This page has only limited features, please log in for full access.

Dr. Mary Kearney
Center for Cancer Research, National Cancer Institute, Frederick, USA

Basic Info

Basic Info is private.

Research Keywords & Expertise

0 HIV translational research
0 HIV persistence
0 Intra-patient viral genetics
0 Single cell viral genetics and expression
0 Clonal expansion of HIV infected cells

Fingerprints

HIV persistence
Clonal expansion of HIV infected cells

Honors and Awards

The user has no records in this section


Career Timeline

The user has no records in this section.


Short Biography

The user biography is not available.
Following
Followers
Co Authors
The list of users this user is following is empty.
Following: 0 users

Feed

Journal article
Published: 25 June 2021 in Viruses
Reads 0
Downloads 0

Efforts to cure HIV-1 infection require better quantification of the HIV-1 reservoir, particularly the clones of cells harboring replication-competent (intact) proviruses, termed repliclones. The digital droplet PCR assays commonly used to quantify intact proviruses do not differentiate among specific repliclones, thus the dynamics of repliclones are not well defined. The major challenge in tracking repliclones is the relative rarity of the cells carrying specific intact proviruses. To date, detection and accurate quantification of repliclones requires in-depth integration site sequencing. Here, we describe a simplified workflow using integration site-specific qPCR (IS-qPCR) to determine the frequencies of the proviruses integrated in individual repliclones. We designed IS-qPCR to determine the frequencies of repliclones and clones of cells that carry defective proviruses in samples from three donors. Comparing the results of IS-qPCR with deep integration site sequencing data showed that the two methods yielded concordant estimates of clone frequencies (r = 0.838). IS-qPCR is a potentially valuable tool that can be applied to multiple samples and cell types over time to measure the dynamics of individual repliclones and the efficacy of treatments designed to eliminate them.

ACS Style

Leah Brandt; Shuang Guo; Kevin Joseph; Jana Jacobs; Asma Naqvi; John Coffin; Mary Kearney; Elias Halvas; Xiaolin Wu; Stephen Hughes; John Mellors. Tracking HIV-1-Infected Cell Clones Using Integration Site-Specific qPCR. Viruses 2021, 13, 1235 .

AMA Style

Leah Brandt, Shuang Guo, Kevin Joseph, Jana Jacobs, Asma Naqvi, John Coffin, Mary Kearney, Elias Halvas, Xiaolin Wu, Stephen Hughes, John Mellors. Tracking HIV-1-Infected Cell Clones Using Integration Site-Specific qPCR. Viruses. 2021; 13 (7):1235.

Chicago/Turabian Style

Leah Brandt; Shuang Guo; Kevin Joseph; Jana Jacobs; Asma Naqvi; John Coffin; Mary Kearney; Elias Halvas; Xiaolin Wu; Stephen Hughes; John Mellors. 2021. "Tracking HIV-1-Infected Cell Clones Using Integration Site-Specific qPCR." Viruses 13, no. 7: 1235.

Review
Published: 12 June 2021 in Viruses
Reads 0
Downloads 0

There is a growing number of perinatally HIV-1-infected children worldwide who must maintain life-long ART. In early life, HIV-1 infection is established in an immunologically inexperienced environment in which maternal ART and immune dynamics during pregnancy play a role in reservoir establishment. Children that initiated early antiretroviral therapy (ART) and maintained long-term suppression of viremia have smaller and less diverse HIV reservoirs than adults, although their proviral landscape during ART is reported to be similar to that of adults. The ability of these early infected cells to persist long-term through clonal expansion poses a major barrier to finding a cure. Furthermore, the effects of life-long HIV persistence and ART are yet to be understood, but growing evidence suggests that these individuals are at an increased risk for developing non-AIDS-related comorbidities, which underscores the need for an HIV cure.

ACS Style

Mary Katusiime; Gert Van Zyl; Mark Cotton; Mary Kearney. HIV-1 Persistence in Children during Suppressive ART. Viruses 2021, 13, 1134 .

AMA Style

Mary Katusiime, Gert Van Zyl, Mark Cotton, Mary Kearney. HIV-1 Persistence in Children during Suppressive ART. Viruses. 2021; 13 (6):1134.

Chicago/Turabian Style

Mary Katusiime; Gert Van Zyl; Mark Cotton; Mary Kearney. 2021. "HIV-1 Persistence in Children during Suppressive ART." Viruses 13, no. 6: 1134.

Journal article
Published: 29 April 2021 in Viruses
Reads 0
Downloads 0

The latent HIV-1 reservoir is comprised of stably integrated and intact proviruses with limited to no viral transcription. It has been proposed that latent infection may be maintained by methylation of pro-viral DNA. Here, for the first time, we investigate the cytosine methylation of a replication competent provirus (AMBI-1) found in a T cell clone in a donor on antiretroviral therapy (ART). Methylation profiles of the AMBI-1 provirus were compared to other proviruses in the same donor and in samples from three other individuals on ART, including proviruses isolated from lymph node mononuclear cells (LNMCs) and peripheral blood mononuclear cells (PBMCs). We also evaluated the apparent methylation of cytosines outside of CpG (i.e., CpH) motifs. We found no evidence for methylation in AMBI-1 or any other provirus tested within the 5′ LTR promoter. In contrast, CpG methylation was observed in the env-tat-rev overlapping reading frame. In addition, we found evidence for differential provirus methylation in cells isolated from LNMCs vs. PBMCs in some individuals, possibly from the expansion of infected cell clones. Finally, we determined that apparent low-level methylation of CpH cytosines is consistent with occasional bisulfite reaction failures. In conclusion, our data do not support the proposition that latent HIV infection is associated with methylation of the HIV 5′ LTR promoter.

ACS Style

Valerie Boltz; Cristina Ceriani; Jason Rausch; Wei Shao; Michael Bale; Brandon Keele; Rebecca Hoh; Jeffrey Milush; Steve Deeks; Frank Maldarelli; Mary Kearney; John Coffin. CpG Methylation Profiles of HIV-1 Proviral DNA in Individuals on ART. Viruses 2021, 13, 799 .

AMA Style

Valerie Boltz, Cristina Ceriani, Jason Rausch, Wei Shao, Michael Bale, Brandon Keele, Rebecca Hoh, Jeffrey Milush, Steve Deeks, Frank Maldarelli, Mary Kearney, John Coffin. CpG Methylation Profiles of HIV-1 Proviral DNA in Individuals on ART. Viruses. 2021; 13 (5):799.

Chicago/Turabian Style

Valerie Boltz; Cristina Ceriani; Jason Rausch; Wei Shao; Michael Bale; Brandon Keele; Rebecca Hoh; Jeffrey Milush; Steve Deeks; Frank Maldarelli; Mary Kearney; John Coffin. 2021. "CpG Methylation Profiles of HIV-1 Proviral DNA in Individuals on ART." Viruses 13, no. 5: 799.

