Antiretroviral Imprints and Genomic Plasticity of HIV-1 pol in Non-clade B: Implications for Treatment

Abstract

Combinational antiretroviral therapy (cART) is the most effective tool to prevent and control HIV-1 infection without an effective vaccine. However, HIV-1 drug resistance mutations (DRMs) and naturally occurring polymorphisms (NOPs) can abrogate cART efficacy. Here, we aimed to characterize the HIV-1 pol mutation landscape in Cameroon, where highly diverse HIV clades circulate, and identify novel treatment-associated mutations that can potentially affect cART efficacy. More than 8,000 functional Cameroonian HIV-1 pol sequences from 1987 to 2020 were studied for DRMs and NOPs. Site-specific amino acid frequencies and quaternary structural features were determined and compared between periods before (≤2003) and after (2004–2020) regional implementation of cART. cART usage in Cameroon induced deep mutation imprints in reverse transcriptase (RT) and to a lower extent in protease (PR) and integrase (IN), according to their relative usage. In the predominant circulating recombinant form (CRF) 02_AG (CRF02_AG), 27 canonical DRMs and 29 NOPs significantly increased or decreased in RT during cART scale-up, whereas in IN, no DRM and only seven NOPs significantly changed. The profound genomic imprints and higher prevalence of DRMs in RT compared to PR and IN mirror the dominant use of reverse transcriptase inhibitors (RTIs) in sub-Saharan Africa and the predominantly integrase strand transfer inhibitor (InSTI)-naïve study population. Our results support the potential of InSTIs for antiretroviral treatment in Cameroon; however, close surveillance of IN mutations will be required to identify emerging resistance patterns, as observed in RT and PR. Population-wide genomic analyses help reveal the presence of selective pressures and viral adaptation processes to guide strategies to bypass resistance and reinstate effective treatment.

Stomach microbiota in gastric cancer development and clinical implications

“…A decreased abundance of Rhizopus is observed in a Chinese cohort, and several species of Rhizopus have been identified to inhibit cancer growth in mice. 53 Other Chinese studies reported the depletion of Aspergillus, Phialocephala, Phaeoacremonium, Umbelopsis, Ustilago, Panellus and Cyberlindnera in patients with GC. 52 54 55 Although no study has portrayed alterations for viruses in gastric carcinogenesis, modified viruses can be used to deliver therapeutic transgenes with selective replication in tumour cells, thereby inhibiting GC and enhancing treatment efficacy.…”

“…However, the accuracy of fungal biomarkers for GC diagnosis is relatively low with AUC values of 0.71-0.80. [52][53][54] Although gastric mucosal microbial biomarkers have shown promising diagnostic potential, it remains invasive and resourcedemanding to collect gastric mucosal samples. To facilitate clinical application, studies have evaluated various non-invasive approaches using oral or gastric fluid samples for GC diagnosis.…”