Page 390 - Review of Medical Microbiology and Immunology ( PDFDrive )

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CHAPTER 45 Human Immunodeficiency Virus
env
gp41
gp120 and gp41.
Reverse
Differences in the base sequence of the gp120 gene are
transcriptase
used to subdivide HIV into subtypes called clades. Differ-
ent clades are found in different areas of the world. For
env
gp120
America. Subtype B preferentially infects mononuclear
RNA
cells and appears to be passed readily during anal sex,
whereas subtype E preferentially infects female genital tract
p17 matrix example, the B clade is the most common subtype in North
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cells and appears to be passed readily during vaginal sex.
protein
Three enzymes are located within the nucleocapsid of
the virion: reverse transcriptase, integrase, and protease
Lipid bilayer
gag
p24
Reverse transcriptase is the RNA-dependent DNA poly-
FIGURE 45–2
Cross-section of human immunodeficiency virus
merase that is the source of the family name retroviruses.
(HIV). In the interior, two molecules of viral RNA are shown associ-
This enzyme transcribes the RNA genome into the proviral
ated with reverse transcriptase. Surrounding those structures is a
DNA. Reverse transcriptase is a bifunctional enzyme; it
rectangular nucleocapsid composed of p24 proteins. Note that the
also has ribonuclease H activity. Ribonuclease H degrades
viral protease and integrase are also located within the nucleocapsid
RNA when it is in the form of an RNA–DNA hybrid mol-
(in addition to the reverse transcriptase), but, for lack of space, are
not shown in the figure. On the exterior are the two envelope pro-
teins, gp120 and gp41, which are embedded in the lipid bilayer
essential step in the synthesis of the double-stranded provi-
derived from the cell membrane. (Reproduced with permission from Green
ral DNA. Integrase, another important enzyme within the
WC. Mechanisms of disease: the molecular biology of human immunodeficiency ecule. The degradation of the viral RNA genome is an
virion, mediates the integration of the proviral DNA into
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virus type I infection. NEJM. 1991;324[5]:309.)
the host cell DNA. The viral protease cleaves the precursor
polyproteins into functional viral polypeptides.
One essential regulatory gene is the tat (transactivation
medically as it is the antigen in the initial serological test
1
that determines whether the patient has antibody to HIV
enhances viral (and perhaps cellular) gene transcription.
(i.e., has been infected with HIV). (See “Laboratory Diag-
The Tat protein and another HIV-encoded regulatory
nosis” section in this chapter.)
protein called Nef repress the synthesis of class I major his-
The pol gene encodes several proteins, including the
tocompatibility complex (MHC) proteins, thereby reducing
virion “reverse transcriptase,” which synthesizes DNA by
the ability of cytotoxic T cells to kill HIV-infected cells. The
using the genome RNA as a template, an integrase that
integrates the viral DNA into the cellular DNA, and a pro-
late mRNA from the nucleus into the cytoplasm. The func-
tease that cleaves the various viral precursor proteins. The
tion of the four accessory genes is described in Table 45–1.
env gene encodes gp160, a precursor glycoprotein that is other essential regulatory gene, rev, controls the passage of
The accessory protein Vif (viral infectivity) enhances
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HIV infectivity by inhibiting the action of APOBEC3G, an
enzyme that causes hypermutation in retroviral DNA.
pol
env
gag
that deaminates cytosines in both mRNA and retroviral
p24 *
INT gp120
LTR
PROT
5'
DNA, thereby inactivating these molecules and reducing
REV NEF
infectivity. APOBEC3G is considered to be an important
FIGURE 45–3
member of the innate host defenses against retroviral infec-
The genome of human immunodeficiency virus
tion. HIV defends itself against this innate host defense by
(HIV). Above the line are the three genes for the main structural pro-
producing Vif, which counteracts APOBEC3G, thereby
teins: (1) gag encodes the internal group-specific antigens (e.g., p24);
(2) pol encodes proteins that have four enzymatic activities: protease
(PROT), polymerase that functions as a reverse transcriptase (POL),
There are several important antigens of HIV:
RNase H (H), and integrase (INT); (3) env encodes the two envelope
(1) gp120 and gp41 are the type-specific envelope gly-
glycoproteins, gp120 and gp41. Below the line are five regulatory preventing hypermutation from occurring.
coproteins. gp120 protrudes from the surface and interacts
proteins: viral infectivity factor (VIF), transactivating protein (TAT),
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with the CD4 receptor (and a second protein, a chemokine
viral protein U (VPU), regulator of expression of virion protein (REV),
and negative regulatory factor (NEF). At both ends are long terminal
repeats (LTR), which are transcription initiation sites. Within the 5′ LTR
is the binding site for the TAT protein, called the transactivation
Transactivation refers to activation of transcription of genes distant from
response element (TAR). TAT enhances the initiation and elongation
of viral mRNA transcription. (*p24 and other smaller proteins such as
DNA). One site of action of the Tat protein is the long terminal repeat at
the 5′ end of the viral genome.
p17 and p7 are encoded by the gag gene.)
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