Journal article
Published: 01 November 2020 in AIDS Research and Human Retroviruses
Reads 0
Downloads 0

The prevalence of HIV-1 drug resistance is increasing worldwide and monitoring its emergence is important for the successful management of populations receiving combination antiretroviral therapy. It is likely that pre-existing drug resistance mutations linked on the same viral genomes are predictive of treatment failure. Because of the large numbers of sequences generated by Ultrasensitive Single-Genome Sequencing (uSGS) and other similar next-generation sequencing methods, it is difficult to assess each sequence individually for linked drug resistance mutations. Several software/programs exist to report the frequencies of individual mutations in large datasets, but they provide no information on linkage of resistance mutations. Here, we report the HIV-DRLink program, a research tool that provides resistance mutation frequencies as well as their genetic linkage by parsing and summarizing the Sierra output from the Stanford HIV Database (https://hivdb.stanford.edu/). The HIV-DRLink program should only be used on datasets generated by methods that eliminate artifacts due to PCR recombination, for example, standard Single-Genome Sequencing (SGS) or uSGS. HIV-DRLink is exclusively a research tool and is not intended to inform clinical decisions.

ACS Style

Wei Shao; Valerie F. Boltz; Junko Hattori; Michael J. Bale; Frank Maldarelli; John M. Coffin; Mary F. Kearney. Short Communication: HIV-DRLink: A Tool for Reporting Linked HIV-1 Drug Resistance Mutations in Large Single-Genome Data Sets Using the Stanford HIV Database. AIDS Research and Human Retroviruses 2020, 36, 942 -947.

AMA Style

Wei Shao, Valerie F. Boltz, Junko Hattori, Michael J. Bale, Frank Maldarelli, John M. Coffin, Mary F. Kearney. Short Communication: HIV-DRLink: A Tool for Reporting Linked HIV-1 Drug Resistance Mutations in Large Single-Genome Data Sets Using the Stanford HIV Database. AIDS Research and Human Retroviruses. 2020; 36 (11):942-947.

Chicago/Turabian Style

Wei Shao; Valerie F. Boltz; Junko Hattori; Michael J. Bale; Frank Maldarelli; John M. Coffin; Mary F. Kearney. 2020. "Short Communication: HIV-DRLink: A Tool for Reporting Linked HIV-1 Drug Resistance Mutations in Large Single-Genome Data Sets Using the Stanford HIV Database." AIDS Research and Human Retroviruses 36, no. 11: 942-947.

Journal article
Published: 05 October 2020 in Journal of Clinical Investigation
Reads 0
Downloads 0

BACKGROUNDHIV-1 viremia that is not suppressed by combination antiretroviral therapy (ART) is generally attributed to incomplete medication adherence and/or drug resistance. We evaluated individuals referred by clinicians for nonsuppressible viremia (plasma HIV-1 RNA above 40 copies/mL) despite reported adherence to ART and the absence of drug resistance to the current ART regimen.METHODSSamples were collected from at least 2 time points from 8 donors who had nonsuppressible viremia for more than 6 months. Single templates of HIV-1 RNA obtained from plasma and viral outgrowth of cultured cells and from proviral DNA were amplified by PCR and sequenced for evidence of clones of cells that produced infectious viruses. Clones were confirmed by host-proviral integration site analysis.RESULTSHIV-1 genomic RNA with identical sequences were identified in plasma samples from all 8 donors. The identical viral RNA sequences did not change over time and did not evolve resistance to the ART regimen. In 4 of the donors, viral RNA sequences obtained from plasma matched those sequences from viral outgrowth cultures, indicating that the viruses were replication competent. Integration sites for infectious proviruses from those 4 donors were mapped to the introns of the MATR3, ZNF268, ZNF721/ABCA11P, and ABCA11P genes. The sizes of the clones were estimated to be from 50 million to 350 million cells.CONCLUSIONThese findings show that clones of HIV-1-infected cells producing virus can cause failure of ART to suppress viremia. The mechanisms involved in clonal expansion and persistence need to be defined to effectively target viremia and the HIV-1 reservoir.FUNDINGNational Cancer Institute, NIH; Howard Hughes Medical Research Fellows Program, Howard Hughes Medical Institute; Bill and Melinda Gates Foundation; Office of AIDS Research; American Cancer Society; National Cancer Institute through a Leidos subcontract; National Institute for Allergy and Infectious Diseases, NIH, to the I4C Martin Delaney Collaboratory; University of Rochester Center for AIDS Research and University of Rochester HIV/AIDS Clinical Trials Unit.

ACS Style

Elias K. Halvas; Kevin W. Joseph; Leah D. Brandt; Shuang Guo; Michele D. Sobolewski; Jana L. Jacobs; Camille Tumiotto; John K. Bui; Joshua C. Cyktor; Brandon F. Keele; Gene D. Morse; Michael J. Bale; Wei Shao; Mary F. Kearney; John M. Coffin; Jason W. Rausch; Xiaolin Wu; Stephen H. Hughes; John W. Mellors. HIV-1 viremia not suppressible by antiretroviral therapy can originate from large T cell clones producing infectious virus. Journal of Clinical Investigation 2020, 130, 5847 -5857.

AMA Style

Elias K. Halvas, Kevin W. Joseph, Leah D. Brandt, Shuang Guo, Michele D. Sobolewski, Jana L. Jacobs, Camille Tumiotto, John K. Bui, Joshua C. Cyktor, Brandon F. Keele, Gene D. Morse, Michael J. Bale, Wei Shao, Mary F. Kearney, John M. Coffin, Jason W. Rausch, Xiaolin Wu, Stephen H. Hughes, John W. Mellors. HIV-1 viremia not suppressible by antiretroviral therapy can originate from large T cell clones producing infectious virus. Journal of Clinical Investigation. 2020; 130 (11):5847-5857.

Chicago/Turabian Style

Elias K. Halvas; Kevin W. Joseph; Leah D. Brandt; Shuang Guo; Michele D. Sobolewski; Jana L. Jacobs; Camille Tumiotto; John K. Bui; Joshua C. Cyktor; Brandon F. Keele; Gene D. Morse; Michael J. Bale; Wei Shao; Mary F. Kearney; John M. Coffin; Jason W. Rausch; Xiaolin Wu; Stephen H. Hughes; John W. Mellors. 2020. "HIV-1 viremia not suppressible by antiretroviral therapy can originate from large T cell clones producing infectious virus." Journal of Clinical Investigation 130, no. 11: 5847-5857.

Commentaries
Published: 21 September 2020 in Proceedings of the National Academy of Sciences
Reads 0
Downloads 0
ACS Style

Jason W. Rausch; Adam A. Capoferri; Mary Grace Katusiime; Sean C. Patro; Mary F. Kearney. Low genetic diversity may be an Achilles heel of SARS-CoV-2. Proceedings of the National Academy of Sciences 2020, 117, 24614 -24616.

