Clonal amplification and maternal-infant transmission of nevirapine-resistant HIV-1 variants in breast milk following single-dose nevirapine prophylaxis

Permar, Sallie R.; Salazar, Maria G.; Gao, Feng; Cai, Fangping; Learn, Gerald H.; Kalilani, Linda; Hahn, Beatrice H.; Shaw, George M.; Salazar-Gonzalez, Jesus F.

doi:10.1186/1742-4690-10-88

Cited by 9 publications

(6 citation statements)

References 37 publications

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“…Clonal amplification is an indicator of local and disproportional replication of one viral variant within a virus population. Clonal amplification has been reported for various anatomical sites in the body, including cerebrospinal fluid (CSF) (53), breast milk (54)(55)(56), and the genital tract (10). Deep sequencing and utilization of a PrimerID approach helped us to study clonal amplification in greater detail than has previously been reported for semen.…”

Section: Discussionmentioning

confidence: 99%

“…If the anatomical compartment is the male genital tract, then both the abundance and increased fitness of such variants might increase their probability of being transmitted to a new host. In support of this idea, one study has shown that clonally amplified drug-resistant HIV-1 variants in breast milk tend to be those which are transmitted from lactating mothers to their infants (54). We considered the possibility that clonal amplifications may have arisen primarily due to proliferation of T cell clones that have integrated HIV-1 genomes (47).…”

Section: Discussionmentioning

confidence: 99%

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Compartmentalization and Clonal Amplification of HIV-1 in the Male Genital Tract Characterized Using Next-Generation Sequencing

Kariuki

Selhorst

Anthony

et al. 2020

J Virol

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Compartmentalization of HIV-1 between the systemic circulation and the male genital tract may have a substantial impact on which viruses are available for sexual transmission to new hosts. We studied compartmentalization and clonal amplification of HIV-1 populations between the blood and the genital tract from 10 antiretroviral-naive men using Illumina MiSeq with a PrimerID approach. We found evidence of some degree of compartmentalization in every study participant, unlike previous studies, which collectively showed that only ∼50% of analyzed individuals exhibited compartmentalization of HIV-1 lineages between the male genital tract (MGT) and blood. Using down-sampling simulations, we determined that this disparity can be explained by differences in sampling depth in that had we sequenced to a lower depth, we would also have found compartmentalization in only ∼50% of the study participants. For most study participants, phylogenetic trees were rooted in blood, suggesting that the male genital tract reservoir is seeded by incoming variants from the blood. Clonal amplification was observed in all study participants and was a characteristic of both blood and semen viral populations. We also show evidence for independent viral replication in the genital tract in the individual with the most severely compartmentalized HIV-1 populations. The degree of clonal amplification was not obviously associated with the extent of compartmentalization. We were also unable to detect any association between history of sexually transmitted infections and level of HIV-1 compartmentalization. Overall, our findings contribute to a better understanding of the dynamics that affect the composition of virus populations that are available for transmission. IMPORTANCE Within an individual living with HIV-1, factors that restrict the movement of HIV-1 between different compartments—such as between the blood and the male genital tract—could strongly influence which viruses reach sites in the body from which they can be transmitted. Using deep sequencing, we found strong evidence of restricted HIV-1 movements between the blood and genital tract in all 10 men that we studied. We additionally found that neither the degree to which particular genetic variants of HIV-1 proliferate (in blood or genital tract) nor an individual’s history of sexually transmitted infections detectably influenced the degree to which virus movements were restricted between the blood and genital tract. Last, we show evidence that viral replication gave rise to a large clonal amplification in semen in a donor with highly compartmentalized HIV-1 populations, raising the possibility that differential selection of HIV-1 variants in the genital tract may occur.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Compartmentalization and Clonal Amplification of HIV-1 in the Male Genital Tract Characterized Using Next-Generation Sequencing

Kariuki

Selhorst

Anthony

et al. 2020

J Virol

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“…SdNVP was given to all of the mothers in the BAN study to prevent transmission during delivery, and NVP R commonly occurs after a single dose [10], although mothers in the BAN study were also given a week of AZT/3TC treatment after delivery to reduce the development of maternal NVP R [11]. Mothers in the maternal-ARV arm could also develop resistant HIV with poor adherence to their regimen.…”

Section: Introductionmentioning

confidence: 99%

Frequent nevirapine resistance in infants infected by HIV-1 via breastfeeding while on nevirapine prophylaxis

