HLA-G/C, miRNAs, and their role in HIV infection and replication

Abstract

In recent years, a number of different mechanisms regulating gene expressions, either in normal or in pathological conditions, have been discovered. This review aims to highlight some of the regulatory pathways involved during the HIV-1 infection and disease progression, focusing on the novel discovered microRNAs (miRNAs) and their relation with immune system's agents. Human leukocyte antigen (HLA) family of proteins plays a key role because it is a crucial modulator of the immune response; here we will examine recent findings, centering especially on HLA-C and -G, novel players lately discovered to engage in modulation of immune system. We hope to provide novel perspectives useful to find out original therapeutic roads against HIV-1 infection and AIDS progression.

Figure 1

HIV virus is formed by a diploid single strand RNA genome (1) enclosed in a truncated cone capsid (2) with a phospholipidic bilayer envelope (3), containing the proteins that allow the virus entry into the cells (4). The HIV-1 infection is mediated by interaction between the proteins of the viral envelope, leukocyte receptor, and coreceptor (5). This interaction causes the membranes fusion and the uncoating of the virion core (6). The viral RNA is reverse transcribed in DNA (7) which enters in the nucleus where the integrase enzyme catalyzes the insertion of the viral genome into the genome of the host cell (8). The expression of integrated viral genome is controlled by the RNA-binding proteins tat and rev. A set of RNAs are transported from the nucleus to the cytoplasm, where they can be translated or packaged (9). The new core proteins localize near the cell membrane (10), while the envelope mRNA is translated at the endoplasmic reticulum (ER) and subsequently the envelope proteins are placed on the cell membrane (11). Finally, the capsid proteins are assembled with the viral genomic RNA (12), and an immature virion begins to bud from cell surface (13).

Figure 2

MHC1 are assembled in the lumen of the endoplasmatic reticulum where interaction with target peptides is mediated by chaperons. These peptides, cellular or viral derived, are produced in the cytosol by proteasome (1) and are transported into the ER lumen by TAP pump (2). Subsequently, the chaperon tapasin interacts with TAP, promoting the bond between peptides and HLA (3). The complex HLA peptide egresses through the golgi complex to the plasma membrane where it can remain (4) or can be released in soluble form to the extracellular space (5). ER: endoplasmic reticulum. GO: golgi apparatus.

Figure 3

The HIV-1 has developed a nef-dependent mechanism to escape the immune system attack to infected cells. Nef alters the expression of HLA-A and -B by recognition of a sequence (Y₃₂₀SQAASS) in the cytoplasmic tail (1), blocking the transport of newly synthesized HLA-A and -B (2), in order to avoid the recognition by CTL (3) while Nef maintains the expression of HLA-C (C₃₂₀SQAASS) and -G (short cytoplasmic tail) unchanged (4) in order to inhibit the innate response of the NK (5). NU: nucleus; GO: golgi apparatus.

Figure 4

The 263del/ins SNP associates strongly with surface expression of HLA-C. (a) 263del disrupts the binding site of miR-148a not altering the expression of HLA-C. (b) 263insG increases the stability of the binding with the miR-148a reducing surface expression of HLA-C and the recognition by CTL.