AMA Style

Jason W. Rausch, Adam A. Capoferri, Mary Grace Katusiime, Sean C. Patro, Mary F. Kearney. Low genetic diversity may be an Achilles heel of SARS-CoV-2. Proceedings of the National Academy of Sciences. 2020; 117 (40):24614-24616.

Chicago/Turabian Style

Jason W. Rausch; Adam A. Capoferri; Mary Grace Katusiime; Sean C. Patro; Mary F. Kearney. 2020. "Low genetic diversity may be an Achilles heel of SARS-CoV-2." Proceedings of the National Academy of Sciences 117, no. 40: 24614-24616.

Preprint content
Published: 06 August 2020
Reads 0
Downloads 0

Despite the effectiveness of antiretroviral (ARV) therapy, virological failure can occur in some HIV-1 infected patients in the absence of mutations in the proteins targeted by these drugs. We previously reported that, in vitro, the lab-adapted NL4-3 strain of HIV-1 can acquire resistance to the integrase inhibitor dolutegravir (DTG) by acquiring mutations in the envelope glycoprotein (Env) that enhance the ability of HIV-1 to spread via cell-cell transmission. In this study, we investigated whether Env-mediated drug resistance extends to ARVs other than DTG and whether it occurs in other HIV-1 isolates. We demonstrate that Env mutations can broadly confer resistance to multiple classes of ARVs in the context of cell-cell but not cell-free infection and also increase resistance to ARVs when coupled with target-gene drug resistance mutations. To investigate the mechanism of Env-mediated drug resistance, we evaluated the impact of the Env mutations on Env stability and conformational dynamics. We observe that the NL4-3 Env mutants display a more stable and closed Env conformation compared to WT virus and reduced rates of gp120 shedding. We also selected for mutations in the gp41 ectodomain of clinically relevant, CCR5-tropic isolates in the presence of DTG. These Env mutants exhibit reduced susceptibility to DTG, with effects on replication kinetics and Env structure that are HIV-1 strain-dependent. Finally, to examine a possible in vivo relevance of Env-mediated drug resistance, we performed single-genome sequencing of plasma-derived virus from five patients failing an integrase inhibitor-containing regimen. This analysis revealed the presence of several mutations in the highly conserved gp120-gp41 interface despite low frequency of resistance mutations in integrase. These results suggest a “stepping-stone” model whereby mutations in Env that enhance the ability of HIV-1 to spread via a cell-cell route increase the opportunity for the virus to acquire high-level drug resistance mutations in ARV-target genes. Author summary Although combination antiretroviral (ARV) therapy has proven highly effective in controlling the progression of HIV disease, drug resistance can be a major obstacle to long-term treatment, particularly in resource-limited settings. In most cases, resistance arises from the accumulation of mutations in the ARV-target genes; however, in some cases, resistance develops without ARV target-gene mutations. We previously reported that mutations in the HIV-1 envelope glycoprotein (Env) confer resistance to an integrase inhibitor. Here we investigated the mechanism of Env-mediated drug resistance and the possible contribution of Env to virological failure in vivo. We demonstrate that Env mutations can confer broad resistance to multiple classes of ARVs and define the effect of the Env mutations on Env subunit interactions and sensitivity to neutralizing antibodies. We also selected for drug resistance mutations in Env in clinically relevant HIV-1 isolates. We observed that many Env mutations accumulated in individuals failing integrase inhibitor therapy despite a low frequency of resistance mutations in integrase. Our findings suggest that broad-based, Env-mediated drug resistance may impact current and possibly future therapeutic strategies. Our findings also provide clues towards understanding how ARV-treated patients can experience virological failure without acquiring drug resistance mutations in ARV-target genes.

ACS Style

Yuta Hikichi; Rachel Van Duyne; Phuong Pham; Jennifer L. Groebner; Ann Wiegand; John W. Mellors; Mary F. Kearney; Eric O. Freed. Mechanistic Analysis of the Broad Antiretroviral Resistance Conferred by HIV-1 Envelope Glycoprotein Mutations. 2020, 1 .

AMA Style

Yuta Hikichi, Rachel Van Duyne, Phuong Pham, Jennifer L. Groebner, Ann Wiegand, John W. Mellors, Mary F. Kearney, Eric O. Freed. Mechanistic Analysis of the Broad Antiretroviral Resistance Conferred by HIV-1 Envelope Glycoprotein Mutations. . 2020; ():1.

Chicago/Turabian Style

Yuta Hikichi; Rachel Van Duyne; Phuong Pham; Jennifer L. Groebner; Ann Wiegand; John W. Mellors; Mary F. Kearney; Eric O. Freed. 2020. "Mechanistic Analysis of the Broad Antiretroviral Resistance Conferred by HIV-1 Envelope Glycoprotein Mutations." , no. : 1.

Preprint content
Published: 31 January 2020
Reads 0
Downloads 0

BACKGROUND HIV-1 viremia that is not suppressed by combination antiretroviral therapy (ART) is generally attributed to incomplete medication adherence and/or drug resistance. We evaluated individuals referred for non-suppressible viremia (plasma HIV-1 RNA above 40 copies/ml) who reported adherence to ART and did not show drug resistance to their current regimen. METHODS Samples were collected from at least two time points from eight donors who had non-suppressible viremia for more than six months on ART. Single templates of HIV-1 RNA obtained from plasma and viral outgrowth of cultured cells and from proviral DNA were PCR-amplified and sequenced for evidence of clones of cells that produced infectious viruses. Clones were identified by host-proviral integration site analysis. RESULTS HIV-1 genomic RNAs with identical sequences were identified in plasma samples from all eight donors. The identical viral RNA sequences did not change over time and lacked resistance to the ART regimen. In four of the donors, viral RNA sequences obtained from plasma matched those sequences from viral outgrowth cultures, indicating that the viruses were replication-competent. Integration sites for infectious proviruses from those four donors were mapped to introns of theMATR3,ZNF268,ZNF721/ABCA11P, andABCA11Pgenes. The sizes of the clones were from 50 million to 350 million cells. CONCLUSION Clones of HIV-1-infected cells producing virus can cause failure of ART to suppress viremia despite medication adherence and absence of drug resistance. The mechanisms involved in clonal expansion and persistence need to be defined to eliminate viremia and the HIV-1 reservoir.

ACS Style

Elias K. Halvas; Kevin W. Joseph; Leah D. Brandt; Shuang Guo; Michele D. Sobolewski; Jana L. Jacobs; Camille Tumiotto; John K. Bui; Joshua C. Cyktor; Brandon F. Keele; Gene D. Morse; Michael J. Bale; Mary F. Kearney; John M. Coffin; Jason W. Rausch; Xiaolin Wu; Stephen H. Hughes; John W. Mellors. HIV-1 Viremia Not Suppressible By Antiretroviral Therapy Can Originate from Large T-Cell Clones Producing Infectious Virus. 2020, 1 .

