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by conformational changes in the gp120 subunit, but such conformational changes are not
sufficient for fusion. The chemokine receptors produce a conformational change in the gp41
subunit of HIV, which allows fusion of HIV.[45]
The differences in chemokine coreceptors that are present on a cell also explain how
different strains of HIV may infect cells selectively. There are strains of HIV known as T-tropic
strains, which selectively interact with the CXCR4 ("X4") chemokine coreceptor to infect
lymphocytes. The M-tropic strains of HIV interact with the CCR5 ("R5") chemokine coreceptor,
and also CCR2 and CCR3, to infect macrophages and dendritic cells. CCR8 has been identified
as a cofactor to permit infection by either T-cell tropic or by M-tropic strains of HIV. Dual
tropic HIV strains have been identified that can use more than one chemokine coreceptor.[45]
Over time, mutations in HIV may increase the ability of the virus to infect cells via these
routes, beginning with dominance of CCR5 tropic strains of virus, then CCR5/CXCR4 dual
tropic virus, and finally the more cytopathic CXCR4 tropic strain predominance. CCR5 tropic
virus predominates early in HIV infection because it more readily infects dendritic cells and
macrophages, has a high rate of replication, and is less visible to cytotoxic lymphocytes.[28]
Infection with cytomegalovirus may serve to enhance HIV infection via this mechanism, because
CMV encodes a chemokine receptor similar to human chemokine receptors.[46] The
gastrointestinal tract is a preferential site for HIV infection because most CD4 cells at that
location are expressing CCR5,[47]
The presence of chemokine coreceptor mutations may explain the phenomenon of
resistance to HIV infection in some persons. Four mutational chemokine variants, including
CCR5-delta32, CCR2-64I, CCR5-P1, and a primary ligand of CXCR4 known as SDF-1-3’A,
have been discovered. These variants may impart resistance to HIV-1 infection and explain
differences in infectivity within and among populations.[48]
Cellular localization of chemokine receptors may help explain how HIV infection can
occur. Macrophages and monocytes, as well as subpopulations of lymphocytes, can express the
CCR5 receptor. Neurons, astrocytes, and microglia in the central nervous system also express
this chemokine receptor. In other tissues, CCR5 is expressed on epithelium, endothelium,
vascular smooth muscle, and fibroblasts. Areas of inflammation contain increased numbers of
mononuclear cells with CCR5, and this may facilitate transmission of HIV at those sites.[49]
Many virions are nonspecifically endocytosed on host cells and never enter the
cytoplasm. The interplay of CD4 and CCR5 receptors with viral proteins for entry is enhanced
by localization of cell surface receptors within cell membrane cholesterol rich lipid rafts that
provide lateral mobility and mediate fusion. Fusion requires formation of membrane pores.
After gaining entry to the host cell, virions can use microtubules for movement to a perinuclear
location. Once within the nucleus HIV integrase localizes to areas of euchromatin.[50]
Once within the cell, the viral particle uncoats from its spherical envelope to release its
RNA. This “plus sense” RNA requires reverse transcription followed by DNA integration. The
enzyme product of the pol gene, a reverse transcriptase that is bound to the HIV RNA,
synthesizes linear double-stranded cDNA that is the template for HIV integrase. It is this HIV
proviral DNA which is then inserted into the host cell genomic DNA by the integrase enzyme of
the HIV. The integrase catalyses an initial 3' processing of the nascent cDNA ends, followed in
the cell nucleus by their covalent attachment to the 5' phosphates of a double-stranded staggered
cut in chromosomal DNA. Proviral DNA is activated and transcribed under direction of HIV tat
and rev genes. Viral components are assembled at the inner part of the host cell membrane, and
virions then begin to bud off. During the budding process, HIV protease cleaves viral proteins