Diminished transmission of drug resistant HIV-1 variants with reduced replication capacity in a human transmission model

Abstract

Background: Different patterns of drug resistance are observed in treated and therapy naïve HIV-1 infected populations. Especially the NRTI-related M184I/V variants, which are among the most frequently encountered mutations in treated patients, are underrepresented in the antiretroviral naïve population. M184I/V mutations are known to have a profound effect on viral replication and tend to revert over time in the new host. However it is debated whether a diminished transmission efficacy of HIV variants with a reduced replication capacity can also contribute to the observed discrepancy in genotypic patterns. As dendritic cells (DCs) play a pivotal role in HIV-1 transmission, we used a model containing primary human Langerhans cells (LCs) and DCs to compare the transmission efficacy M184 variants (HIV-M184V/I/T) to HIV wild type (HIV-WT). As control, we used HIV harboring the NNRTI mutation K103N (HIV-K103N) which has a minor effect on replication and is found at a similar prevalence in treated and untreated individuals.

New resistance mutations to nucleoside reverse transcriptase inhibitors at codon 184 of HIV‐1 reverse transcriptase (M184L and M184T)

“…It is now well established that M184V and M184I mutations occurring in the RT polymerase active site of HIV‐1 reduced its susceptibility to 3TC/FTC drugs. Whereas other mutations, such as M184L, M184T, or M184A, have been described and studied in vitro , there is still a lack of data that allow considering these variants as NRTI‐resistant mutants. In a large cohort of HIV‐1‐infected patients, we observed that M184L and M184T mutations occurred under and/or after NRTI treatment.…”

“…Compared to the wild type (WT), M184V mutation confers a reduced fitness, which may explain that the HIV‐1 reverts to wild type when NRTI treatment ceases . It has also been shown that this variant increases fidelity of HIV‐1 RT, thus reducing genetic diversification, one of key natural defensive mechanisms. M184I is considered as a transient variant since it appears early under 3TC‐based regimens and then disappears in favor of M184V mutant due to its lower fitness .…”

“…It has also been shown that this variant increases fidelity of HIV‐1 RT, thus reducing genetic diversification, one of key natural defensive mechanisms. M184I is considered as a transient variant since it appears early under 3TC‐based regimens and then disappears in favor of M184V mutant due to its lower fitness . It has been observed that both variants increase or restore susceptibility to other NRTI, such as zidovudine (AZT), tenofovir (TDF), or stavudine (d4T); therefore, these mutations do not contraindicate continuation of 3TC or FTC therapy if combined to other NRTI drugs.…”

“…In vitro analyses revealed other potential NRTI resistance substitutions at this site, such as M184A, M184L,, and M184T, whereas they have never been investigated in vivo to date. M184L and M184T mutations have been reported by the Stanford University HIV‐1 drug resistance database, but (a) difference of M184L mutation frequencies between untreated and treated isolates does not reach statistical significance, and (b) for M184T mutation, the association with non NRTI therapies could not be excluded; therefore, those mutations have not been retained as NRTI resistance mutations.…”

Transmission of HIV-1 Drug Resistance

“…In a skin model, drug-resistant variants with a low replicative capacity (M184V/I/T) were less 2015 able to infect primary Langerhans cells compared to resistant viruses with a higher replicative capacity (K103N) or wild-type virus. Subsequent transmission to target cells was also decreased in these resistant variants (Pingen et al 2014). This issue needs further study in the future.…”