AMA Style

Elias K. Halvas, Kevin W. Joseph, Leah D. Brandt, Shuang Guo, Michele D. Sobolewski, Jana L. Jacobs, Camille Tumiotto, John K. Bui, Joshua C. Cyktor, Brandon F. Keele, Gene D. Morse, Michael J. Bale, Mary F. Kearney, John M. Coffin, Jason W. Rausch, Xiaolin Wu, Stephen H. Hughes, John W. Mellors. HIV-1 Viremia Not Suppressible By Antiretroviral Therapy Can Originate from Large T-Cell Clones Producing Infectious Virus. . 2020; ():1.

Chicago/Turabian Style

Elias K. Halvas; Kevin W. Joseph; Leah D. Brandt; Shuang Guo; Michele D. Sobolewski; Jana L. Jacobs; Camille Tumiotto; John K. Bui; Joshua C. Cyktor; Brandon F. Keele; Gene D. Morse; Michael J. Bale; Mary F. Kearney; John M. Coffin; Jason W. Rausch; Xiaolin Wu; Stephen H. Hughes; John W. Mellors. 2020. "HIV-1 Viremia Not Suppressible By Antiretroviral Therapy Can Originate from Large T-Cell Clones Producing Infectious Virus." , no. : 1.

Journal article
Published: 31 January 2020 in Journal of Virology
Reads 0
Downloads 0

There are limited data about the proviral landscape in children exhibiting long-term suppression after early treatment, particularly in Sub-Saharan Africa where HIV-1 subtype C predominates. Investigating the sequence-intact reservoir could provide insight on the mechanisms by which intact proviruses persist and inform ongoing cure efforts. Through nearly full-length proviral amplification and sequencing (NFL-PAS), we generated 733 NFL-PAS amplicons from eight children. We showed that rare, genetically intact proviruses could be detected in children who initiated ART after 2.3 months of age. The frequency of intact proviruses was lower ( P < 0.05) than that reported for HIV subtype B-infected adults treated during early HIV infection. We show that cells harboring genetically intact HIV proviruses are rare in children exhibiting long-term suppression after early treatment and may require the processing of a large number of cells to assess reservoir size. This points to the need for efficient methods to accurately quantify latent reservoirs, particularly in pediatric studies where sample availability is limited.

ACS Style

Mary Grace Katusiime; Elias K. Halvas; Imogen Wright; Kevin Joseph; Michael J. Bale; Bronwyn Kirby-McCullough; Susan Engelbrecht; Wei Shao; Wei-Shau Hu; Mark F. Cotton; John W. Mellors; Mary Kearney; Gert U. van Zyl. Intact HIV Proviruses Persist in Children Seven to Nine Years after Initiation of Antiretroviral Therapy in the First Year of Life. Journal of Virology 2020, 94, 1 .

AMA Style

Mary Grace Katusiime, Elias K. Halvas, Imogen Wright, Kevin Joseph, Michael J. Bale, Bronwyn Kirby-McCullough, Susan Engelbrecht, Wei Shao, Wei-Shau Hu, Mark F. Cotton, John W. Mellors, Mary Kearney, Gert U. van Zyl. Intact HIV Proviruses Persist in Children Seven to Nine Years after Initiation of Antiretroviral Therapy in the First Year of Life. Journal of Virology. 2020; 94 (4):1.

Chicago/Turabian Style

Mary Grace Katusiime; Elias K. Halvas; Imogen Wright; Kevin Joseph; Michael J. Bale; Bronwyn Kirby-McCullough; Susan Engelbrecht; Wei Shao; Wei-Shau Hu; Mark F. Cotton; John W. Mellors; Mary Kearney; Gert U. van Zyl. 2020. "Intact HIV Proviruses Persist in Children Seven to Nine Years after Initiation of Antiretroviral Therapy in the First Year of Life." Journal of Virology 94, no. 4: 1.

Journal article
Published: 25 January 2020 in Viruses
Reads 0
Downloads 0

Combination antiretroviral therapy (cART) controls but does not eradicate HIV infection; HIV persistence is the principal obstacle to curing infections. The proportion of defective proviruses increases during cART, but the dynamics of this process are not well understood, and a quantitative analysis of how the proviral landscape is reshaped after cART is initiated is critical to understanding how HIV persists. Here, we studied longitudinal samples from HIV infected individuals undergoing long term cART using multiplexed Droplet Digital PCR (ddPCR) approaches to quantify the proportion of deleted proviruses in lymphocytes. In most individuals undergoing cART, HIV proviruses that contain gag are lost more quickly than those that lack gag. Increases in the fraction of gag-deleted proviruses occurred only after 1–2 years of therapy, suggesting that the immune system, and/or toxicity of viral re-activation helps to gradually shape the proviral landscape. After 10–15 years on therapy, there were as many as 3.5–5 times more proviruses in which gag was deleted or highly defective than those containing intact gag. We developed a provirus-specific ddPCR approach to quantify individual clones. Investigation of a clone of cells containing a deleted HIV provirus integrated in the HORMAD2 gene revealed that the cells underwent a massive expansion shortly after cART was initiated until the clone, which was primarily in effector memory cells, dominated the population of proviruses for over 6 years. The expansion of this HIV-infected clone had substantial effects on the overall proviral population.

ACS Style

Elizabeth M. Anderson; Francesco R. Simonetti; Robert J. Gorelick; Shawn Hill; Monica A. Gouzoulis; Jennifer Bell; Catherine Rehm; Liliana Pérez; Eli Boritz; Xiaolin Wu; Daria Wells; Stephen H. Hughes; Venigalla Rao; John M. Coffin; Mary F. Kearney; Frank Maldarelli. Dynamic Shifts in the HIV Proviral Landscape During Long Term Combination Antiretroviral Therapy: Implications for Persistence and Control of HIV Infections. Viruses 2020, 12, 136 .

AMA Style

Elizabeth M. Anderson, Francesco R. Simonetti, Robert J. Gorelick, Shawn Hill, Monica A. Gouzoulis, Jennifer Bell, Catherine Rehm, Liliana Pérez, Eli Boritz, Xiaolin Wu, Daria Wells, Stephen H. Hughes, Venigalla Rao, John M. Coffin, Mary F. Kearney, Frank Maldarelli. Dynamic Shifts in the HIV Proviral Landscape During Long Term Combination Antiretroviral Therapy: Implications for Persistence and Control of HIV Infections. Viruses. 2020; 12 (2):136.

Chicago/Turabian Style

Elizabeth M. Anderson; Francesco R. Simonetti; Robert J. Gorelick; Shawn Hill; Monica A. Gouzoulis; Jennifer Bell; Catherine Rehm; Liliana Pérez; Eli Boritz; Xiaolin Wu; Daria Wells; Stephen H. Hughes; Venigalla Rao; John M. Coffin; Mary F. Kearney; Frank Maldarelli. 2020. "Dynamic Shifts in the HIV Proviral Landscape During Long Term Combination Antiretroviral Therapy: Implications for Persistence and Control of HIV Infections." Viruses 12, no. 2: 136.

