Presence of HIV-1 G-to-A mutations linked to APOBEC editing is more prevalent in non-B HIV-1 subtypes and is associated with lower HIV-1 reservoir

Abstract

Objectives APOBEC3 editing activity contributes to sequences variation and viral diversification. We aimed to characterize virological and clinical factors associated with G-to-A mutations and stop codons in the HIV-1 reservoir, markers of APOBEC3 footprints, in order to better understand HIV-1 diversity among virologically suppressed HIV-1-infected patients. Methods Immuno-virological and clinical factors were compared between 92 patients harbouring G-to-A mutations and stop codons (APOBEC+) in the reverse transcriptase gene and 92 patients without G-to-A mutations (APOBEC–) and stop codons in their DNA genotypes. Results Patients were predominantly men (74.5%) and were mostly infected by B-subtype (69.0%), with 44.1% and 55.9% in APOBEC+ and APOBEC– groups, respectively. At time of HIV DNA genotypes, the total cell-associated HIV-1 DNA load was 2.34 log10 copies/106 cells (IQR 1.85–2.67) and 33.2% of them had a detectable ultrasensitive plasma viral load. Hypermutated sequences were identified in 28.2% of the APOBEC+ group. The median total cell-associated HIV-1 DNA level was significantly lower in APOBEC+ than APOBEC– group: 2.13 log10 copies/106 cells (IQR 1.60–2.60) versus 2.52 log10 copies/106 cells (IQR 2.19–2.71) (P < 0.001), respectively. Presence of G-to-A mutations and stop codon was independently associated with HIV-1 subtype non-B (P = 0.017). Conclusions These results show an independent association between the presence of G-to-A mutations and stop codons with HIV-1 subtype non-B and low proviral DNA that could be explained by the APOBEC3 footprints and restriction of DNA synthesis and integration. However, further investigations are needed to study the contribution of Vif amino acid variability among HIV-1 subtypes.

HIV-1 env gene mutations outside the targeting probe affects IPDA efficiency

“… 33 , 34 Some articles also reported that env is prone to mutations, and changes in some bases within env lead to the loss of HIV-1 infection ability. 35 , 36 , 37 The IPDA targets only a segment of env , and mutations in other regions may also cause the inactivation of HIV-1, so we applied monoclonal screening techniques to obtain a larger number of env sequences isolated from HIV-1 patients and constructed pseudoviruses. The env probe binding sites of these pseudoviruses were consistent, but there were many mutations in env gene outside the probe binding site, causing the formation of stop codons that prevent the formation of viruses.…”

HIV-1 subtypes and latent reservoirs

“…The paucity of a universal assay to quantify the latent reservoir across subtypes could be one of the reasons why only a handful of studies examined the latent reservoir characteristics among the viral subtypes. These assays primarily quantify the reservoir in the proviral DNA Compartment [45,46 ▪ ,47,48]. Despite the low number of such studies on non-B viral reservoirs, interesting observations have been reported, especially when the differences are semi-qualitative.…”

“…Another interesting observation is the demonstration that the total latent reservoir size in HIV-1B infections is relatively larger than those of non-B infections [45,46 ▪ ,47,48] or comparable [53,54]. Surprisingly, no study demonstrated that the latent reservoir size of HIV-1B is smaller than other subtypes; therefore, caution must be applied while interpreting these results.…”