Page 392 - Review of Medical Microbiology and Immunology ( PDFDrive )

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mebooksfree.com mebooksfree.com (enfuvirtide, maraviroc) Provirus mebooksfree.com mebooksfree.com mebooksfree.com
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CHAPTER 45 Human Immunodeficiency Virus
381
Inhibited by entry inhibitors
Virion
CD4
Nucleus
CCR5
or CXCR4

inhibitors (raltegravir) mebooksfree.com
mebooksfree.com mebooksfree.com Inhibited by mebooksfree.com mRNAs Translation polyproteins Cleavage mebooksfree.com mebooksfree.com
Integration Transcription
RNA genomes
Reverse
transcription
Precursor
Assembly into
by
nucleocapsid
protease
DNA copy
reverse transcriptase
inhibitors (zidovudine
of genome
and others)
Inhibited
by protease
Inhibited by integrase
inhibitors
(indinavir
and others)
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FIGURE 45–4
Replicative cycle of human immunodeficiency virus (HIV). Showing the sites of action of the important drugs
used to treat HIV infection. The mode of action of the reverse transcriptase inhibitors, the entry inhibitors, the integrase inhibitor, and
the protease inhibitors is described in Chapter 35. On the right side of the figure, “cleavage by protease” describes the process by
which the virus-encoded protease cleaves the Gag-Pol polyprotein into functional viral proteins as the virion buds from the cell mem-
brane. These newly formed functional proteins are transported by the mature virion to the next cell and function within that newly
infected cell. The viral reverse transcriptase and integrase are two such proteins. (Reproduced with permission from Ryan K et al.
Sherris Medical Microbiology. 3rd ed. Originally published by Appleton & Lange. Copyright 1994 McGraw-Hill.)
whereas the macrophage-tropic strains bind to CCR5.
transcriptase, integrase, and protease. The immature virion
Mutations in the gene encoding CCR5 endow the individ-
ual with protection from infection with HIV. People who
containing the precursor polyproteins forms in the cyto-
are homozygotes are completely resistant to infection, and proteins. The Pol polyprotein is cleaved to form the reverse
plasm, and cleavage by the viral protease occurs as the
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immature virion buds from the cell membrane. It is this
heterozygotes progress to disease more slowly. Approxi-
cleavage process that results in the mature, infectious
mately 1% of people of Western European ancestry have
homozygous mutations in this gene, and about 10% to 15%
virion.
Note that HIV replication is dependent on cell proteins
are heterozygotes. One of the best-characterized mutations
is the delta-32 mutation, in which 32 base pairs are deleted
as well as viral proteins. First there are the cell proteins
from the CCR5 gene.
required during the early events, namely CD4, and the che-
In the cytoplasm, reverse transcriptase transcribes the
mokine receptors, CCR5 and CXCR4. Cell proteins, such as
genome RNA into double-stranded DNA, which migrates
actin and tubulin, are involved with the movement of viral
DNA into the nucleus. The cell protein cyclin T1 and the
to the nucleus, where it integrates into the host cell DNA.
The viral DNA can integrate at different sites in the host
cell DNA, and multiple copies of viral DNA can integrate.
viral mRNA. Cell proteins are also involved in the budding
Integration is mediated by a virus-encoded endonuclease
(integrase). Viral mRNA is transcribed from the integrated viral protein Tat are part of the complex that transcribes
(proviral) DNA by host cell RNA polymerase (augmented
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Transmission & Epidemiology
by virus-encoded Tat protein) and translated into several
Transmission of HIV occurs primarily by sexual contact
large polyproteins. The Gag and Pol polyproteins are
cleaved by the viral protease, whereas the Env polyprotein
is cleaved by a cellular protease.
from infected mother to neonate also occurs, either across
The Gag polyprotein is cleaved to form the main core
the placenta, at birth, or via breast milk. It is estimated that
protein (p24), the matrix protein (p17), and several smaller
more than 50% of neonatal infections occur at the time of
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