Letters to the editor
Published: 01 January 2020 in AIDS Research and Human Retroviruses
Reads 0
Downloads 0
ACS Style

Wei Shao; Jigui Shan; Wei-Shau Hu; Elias Konstantine Halvas; John W. Mellors; John M. Coffin; Mary Kearney. HIV Proviral Sequence Database: A New Public Database for Near Full-Length HIV Proviral Sequences and Their Meta-Analyses. AIDS Research and Human Retroviruses 2020, 36, 1 -3.

AMA Style

Wei Shao, Jigui Shan, Wei-Shau Hu, Elias Konstantine Halvas, John W. Mellors, John M. Coffin, Mary Kearney. HIV Proviral Sequence Database: A New Public Database for Near Full-Length HIV Proviral Sequences and Their Meta-Analyses. AIDS Research and Human Retroviruses. 2020; 36 (1):1-3.

Chicago/Turabian Style

Wei Shao; Jigui Shan; Wei-Shau Hu; Elias Konstantine Halvas; John W. Mellors; John M. Coffin; Mary Kearney. 2020. "HIV Proviral Sequence Database: A New Public Database for Near Full-Length HIV Proviral Sequences and Their Meta-Analyses." AIDS Research and Human Retroviruses 36, no. 1: 1-3.

Preprint content
Published: 06 December 2019
Reads 0
Downloads 0

The prevalence of HIV-1 drug resistance is increasing worldwide and monitoring its emergence is important for the successful management of populations receiving combination antiretroviral therapy (cART). Using Ultrasensitive Single-Genome Sequencing (uSGS), a next-generation method that avoids PCR bias and PCR recombination, a recent report showed that pre-existing dual-class drug resistance mutations linked on the same viral genomes were predictive of treatment failure while unlinked mutations were not. Because of the large numbers of sequences generated by uSGS and other next-generation sequencing methods, it is difficult to assess each sequence individually for linked resistance mutations. Several software/programs exist to report the frequencies of individual mutations in large datasets but they provide no information on their linkage. Here, we report the HIV-DRLink program, a research tool that provides mutation frequencies in the total dataset as well as their linkage to other mutations conferring resistance to the same or different drug classes. The HIV-DRLink program should only be used on datasets generated by methods that eliminate artifacts due to PCR recombination, for example, standard Single-Genome Sequencing (SGS) or Ultrasensitive Single-Genome Sequencing (uSGS). HIV-DRLink is exclusively a research tool and is not intended to inform clinical decisions.

ACS Style

Wei Shao; Valerie F. Boltz; Junko Hattori; Michael J. Bale; Frank Maldarelli; John M. Coffin; Mary F. Kearney. HIV-DRLink: A tool for detecting linked HIV-1 drug resistance mutations in next generation sequencing data. 2019, 866715 .

AMA Style

Wei Shao, Valerie F. Boltz, Junko Hattori, Michael J. Bale, Frank Maldarelli, John M. Coffin, Mary F. Kearney. HIV-DRLink: A tool for detecting linked HIV-1 drug resistance mutations in next generation sequencing data. . 2019; ():866715.

Chicago/Turabian Style

Wei Shao; Valerie F. Boltz; Junko Hattori; Michael J. Bale; Frank Maldarelli; John M. Coffin; Mary F. Kearney. 2019. "HIV-DRLink: A tool for detecting linked HIV-1 drug resistance mutations in next generation sequencing data." , no. : 866715.

Journal article
Published: 27 November 2019 in Proceedings of the National Academy of Sciences
Reads 0
Downloads 0

Understanding HIV-1 persistence despite antiretroviral therapy (ART) is of paramount importance. Both single-genome sequencing (SGS) and integration site analysis (ISA) provide useful information regarding the structure of persistent HIV DNA populations; however, until recently, there was no way to link integration sites to their cognate proviral sequences. Here, we used multiple-displacement amplification (MDA) of cellular DNA diluted to a proviral endpoint to obtain full-length proviral sequences and their corresponding sites of integration. We applied this method to lymph node and peripheral blood mononuclear cells from 5 ART-treated donors to determine whether groups of identical subgenomic sequences in the 2 compartments are the result of clonal expansion of infected cells or a viral genetic bottleneck. We found that identical proviral sequences can result from both cellular expansion and viral genetic bottlenecks occurring prior to ART initiation and following ART failure. We identified an expanded T cell clone carrying an intact provirus that matched a variant previously detected by viral outgrowth assays and expanded clones with wild-type and drug-resistant defective proviruses. We also found 2 clones from 1 donor that carried identical proviruses except for nonoverlapping deletions, from which we could infer the sequence of the intact parental virus. Thus, MDA-SGS can be used for “viral reconstruction” to better understand intrapatient HIV-1 evolution and to determine the clonality and structure of proviruses within expanded clones, including those with drug-resistant mutations. Importantly, we demonstrate that identical sequences observed by standard SGS are not always sufficient to establish proviral clonality.

ACS Style

Sean C. Patro; Leah D. Brandt; Michael Bale; Elias K. Halvas; Kevin W. Joseph; Wei Shao; Xiaolin Wu; Shuang Guo; Ben Murrell; Ann Wiegand; Jonathan Spindler; Castle Raley; Christopher Hautman; Michele Sobolewski; Christine M. Fennessey; Wei-Shau Hu; Brian Luke; Jenna M. Hasson; Aurelie Niyongabo; Adam A. Capoferri; Brandon F. Keele; Jeff Milush; Rebecca Hoh; Steven Deeks; Frank Maldarelli; Stephen H. Hughes; John M. Coffin; Jason W. Rausch; John W. Mellors; Mary Kearney. Combined HIV-1 sequence and integration site analysis informs viral dynamics and allows reconstruction of replicating viral ancestors. Proceedings of the National Academy of Sciences 2019, 116, 25891 -25899.

AMA Style

Sean C. Patro, Leah D. Brandt, Michael Bale, Elias K. Halvas, Kevin W. Joseph, Wei Shao, Xiaolin Wu, Shuang Guo, Ben Murrell, Ann Wiegand, Jonathan Spindler, Castle Raley, Christopher Hautman, Michele Sobolewski, Christine M. Fennessey, Wei-Shau Hu, Brian Luke, Jenna M. Hasson, Aurelie Niyongabo, Adam A. Capoferri, Brandon F. Keele, Jeff Milush, Rebecca Hoh, Steven Deeks, Frank Maldarelli, Stephen H. Hughes, John M. Coffin, Jason W. Rausch, John W. Mellors, Mary Kearney. Combined HIV-1 sequence and integration site analysis informs viral dynamics and allows reconstruction of replicating viral ancestors. Proceedings of the National Academy of Sciences. 2019; 116 (51):25891-25899.

