Alessandri-Gradt, E. | Search bioRxiv

bioRxiv2023

In vitro phenotypic susceptibility of HIV-1 non-group M to CCR5 inhibitor (Maraviroc): TROPI-CO study

The susceptibility of genetically divergent HIV-1 strains (HIV-1 non-M) from group O, N and P to the CCR5 co-receptor antagonist, Maraviroc (MVC) was investigated among a large panel of 45 clinical strains, representative of the genetic diversity. The results were compared to reference strains of HIV-1 group M (HIV-1/M) with known tropism. Among the non-M strains, a wide range of phenotypic susceptibilities to MVC was observed. The large majority of HIV-1/O strains (40/42) displayed a high susceptibility to MVC with median and mean IC50 values at 1.23 and 1.33 nM respectively, similar to the HIV-1/M R5 strain (1.89 nM). However, the 2 remaining HIV-1/O strains exhibited a lower susceptibility (IC50 at 482 and 496 nM), in accordance with their dual/mixed (DM) tropism. Interestingly, the 2 HIV-1/N strains demonstrated varying susceptibility patterns, despite always having relatively low IC50 values (2.87 and 47.5 nM). This emphasized the complexity of determining susceptibility solely based on IC50 values. Our study examined the susceptibility of all HIV-1 non-M groups to MVC and correlated these findings with virus tropism (X4, R5 or DM). The results confirm the critical significance of tropism determination before initiating MVC treatment in patients infected with HIV-1 non-M. Furthermore, we advocate for the consideration of additional parameters, such as the slope of inhibition curves, to provide a more thorough characterization of phenotypic susceptibility profiles.

microbiology↗

bioRxiv2022

In vitro replicative potential of an HIV-1/MO intergroup recombinant virus compared to HIV-1/M and HIV-1/O parental viruses

HIV-1 is characterized by high genetic diversity and genetic recombination is one of the major evolution processes. Despite their great genetic divergence, HIV-1 group M, pandemic, and group O, endemic in Cameroon, can generate HIV-1/MO intergroup recombinants. The current description of 19 HIV-1/MO recombinant forms (URF_MO) raises the question of a possible benefit of the recombination and the modalities of their emergence. Therefore, the objectives of this work were to study in vitro the replicative potential of HIV-1/MO recombinant forms. The replicative potential was analyzed, based on a simple recombination pattern, [Ogag/pol-Menv], harboring a breakpoint in Vpr, due to a recombination hotspot in this region. For this, a chimeric infectious molecular clone (IMC) was synthesized from HIV-1/M subtype B and HIV-1/O subgroup T and recombinant viruses were obtained by transfection and co-culture. To compare the replicative potential of recombinant viruses with HIV-1/M and HIV-1/O parental viruses, two markers were monitored in culture supernatants: Reverse Transcriptase (RT) activity and P24 antigen concentration. The results showed a superiority of the group M parental virus compared to group O for both markers. In contrast, for the HIV-1/OM recombinant virus, RT activity data did not overlap with the concentration of P24 antigen, suggesting a hybrid behavior of the recombinant, in terms of enzyme activity and P24 production. These results highlighted many hypotheses about the impact of recombination on replicative potential and demonstrated once again the significant plasticity of HIV genomes and their infinite possibility of evolution. ImportanceHIV-1/M and HIV-1/O can generate HIV-1/MO intergroup recombinants. The current description of 19 URF_MO raises the question of a possible benefit of recombination in terms of emergence. The objectives of this work were to study in vitro the replicative potential of HIV-1/MO recombinant viruses. For this, a chimeric infectious molecular clone (IMC) generated from HIV-1/M subtype B and HIV-1/O subgroup T and recombinant viruses were obtained by transfection and co-culture. To compare the replicative potential of recombinant viruses with HIV-1/M and HIV-1/O parental viruses, RT activity and P24 antigen concentration were monitored in culture supernatants. A superiority of the group M parental virus compared to group O was observed for both markers whereas a hybrid behavior in terms of enzyme activity and P24 production was found for the recombinant virus. These results demonstrated once again the significant plasticity of HIV genomes and their infinite possibility of evolution.

microbiology↗