, contributes to persistence of infection (24). The viremia during acute HIV
infection falls as HIV is sequestered in lymphoid tissue, largely bound to follicular dendritic
cells (FDCs), and as cytotoxic lymphocyte (CTL) response to HIV arises. Both
infected and uninfected T-lymphocytes are also sequestered in the lymphoid tissues, in
response to cytokine signaling and adhesion molecule expression. A significant amount
of neutralizing antibody to HIV is usually detectable in the peripheral blood weeks
after the plasma viral burden has fallen, suggesting that cell-mediated immunity is the
more important initial host immune response (25).
Studies of the breadth of CTL receptor V-� repertoire demonstrated more rapid disease
progression when the repertoire was most limited (26). In contrast to the fall in
CD4� T-cell numbers and function, CD8� T-cells are increased in both number and