Chicago/Turabian Style

Sean C. Patro; Leah D. Brandt; Michael Bale; Elias K. Halvas; Kevin W. Joseph; Wei Shao; Xiaolin Wu; Shuang Guo; Ben Murrell; Ann Wiegand; Jonathan Spindler; Castle Raley; Christopher Hautman; Michele Sobolewski; Christine M. Fennessey; Wei-Shau Hu; Brian Luke; Jenna M. Hasson; Aurelie Niyongabo; Adam A. Capoferri; Brandon F. Keele; Jeff Milush; Rebecca Hoh; Steven Deeks; Frank Maldarelli; Stephen H. Hughes; John M. Coffin; Jason W. Rausch; John W. Mellors; Mary Kearney. 2019. "Combined HIV-1 sequence and integration site analysis informs viral dynamics and allows reconstruction of replicating viral ancestors." Proceedings of the National Academy of Sciences 116, no. 51: 25891-25899.

Research article
Published: 14 October 2019 in PLOS Pathogens
Reads 0
Downloads 0

Studies have demonstrated that intensive ART alone is not capable of eradicating HIV-1, as the virus rebounds within a few weeks upon treatment interruption. Viral rebound may be induced from several cellular subsets; however, the majority of proviral DNA has been found in antigen experienced resting CD4+ T cells. To achieve a cure for HIV-1, eradication strategies depend upon both understanding mechanisms that drive HIV-1 persistence as well as sensitive assays to measure the frequency of infected cells after therapeutic interventions. Assays such as the quantitative viral outgrowth assay (QVOA) measure HIV-1 persistence during ART by ex vivo activation of resting CD4+ T cells to induce latency reversal; however, recent studies have shown that only a fraction of replication-competent viruses are inducible by primary mitogen stimulation. Previous studies have shown a correlation between the acquisition of effector memory phenotype and HIV-1 latency reversal in quiescent CD4+ T cell subsets that harbor the reservoir. Here, we apply our mechanistic understanding that differentiation into effector memory CD4+ T cells more effectively promotes HIV-1 latency reversal to significantly improve proviral measurements in the QVOA, termed differentiation QVOA (dQVOA), which reveals a significantly higher frequency of the inducible HIV-1 replication-competent reservoir in resting CD4+ T cells.

ACS Style

Elizabeth R. Wonderlich; Krupa Subramanian; Bryan Cox; Ann Wiegand; Carol Lackman-Smith; Michael Bale; Mars Stone; Rebecca Hoh; Mary Kearney; Frank Maldarelli; Steven G. Deeks; Michael P. Busch; Roger G. Ptak; Deanna A. Kulpa. Effector memory differentiation increases detection of replication-competent HIV-l in resting CD4+ T cells from virally suppressed individuals. PLOS Pathogens 2019, 15, e1008074 .

AMA Style

Elizabeth R. Wonderlich, Krupa Subramanian, Bryan Cox, Ann Wiegand, Carol Lackman-Smith, Michael Bale, Mars Stone, Rebecca Hoh, Mary Kearney, Frank Maldarelli, Steven G. Deeks, Michael P. Busch, Roger G. Ptak, Deanna A. Kulpa. Effector memory differentiation increases detection of replication-competent HIV-l in resting CD4+ T cells from virally suppressed individuals. PLOS Pathogens. 2019; 15 (10):e1008074.

Chicago/Turabian Style

Elizabeth R. Wonderlich; Krupa Subramanian; Bryan Cox; Ann Wiegand; Carol Lackman-Smith; Michael Bale; Mars Stone; Rebecca Hoh; Mary Kearney; Frank Maldarelli; Steven G. Deeks; Michael P. Busch; Roger G. Ptak; Deanna A. Kulpa. 2019. "Effector memory differentiation increases detection of replication-competent HIV-l in resting CD4+ T cells from virally suppressed individuals." PLOS Pathogens 15, no. 10: e1008074.

Journal article
Published: 03 October 2019 in JCI Insight
Reads 0
Downloads 0

We hypothesized that HIV-1 with dual-class but not single-class drug resistance mutations linked on the same viral genome, present in the virus population before initiation of antiretroviral therapy (ART), would be associated with failure of ART to suppress viremia. To test this hypothesis, we utilized an ultrasensitive single-genome sequencing assay that detects rare HIV-1 variants with linked drug resistance mutations (DRMs). A case (ART failure) control (nonfailure) study was designed to assess whether linkage of DRMs in pre-ART plasma samples was associated with treatment outcome in the nevirapine/tenofovir/emtricitabine arm of the AIDS Clinical Trials Group A5208/Optimal Combined Therapy After Nevirapine Exposure (OCTANE) Trial 1 among women who had received prior single-dose nevirapine. Ultrasensitive single-genome sequencing revealed a significant association between pre-ART HIV variants with DRMs to 2 drug classes linked on the same genome (dual class) and failure of combination ART with 3 drugs to suppress viremia. In contrast, linked, single-class DRMs were not associated with ART failure. We conclude that linked dual-class DRMs present before the initiation of ART are associated with ART failure, whereas linked single-class DRMs are not.

ACS Style

Valerie F. Boltz; Wei Shao; Michael J. Bale; Elias K. Halvas; Brian Luke; James A. McIntyre; Robert T. Schooley; Shahin Lockman; Judith S. Currier; Fred Sawe; Evelyn Hogg; Michael D. Hughes; Mary Kearney; John M. Coffin; John W. Mellors. Linked dual-class HIV resistance mutations are associated with treatment failure. JCI Insight 2019, 4, 1 .

AMA Style

Valerie F. Boltz, Wei Shao, Michael J. Bale, Elias K. Halvas, Brian Luke, James A. McIntyre, Robert T. Schooley, Shahin Lockman, Judith S. Currier, Fred Sawe, Evelyn Hogg, Michael D. Hughes, Mary Kearney, John M. Coffin, John W. Mellors. Linked dual-class HIV resistance mutations are associated with treatment failure. JCI Insight. 2019; 4 (19):1.

Chicago/Turabian Style

Valerie F. Boltz; Wei Shao; Michael J. Bale; Elias K. Halvas; Brian Luke; James A. McIntyre; Robert T. Schooley; Shahin Lockman; Judith S. Currier; Fred Sawe; Evelyn Hogg; Michael D. Hughes; Mary Kearney; John M. Coffin; John W. Mellors. 2019. "Linked dual-class HIV resistance mutations are associated with treatment failure." JCI Insight 4, no. 19: 1.

