No Substantial Evidence for Sexual Transmission of Minority HIV Drug Resistance Mutations in Men Who Have Sex with Men

Abstract

During primary HIV infection, the presence of minority drug resistance mutations (DRM) may be a consequence of sexual transmission, mutations, or technical errors in identification. Baseline blood samples were collected from 24 HIV-infected antiretroviral-naive, genetically and epidemiologically linked source and recipient partners shortly after the recipient's estimated date of infection. An additional 32 longitudinal samples were available from 11 recipients. Deep sequencing of HIV reverse transcriptase (RT) was performed (Roche/454), and the sequences were screened for nucleoside and nonnucleoside RT inhibitor DRM. The likelihood of sexual transmission and persistence of DRM was assessed using Bayesian-based statistical modeling. While the majority of DRM (>20%) were consistently transmitted from source to recipient, the probability of detecting a minority DRM in the recipient was not increased when the same minority DRM was detected in the source (Bayes factor [BF] = 6.37). Longitudinal analyses revealed an exponential decay of DRM (BF = 0.05) while genetic diversity increased. Our analysis revealed no substantial evidence for sexual transmission of minority DRM (BF = 0.02). The presence of minority DRM during early infection, followed by a rapid decay, is consistent with the "mutation-selection balance" hypothesis, in which deleterious mutations are more efficiently purged later during HIV infection when the larger effective population size allows more efficient selection. Future studies using more recent sequencing technologies that are less prone to single-base errors should confirm these results by applying a similar Bayesian framework in other clinical settings. The advent of sensitive sequencing platforms has led to an increased identification of minority drug resistance mutations (DRM), including among antiretroviral therapy-naive HIV-infected individuals. While transmission of DRM may impact future therapy options for newly infected individuals, the clinical significance of the detection of minority DRM remains controversial. In the present study, we applied deep-sequencing techniques within a Bayesian hierarchical framework to a cohort of 24 transmission pairs to investigate whether minority DRM detected shortly after transmission were the consequence of (i) sexual transmission from the source, (ii) emergence shortly after infection followed by viral selection and evolution, or (iii) technical errors/limitations of deep-sequencing methods. We found no clear evidence to support the sexual transmission of minority resistant variants, and our results suggested that minor resistant variants may emerge shortly after transmission, when the small effective population size limits efficient purge by natural selection.

Caution is needed in interpreting HIV transmission chains by ultradeep sequencing

“…However, when multiple, the minimum number of founder variants initiating infection was estimated to range between 2 and 10, depending on the genetic fragment. These estimates are in agreement with studies conducted in individuals with acute or very recent HIV infections [38] Chaillon et al [40]. This suggests either preferential transmission of majority variants and/or minority drug-sensitive variants or post transmission reversion to wild type.…”

Trends in the Molecular Epidemiology and Genetic Mechanisms of Transmitted Human Immunodeficiency Virus Type 1 Drug Resistance in a Large US Clinic Population

“…Endemic strains may carry a greater risk of ongoing transmission consistent with their ability to persist in a population in the absence of selective drug pressure [29]. However, they may also be less likely to harbor additional DRMs as the process of ongoing transmission among ART-naive individuals would be expected to filter out minority variants that may have originally been transmitted from an ART-experienced individual [36, 37].…”

Proliferative memory SAMHD1low CD4+ T cells harbour high levels of HIV-1 with compartmentalized viral populations

“…To overcome this limitation, we applied rigorous quality control procedures for deep sequencing, as previously described in our group and others [54–56]. Our validated bioinformatics pipeline includes strict quality filtering steps [57–59] and only quality-controlled reads were included in the analysis [60]. Future studies using more recent sequencing technologies that are less prone to single-base errors, the use of Primer ID [61] or single genome amplification/Sanger sequencing [62] in different settings could also be enlightening.…”