Entry inhibitors represent a new generation of antivirals for the treatment of HIV infection. Several compounds which block the attachment of HIV gp120 to either the CD4 T cell receptor or the CCR5/CXCR4 co-receptors are currently in clinical development. Most of these compounds have different molecular structures and specific mechanisms of action. These agents are eagerly awaited by a growing number of patients carrying viruses resistant viruses to many of the current available reverse transcriptase and protease inhibitors. For enfuvirtide, the first and, so far, only entry inhibitor approved for clinical use, the main mechanism of resistance is the selection of changes within a 10 amino acid segment encompassing residues 36–45 within the HR1 region of gp41. For other entry inhibitors, multiple changes in different gp120 domains (V1, V2, V3, C2 and C4) have been associated with loss of susceptibility to these agents, although in most cases with limited cross-resistance.

Antiretroviral therapy (ART) allows suppressed viremia to reach less than 50 copies/mL in most treated persons living with HIV (PLWH). However, the existence of PLWH that show events of persistent low-level viremia (pLLV) between 50 and 1000 copies/mL and with different virological consequences have been observed. PLLV has been associated with higher virological failure (VF), viral genotype resistance, adherence difficulties and AIDS events. Moreover, some reports show that pLLV status can lead to residual immune activation and inflammation, with an increased risk of immunovirological failure and a pro-inflammatory cytokine level which can lead to a higher occurrence of non-AIDS defining events (NADEs) and other adverse clinical outcomes. Until now, however, published data have shown controversial results that hinder understanding of the true cause(s) and origin(s) of this phenomenon. Molecular mechanisms related to viral reservoir size and clonal expansion have been suggested as the possible origin of pLLV. This review aims to assess recent findings to provide a global view of the role of pLLV in PLWH and the impact this status may cause on the clinical progression of these patients.

Gene therapy, in which oligomeric genetic material is carried into cells by nano-sized gene delivery vehicles to interfere with gene expression, represents a promising approach for preventive therapy against HIV/AIDS pandemic. Herein, we evaluate the usefulness of a phosphorus-containing dendrimer G4(NH+Et2Cl-)96 as a delivery agent of ODNs and siRNAs. G4(NH+Et2Cl-)96 formed stable complexes with ODNs or siRNAs and exhibited very low cytotoxicity in Sup T1 cells or PBMC. Functional validation was performed by using specific siRNA against HIV-1 Nef, siNEF to interfere in HIV-1 replication. G4(NH+Et2Cl-)96/siNEF dendriplex showed a high efficiency in Nef silencing. Furthermore, in vitro treatment of HIV-infected PBMC with G4(NH+Et2Cl-)96/siNEF dendriplex significantly reduced the viral replication. Our results prove the usefulness of phosphorus-containing dendrimers to deliver and transfect siRNA into CD4-T cells as a potential alternative therapy in the HIV-1 infection.

To estimate to what extent darunavir might be effective in patients failing distinct protease inhibitors (PIs), the genotypic resistance scores recently reported for the drug were examined in a large clinical HIV-1 drug resistance database. All clinical specimens from HIV-infected patients failing PI-based regimens referred for drug resistance testing between 1999 and 2007 to a reference centre in Madrid were analysed. Darunavir-specific resistance mutations listed by the September 2006 IAS-USA panel update were considered. A total of 1021 genotypes from patients failing lopinavir (39.2%), nelfinavir (28.1%), saquinavir (14.5%), indinavir (13.7%), atazanavir (6.6%), fosamprenavir (5.3%) and tipranavir (1.1%) were identified. The prevalence of major darunavir resistance mutations was I50V 2.1%, I54M 1.3%, L76V 2.7% and I84V 14.5%. For minor darunavir resistance mutations, the rates were V11I 3.3%, V32I 3.9%, L33F 11%, I47V 2.1%, I54L 2.3%, G73S 12.8% and L89V 2.4%. Overall, 6.7% (n = 68) of the genotypes had three or more darunavir resistance mutations, which corresponded to a mean total number of PI resistance mutations of 12.3 ± 1.9. In the multivariate analysis, prior fosamprenavir failure, prior saquinavir failure, the total number of PI resistance mutations and the number of prior PIs used were all independently associated with having more darunavir resistance mutations. The prevalence of darunavir resistance mutations is low in patients failing other PI-based regimens, although prior failure to amprenavir and saquinavir might produce more cross-resistance to darunavir. Thus, darunavir may be a good option for patients who have failed other PI-based regimens.

The activity of raltegravir and etravirine was assessed in vitro in HIV-1 group O isolates. Despite the presence of some natural polymorphisms associated with resistance to raltegravir (V72I, L74I, S153A, V201I, and T206S) and etravirine (G190A), both drugs showed significant antiviral activity. Subsequently, the clinical benefit was shown in an HIV-1 group O-infected individual in whom enfuvirtide was replaced by raltegravir. Therefore, individuals infected with HIV-1 group O might benefit from raltegravir and/or etravirine therapy.