Original research article
Published: 01 October 2019 in Frontiers in Microbiology
Reads 0
Downloads 0

Background: HIV-1 proviruses can persist during ART in clonally-expanded populations of CD4+ T cells. To date, few examples of an expanded clones containing replication-competent proviruses exist, although it is suspected to be common. One such clone, denoted AMBI-1 (Maldarelli et al., 2014), was also a source of persistent viremia on ART, begging the question of how the AMBI-1 clone can survive despite infection with a replication-competent, actively-expressing provirus. We hypothesized that only a small fraction of cells within the AMBI-1 clone are activated to produce virus particles during cell division while the majority remain latent despite division, ensuring their survival. To address this question, we determined the fraction of HIV-1 proviruses within the AMBI-1 clone that expresses unspliced cell-associated RNA during ART and compared this fraction to 33 other infected T cell clones within the same individual. Results: In total, 34 different clones carrying either intact or defective proviruses in “Patient 1” from Maldarelli et al. (2014) were assessed. We found that 2.3% of cells within the AMBI-1 clone contained unspliced HIV-1 RNA. Highest levels of HIV-1 RNA were found in the effector memory (EM) T cell subset. The fraction of cells within clones that contained HIV-1 RNA was not different in clones with intact (median 2.3%) versus defective (median 3.5%) proviruses (p = 0.2). However, higher fractions and levels of RNA were found in cells with proviruses containing multiple drug resistance mutations, including those contributing to rebound viremia. Conclusion: These findings show that the vast majority of HIV-1 proviruses within expanded T cell clones, including intact proviruses, may be transcriptionally silent at any given time, implying that infected T cells may be able to be activated to proliferate without inducing the expression of the integrated provirus or, alternatelively, may be able to proliferate without cellular activation. The results of this study suggest that the long, presumed correlation between the level of cellular and proviral activation may not be accurate and, therefore, requires further investigation.

ACS Style

Andrew Musick; Jonathan Spindler; Eli Boritz; Liliana Pérez; Daniel Crespo-Vélez; Sean C. Patro; Michele D. Sobolewski; Michael Bale; Carolyn Reid; Brandon F. Keele; Adam Capoferri; Wei Shao; Ann Wiegand; Francesco Roberto Simonetti; John W. Mellors; Stephen H. Hughes; John M. Coffin; Frank Maldarelli; Mary F. Kearney. HIV Infected T Cells Can Proliferate in vivo Without Inducing Expression of the Integrated Provirus. Frontiers in Microbiology 2019, 10, 2204 .

AMA Style

Andrew Musick, Jonathan Spindler, Eli Boritz, Liliana Pérez, Daniel Crespo-Vélez, Sean C. Patro, Michele D. Sobolewski, Michael Bale, Carolyn Reid, Brandon F. Keele, Adam Capoferri, Wei Shao, Ann Wiegand, Francesco Roberto Simonetti, John W. Mellors, Stephen H. Hughes, John M. Coffin, Frank Maldarelli, Mary F. Kearney. HIV Infected T Cells Can Proliferate in vivo Without Inducing Expression of the Integrated Provirus. Frontiers in Microbiology. 2019; 10 ():2204.

Chicago/Turabian Style

Andrew Musick; Jonathan Spindler; Eli Boritz; Liliana Pérez; Daniel Crespo-Vélez; Sean C. Patro; Michele D. Sobolewski; Michael Bale; Carolyn Reid; Brandon F. Keele; Adam Capoferri; Wei Shao; Ann Wiegand; Francesco Roberto Simonetti; John W. Mellors; Stephen H. Hughes; John M. Coffin; Frank Maldarelli; Mary F. Kearney. 2019. "HIV Infected T Cells Can Proliferate in vivo Without Inducing Expression of the Integrated Provirus." Frontiers in Microbiology 10, no. : 2204.

Research article
Published: 25 September 2019 in Science Advances
Reads 0
Downloads 0

HIV persistence during combination antiretroviral therapy (cART) is the principal obstacle to cure. Mechanisms responsible for persistence remain uncertain; infections may be maintained by persistence and clonal expansion of infected cells or by ongoing replication in anatomic locations with poor antiretroviral penetration. These mechanisms require different strategies for eradication, and determining their contributions to HIV persistence is essential. We used phylogenetic approaches to investigate, at the DNA level, HIV populations in blood, lymphoid, and other infected tissues obtained at colonoscopy or autopsy in individuals who were on cART for 8 to 16 years. We found no evidence of ongoing replication or compartmentalization of HIV; we did detect clonal expansion of infected cells that were present before cART. Long-term persistence, and not ongoing replication, is primarily responsible for maintaining HIV. HIV-infected cells present when cART is initiated represent the only identifiable source of persistence and is the appropriate focus for eradication.

ACS Style

G. Bozzi; F. R. Simonetti; S. A. Watters; E. M. Anderson; M. Gouzoulis; M. F. Kearney; P. Rote; C. Lange; W. Shao; R. Gorelick; B. Fullmer; S. Kumar; S. Wank; S. Hewitt; D. E. Kleiner; J. Hattori; M. J. Bale; S. Hill; J. Bell; C. Rehm; Z. Grossman; R. Yarchoan; T. Uldrick; F. Maldarelli. No evidence of ongoing HIV replication or compartmentalization in tissues during combination antiretroviral therapy: Implications for HIV eradication. Science Advances 2019, 5, eaav2045 .

AMA Style

G. Bozzi, F. R. Simonetti, S. A. Watters, E. M. Anderson, M. Gouzoulis, M. F. Kearney, P. Rote, C. Lange, W. Shao, R. Gorelick, B. Fullmer, S. Kumar, S. Wank, S. Hewitt, D. E. Kleiner, J. Hattori, M. J. Bale, S. Hill, J. Bell, C. Rehm, Z. Grossman, R. Yarchoan, T. Uldrick, F. Maldarelli. No evidence of ongoing HIV replication or compartmentalization in tissues during combination antiretroviral therapy: Implications for HIV eradication. Science Advances. 2019; 5 (9):eaav2045.

Chicago/Turabian Style

G. Bozzi; F. R. Simonetti; S. A. Watters; E. M. Anderson; M. Gouzoulis; M. F. Kearney; P. Rote; C. Lange; W. Shao; R. Gorelick; B. Fullmer; S. Kumar; S. Wank; S. Hewitt; D. E. Kleiner; J. Hattori; M. J. Bale; S. Hill; J. Bell; C. Rehm; Z. Grossman; R. Yarchoan; T. Uldrick; F. Maldarelli. 2019. "No evidence of ongoing HIV replication or compartmentalization in tissues during combination antiretroviral therapy: Implications for HIV eradication." Science Advances 5, no. 9: eaav2045.

Journal article
Published: 23 September 2019 in Journal of Clinical Investigation
Reads 0
Downloads 0

To investigate the possibility that HIV-1 replication in lymph nodes sustains the reservoir during ART, we looked for evidence of viral replication in 5 donors after up to 13 years of viral suppression. We characterized proviral populations in lymph nodes and peripheral blood before and during ART, evaluated the levels of viral RNA expression in single lymph node and blood cells, and characterized the proviral integration sites in paired lymph node and blood samples. Proviruses with identical sequences, identical integration sites, and similar levels of RNA expression were found in lymph nodes and blood samples collected during ART, and no single sequence with significant divergence from the pretherapy population was present in either blood or lymph nodes. These findings show that all detectable persistent HIV-1 infection is consistent with maintenance in lymph nodes by clonal proliferation of cells infected before ART and not by ongoing viral replication during ART.

