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viral RNA transcripts to a pattern that predominates with established infection, leading to
production of viral structural and enzymatic proteins. The long terminal repeat (LTR) serves as a
promoter of transcription.[22,28,29,30]
The tat gene plays multiple roles in HIV pathogenesis. It produces a regulatory protein
that speeds up transcription of the HIV provirus to full-length viral mRNAs. It functions in
transactivation of viral genes. In addition, tat modulates host cell gene expression. The effects of
such modulation may include enhanced immune suppression, apoptosis, and oxidative stress.[33]
The nef gene produces a regulatory protein that modifies the infected cell to make it more
suitable for producing HIV virions, by accelerating endocytosis of CD4 from the surface of
infected cells. The vif, vpr, and vpu genes encode proteins that appear to play a role in
generating infectivity and pathologic effects. Vif, vpu, and vpr protein products link to members
of a superfamily of modular ubiquitin ligases to induce the polyubiquitylation and proteasomal
degradation of their cellular targets. More specifically, vpr has the ability to delay or arrest
infected cells in the G2 phase of the cell cycle and facilitates infection of macrophages. Vif
antagonizes the antiviral effect of apolipoprotein B mRNA-editing enzyme catalytic polypeptide-
like 3G, or the protein product of the gene APOBEC3G (A3G). Vpu enhances efficient release of
virions from infected cells.[34]
Retroviruses are unable to replicate outside of living host cells and do not contain
deoxyribonucleic acid (DNA). The pathogenesis of HIV infection is a function of the virus life
cycle, host cellular environment, and quantity of viruses in the infected individual. After
entering the body, the viral particle is attracted to a cell with the appropriate CD4 receptor
molecules where it attaches by fusion to a susceptible cell membrane or by endocytosis and then
enters the cell. The probability of infection is a function of both the number of infective HIV
virions in the body fluid which contacts the host as well as the number of cells available at the
site of contact that have appropriate CD4 receptors.[30]
HIV infection can occur through oropharyngeal, cervical, vaginal, and gastrointestinal
mucosal surfaces, even in the absence of mucosal disruption. Routes of HIV entry into mucosal
lamina propria include dendritic cells, epithelial cells, and microfold (M) cells. Dendritic cells
can bind to gp120 through a C type lectin, suggesting that dendritic cells that squeeze between
“tight” epithelium may capture HIV-1 and deliver it to underlying T cells, resulting in
dissemination to lymphoid organs. HIV can cross a tight epithelial barrier by transcytosis during
contact between HIV-infected cells and the apical surface of an epithelial cell. The presence of
mucus on epithelial surfaces further retards viral entry, particularly in the endocervix where there
is just a single columnar epithelial cell layer.[35,36]
HIV can transmigrate across fetal oral mucosal squamous epithelium that has few layers,
5 or less. HIV-infected macrophages, but not lymphocytes, are able to transmigrate across fetal
oral epithelia. HIV-infected macrophages and, to a lesser extent, lymphocytes can transmigrate
across fetal intestinal epithelia. However, efficient viral transmission through adult mucosal
epithelia is difficult because of a mechanical barrier of stratified epithelia with tight junctions
that prevent penetration of virions into the deeper layers of the epithelium, and from expression
of the anti-HIV innate proteins HBD2, HBD3, and SLPI that inactivate virions.[37]
Transcytosis of virions through intact epithelium is favored via surface expression of
syndecans and chemokine receptors by epithelial cells. However, the efficiency of transcytosis
is poor, with only 0.02% of the original inoculum of HIV able to navigate across genital
epithelium. Thus, intact epithelium is a significant barrier to HIV infection, but the presence of
antigen processing cells and inflammatory cells increases HIV transmission.[38] Exposure to