Page 13 - AIDSBK23C

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into their functional forms.[32,51,52]
The principal constituent of HIV-1 is Gag, accounting for half the entire virion mass.
Viral membrane lipids account for about a third of the mass, and other viral and cellular proteins
together contribute an additional 20%. The HIV-1 genomic RNA and other small RNAs
comprise only 2.5% of virion mass. The Gag, Gag-Pro-Pol, Env, the two copies of genomic
RNA, the tRNA primer, and the lipid envelope are all necessary for viral replication. HIV gene
products are encoded on the genomic RNA, which also serves as mRNA for Gag and Gag-Pro-
Pol, whereas singly or multiply spliced RNAs are translated to produce Env and accessory
proteins, respectively. The HIV Gag and Gag-Pro-Pol proteins move from cytoplasmic sites of
synthesis to the infected cell plasma membrane. These proteins then sort into detergent-resistant
membrane microdomains. Virion productionis cholesterol and sphingolipid dependent, and the
virus is enriched in “raft”-associated proteins and lipids from the host cell membrane. The viral
Env glycoproteins reach the plasma membrane independently of Gag.[30,53]
Viral maturation begins along with, or immediately following, virion budding, and is
driven by viral PR cleavage of the Gag and Gag-Pro-Pol polyproteins at ten different sites.
Assembly of HIV requires the viral Gag protein, a multi-domain polyprotein with three folded
domains: matrix (MA), capsid (CA) and nucleocapsid (NC). There are three shorter peptides
SP1, SP2 and p6. The virus is initially formed as a noninfectious, immature virion, containing
largely uncleaved Gag polyproteins. Formation of an infectious virion requires processing of
Gag by HIV protease at five specific sites, leading to separation of functional domains and a
dramatic rearrangement of the interior virion organization.[30,53]
Maturation produces the fully processed components MA, CA, NC, p6, protease, reverse
transcriptase, and integrase proteins, which rearrange to create a mature infectious virion. With
viral assembly two copies of the capped and polyadenylated full-length RNA genome are
incorporated into the virion. The outer capsid shell of the core particle is typically conical and
consists of roughly 250 hexameric subunits with a 9.6-nm hexamer–hexamer spacing and
exactly 12 pentamers, 5 at the narrow and 7 at the broad end. The capsid approaches the matrix
closely at both ends. The capsid surrounds the nucleocapsid, which typically resides at the wide
end of the capsid.[30,53]
Release of HIV from the host cell occurs in several steps. The p55 protein of HIV directs
formation of a capsid (CA) protein that surrounds the RNA of HIV, a nucleocapsid (NC) protein
that interacts with the RNA within the capsid, and matrix (MA) protein that surrounds the capsid
and lies just beneath the viral envelope. A protease enzyme encoded by the pol gene of HIV
cleaves the large precursor proteins to produce the MA, CA, and NC proteins. Budding virions
utilize host cell membrane to help form the outer virion envelope of the budding virion necessary
for production of infectious particles. The process of viral budding relies on cellular endosomal
sorting complexes required for transport (ESCRT) that sort proteins and form multvesicular
bodies (MVBs) that are intermediates in the formation of secretory lysosomes.[43,53]
Infective virions can enter susceptible host cells. Most often, cells with CD4 receptors at
the site of HIV entry become infected and viral replication begins within them. The infected
cells can then release virions by surface budding, or infected cells can undergo lysis with release
of new HIV virions, which can then infect additional cells. Some of the HIV virions are carried
via the lymphatics to regional lymph nodes.[32,51,54]
Though most macrophages become infected via HIV binding to gp120 and chemokine
coreceptor with cell membrane fusion, macropinocytosis without cell surface binding can
introduce HIV into macrophages. Most of the HIV is taken up into cytoplasmic