ACS Style

William McManus; Michael J. Bale; Jonathan Spindler; Ann Wiegand; Andrew Musick; Sean C. Patro; Michele D. Sobolewski; Victoria K. Musick; Elizabeth M. Anderson; Joshua C. Cyktor; Elias K. Halvas; Wei Shao; Daria Wells; Xiaolin Wu; Brandon F. Keele; Jeffrey M. Milush; Rebecca Hoh; John W. Mellors; Stephen H. Hughes; Steven G. Deeks; John M. Coffin; Mary Kearney. HIV-1 in lymph nodes is maintained by cellular proliferation during antiretroviral therapy. Journal of Clinical Investigation 2019, 129, 4629 -4642.

AMA Style

William McManus, Michael J. Bale, Jonathan Spindler, Ann Wiegand, Andrew Musick, Sean C. Patro, Michele D. Sobolewski, Victoria K. Musick, Elizabeth M. Anderson, Joshua C. Cyktor, Elias K. Halvas, Wei Shao, Daria Wells, Xiaolin Wu, Brandon F. Keele, Jeffrey M. Milush, Rebecca Hoh, John W. Mellors, Stephen H. Hughes, Steven G. Deeks, John M. Coffin, Mary Kearney. HIV-1 in lymph nodes is maintained by cellular proliferation during antiretroviral therapy. Journal of Clinical Investigation. 2019; 129 (11):4629-4642.

Chicago/Turabian Style

William McManus; Michael J. Bale; Jonathan Spindler; Ann Wiegand; Andrew Musick; Sean C. Patro; Michele D. Sobolewski; Victoria K. Musick; Elizabeth M. Anderson; Joshua C. Cyktor; Elias K. Halvas; Wei Shao; Daria Wells; Xiaolin Wu; Brandon F. Keele; Jeffrey M. Milush; Rebecca Hoh; John W. Mellors; Stephen H. Hughes; Steven G. Deeks; John M. Coffin; Mary Kearney. 2019. "HIV-1 in lymph nodes is maintained by cellular proliferation during antiretroviral therapy." Journal of Clinical Investigation 129, no. 11: 4629-4642.

Journal article
Published: 20 June 2019 in JCI Insight
Reads 0
Downloads 0

In HIV-infected individuals on long-term antiretroviral therapy (ART), more than 40% of the infected cells are in clones. Although most HIV proviruses present in individuals on long-term ART are defective, including those in clonally expanded cells, there is increasing evidence that clones carrying replication-competent proviruses are common in patients on long-term ART and form part of the HIV reservoir that makes it impossible to cure HIV infection with current ART alone. Given the importance of clonal expansion in HIV persistence, we determined how soon after HIV acquisition infected clones can grow large enough to be detected (clones larger than ca. 1 × 105 cells). We studied 12 individuals sampled in early HIV infection (Fiebig stage III-V/VI) and 5 who were chronically infected. The recently infected individuals were started on ART at or near the time of diagnosis. We isolated more than 6,500 independent integration sites from peripheral blood mononuclear cells before ART was initiated and after 0.5-18 years of suppressive ART. Some infected clones could be detected approximately 4 weeks after HIV infection and some of these clones persisted for years. The results help to explain how the reservoir is established early and persists for years.

ACS Style

John M. Coffin; David W. Wells; Jennifer M. Zerbato; JoAnn D. Kuruc; Shuang Guo; Brian T. Luke; Joseph J. Eron; Michael Bale; Jonathan Spindler; Francesco Roberto Simonetti; Shawn Hill; Mary F. Kearney; Frank Maldarelli; Xiaolin Wu; John W. Mellors; Stephen H. Hughes. Clones of infected cells arise early in HIV-infected individuals. JCI Insight 2019, 4, 1 .

AMA Style

John M. Coffin, David W. Wells, Jennifer M. Zerbato, JoAnn D. Kuruc, Shuang Guo, Brian T. Luke, Joseph J. Eron, Michael Bale, Jonathan Spindler, Francesco Roberto Simonetti, Shawn Hill, Mary F. Kearney, Frank Maldarelli, Xiaolin Wu, John W. Mellors, Stephen H. Hughes. Clones of infected cells arise early in HIV-infected individuals. JCI Insight. 2019; 4 (12):1.

Chicago/Turabian Style

John M. Coffin; David W. Wells; Jennifer M. Zerbato; JoAnn D. Kuruc; Shuang Guo; Brian T. Luke; Joseph J. Eron; Michael Bale; Jonathan Spindler; Francesco Roberto Simonetti; Shawn Hill; Mary F. Kearney; Frank Maldarelli; Xiaolin Wu; John W. Mellors; Stephen H. Hughes. 2019. "Clones of infected cells arise early in HIV-infected individuals." JCI Insight 4, no. 12: 1.

Review
Published: 01 May 2019 in Current Opinion in HIV and AIDS
Reads 0
Downloads 0

Purpose of review Studies of HIV-1 genetic diversity can provide clues on the effect of antiretroviral therapy (ART) on viral replication, the mechanisms for viral persistence, and the efficacy of new interventions. This article reviews methods for interrogating intrahost HIV-1 diversity, addresses the ongoing debate regarding HIV-1 compartmentalization and replication during ART, and summarizes recent findings on the effects of curative strategies on HIV-1 populations. Recent findings HIV-1 replication in the blood is virtually halted upon the initiation of ART. However, proliferation of cells infected prior to ART provides a self-renewing reservoir for infection during ART. Current evidence supports that proliferation of infected cells is a mechanism for HIV-1 persistence in both the blood and the tissues. However, more studies are required to determine if tissue sanctuaries exist that may also allow viral replication during ART. Recent studies investigating potential curative interventions show little effect on the genetic landscape of HIV-1 infection and highlight the need to develop strategies targeting the proliferation of infected cells. Summary Using phylogeny to characterize HIV-1 genetic diversity and evolution during ART has demonstrated a lack of viral replication, the proliferation of infected cells, and provides one metric to measure the effect of new interventions aimed at achieving a functional cure for HIV-1.

ACS Style

Michael J. Bale; Mary Kearney. Review. Current Opinion in HIV and AIDS 2019, 14, 188 -193.

AMA Style

Michael J. Bale, Mary Kearney. Review. Current Opinion in HIV and AIDS. 2019; 14 (3):188-193.

Chicago/Turabian Style

Michael J. Bale; Mary Kearney. 2019. "Review." Current Opinion in HIV and AIDS 14, no. 3: 188-193.