Nelson

Fokar²,

Hudgens

et al. 2015

Aids

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Objective Assess nevirapine (NVP) resistance in infants who became infected in the three arms of the Breastfeeding, Antiretrovirals, and Nutrition (BAN) study: daily infant NVP prophylaxis, triple maternal antiretrovirals (ARV), or no extra intervention for 28 weeks of breastfeeding. Design Prospective cohort study. Methods The latest available plasma or dried blood spot specimen was tested from infants who became HIV-positive between 3 and 48 weeks of age. Population sequencing was used to detect mutations associated with reverse transcriptase inhibitor resistance. Sequences were obtained from 22/25 transmissions in the infant-NVP arm, 23/30 transmissions in the maternal-ARV arm, and 33/38 transmissions in the control arm. Results HIV-infected infants in the infant-NVP arm were significantly more likely to have NVP resistance than infected infants in the other two arms of the trial, especially during breastfeeding through 28 weeks of age (56% in infant-NVP arm vs. 6% in maternal-ARV arm and 11% in control arm, p=0.004). There was a nonsignificant trend suggesting infants with NVP resistance tended to be infected earlier and exposed to NVP while infected for a greater duration than infants without resistance. Conclusions Infants on NVP prophylaxis during breastfeeding are at reduced risk of acquiring HIV, but are at increased risk of NVP resistance if they do become infected. These findings point to the need for frequent HIV testing of infants while on NVP prophylaxis, and for availability of antiretroviral regimens excluding NVP for treating infants who become infected while on such a prophylactic regimen.

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“…Because this current study does not show sequencing data on the samples that were amplified using this SGA protocol, it is incomplete as presented. Ultimately, the goal of a program that utilizes SGA technology for clinically relevant purposes (e.g., detect minority drug-resistance viral variants from patient samples (Palmer et al, 2005; McKinnon et al, 2011; Geng et al, 2010; Shi et al, 2010) or identify transmitted/founder HIV genomes during MTCT (Permar et al, 2013; Salazar-Gonzalez et al, 2008; Salazar-Gonzalez et al, 2009) will necessitate the sequencing of these amplicons and can incorporate this into existing HIV drug resistance testing programs (Hamers et al, 2012). …”

mentioning

confidence: 99%

Single genome amplification of proviral HIV-1 DNA from dried blood spot specimens collected during early infant screening programs in Lusaka, Zambia

Seu

Mwape

Guffey

2014

Journal of Virological Methods

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The ability to evaluate individual HIV-1 virions from the quasispecies of vertically infected infants was evaluated in a field setting at the Centre for Infectious Disease Research in Zambia. Infant heel-prick blood specimens were spotted onto dried blood spot (DBS) filter paper cards at government health clinics. Nucleic acid was extracted and used as a template for HIV-1 proviral DNA detection by a commercial Amplicor HIV-1 PCR test (Roche, version 1.5). On samples that tested positive by commercial diagnostic assay, amplification of DNA was performed using an in-house assay of the 5′ and 3′ region of the HIV-1 genome. Additionally, fragments covering 1200 nucleotides within pol (full length protease and partial reverse transcriptase) and 1400 nucleotides within env (variable 1-variable 5 region) were further analyzed by single genome amplification (SGA). In summary, we have demonstrated an in-house assay for amplifying the 5′ and 3′ proviral HIV-1 DNA as well as pol and env proviral DNA fragments from DBS cards collected and analyzed entirely in Zambia. In conclusion, this study shows the feasibility of utilizing DBS cards to amplify the whole proviral HIV-1 genome as well as perform SGA on key HIV-1 genes.

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Clonal amplification and maternal-infant transmission of nevirapine-resistant HIV-1 variants in breast milk following single-dose nevirapine prophylaxis

Cited by 9 publications

References 37 publications

Compartmentalization and Clonal Amplification of HIV-1 in the Male Genital Tract Characterized Using Next-Generation Sequencing

Compartmentalization and Clonal Amplification of HIV-1 in the Male Genital Tract Characterized Using Next-Generation Sequencing

Frequent nevirapine resistance in infants infected by HIV-1 via breastfeeding while on nevirapine prophylaxis

Single genome amplification of proviral HIV-1 DNA from dried blood spot specimens collected during early infant screening programs in Lusaka, Zambia

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