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1.  HIV and Zika: When will we be able to end these epidemics? 
Retrovirology  2016;13:80.
doi:10.1186/s12977-016-0315-4
PMCID: PMC5111273  PMID: 27846847
2.  Resistance to reverse transcriptase inhibitors used in the treatment and prevention of HIV-1 infection 
Future microbiology  2015;10(11):1773-1782.
Inhibitors that target the retroviral enzyme reverse transcriptase (RT) have played an indispensable role in the treatment and prevention of HIV-1 infection. They can be grouped into two distinct therapeutic groups; namely the nucleoside and nucleotide RT inhibitors (NRTIs), and the nonnucleoside RT inhibitors (NNRTIs). NRTIs form the backbones of most first- and second-line antiretroviral therapy (ART) regimens formulated for the treatment of HIV-1 infection. They are also used to prevent mother-to-child transmission, and as pre-exposure prophylaxis in individuals at risk of HIV-1 infection. The NNRTIs nevirapine (NVP), efavirenz and rilpivirine also used to form part of first-line ART regimens, although this is no longer recommended, while etravirine can be used in salvage ART regimens. A single-dose of NVP administered to both mother and child has routinely been used in resource-limited settings to reduce the rate of HIV-1 transmission. Unfortunately, the development of HIV-1 resistance to RT inhibitors can compromise the efficacy of these antiviral drugs in both the treatment and prevention arenas. Here, we provide an up-to-date review on drug-resistance mutations in HIV-1 RT, and discuss their cross-resistance profiles, molecular mechanisms and clinical significance.
doi:10.2217/fmb.15.106
PMCID: PMC4813512  PMID: 26517190
HIV; reverse transcriptase; resistance; mutations; nucleoside; nonnucleoside
3.  Dolutegravir maintains a durable effect against HIV replication in tissue culture even after drug washout 
Journal of Antimicrobial Chemotherapy  2015;70(10):2810-2815.
Objectives
Of the currently approved HIV integrase strand transfer inhibitors (INSTIs), dolutegravir has shown greater efficacy than raltegravir at suppressing HIV-1 replication in treatment-experienced individuals. Biochemical experiments have also shown that dolutegravir has a longer dissociative half-life when bound to HIV integrase than does raltegravir. In order to study the intracellular efficacy of various INSTIs, we asked whether drug removal from INSTI-treated HIV-1-infected cells would result in different times to viral rebound. In addition, we assessed the role of the R263K substitution within the integrase ORF that is associated with low-level resistance to dolutegravir.
Methods
HIV-infected MT-2 cells were treated with dolutegravir, raltegravir or a third experimental INSTI (MK-2048) and the drugs were washed out after varying times. Viral replication was monitored by measuring reverse transcriptase (RT) activity in the culture fluids.
Results
We observed a significantly slower increase in RT activity after the removal of dolutegravir compared with raltegravir or MK-2048. The incubation time before the drug was removed also had an impact on the level of RT activity independently of the drug and virus used. The R263K substitution did not significantly impact on levels of RT activity after drug washout, suggesting that dolutegravir remained tightly bound to the integrase enzyme despite the presence of this mutation.
Conclusions
These results suggest that the residency time of INSTIs on integrase is a key factor in the activity of these drugs and that the anti-HIV activity of dolutegravir persists more effectively than that of other INSTIs after drug washout.
doi:10.1093/jac/dkv176
PMCID: PMC4566961  PMID: 26142476
4.  Reviewer acknowledgement 2015 
Retrovirology  2016;13:52.
doi:10.1186/s12977-016-0288-3
PMCID: PMC4972965
5.  Afri-Can Forum 2 
Mukudu, Hillary | Martinson, Neil | Sartorius, Benn | Coetzee, Jenny | Dietrich, Janan | Mokgatswana, Kgaugelo | Jewkes, Rachel | Gray, Glenda E. | Dugas, Marylène | Béhanzin, Luc | Guédou, Fernand A. | Gagnon, Marie-Pierre | Alary, Michel | Rutakumwa, Rwamahe | Mbonye, Martin | Kiwanuka, Thadeus | Nakamanya, Sarah | Muhumuza, Richard | Nalukenge, Winfred | Seeley, Janet | Atujuna, Millicent | Wallace, Melissa | Brown, Ben | Bekker, Linda Gail | Newman, Peter A. | Harryparsad, Rushil | Olivier, Abraham J. | Jaspan, Heather B. | Wilson, Douglas | Dietrich, Janan | Martinson, Neil | Mukudu, Hillary | Mkhize, Nonhlanhla | Morris, Lynn | Cianci, Gianguido | Dinh, Minh | Hope, Thomas | Passmore, Jo-Ann S. | Gray, Clive M. | Henrick, Bethany M. | Yao, Xiao-Dan | Rosenthal, Kenneth L. | Henrick, Bethany M. | Yao, Xiao-Dan | Drannik, Anna G. | Abimiku, Alash’le | Rosenthal, Kenneth L. | Chanzu, Nadia | Mwanda, Walter | Oyugi, Julius | Anzala, Omu | Mbow, Moustapha | Jallow, Sabelle | Thiam, Moussa | Davis, Alberta | Diouf, Assane | Ndour, Cheikh T. | Seydi, Moussa | Dieye, Tandakha N. | Mboup, Souleymane | Goodier, Martin | Rilley, Eleanor | Jaye, Assan | Yao, Xiao-Dan | Omange, RW. | Henrick, Bethany M. | Lester, Richard T. | Kimani, Joshua | Ball, T. Blake | Plummer, Francis A. | Rosenthal, Kenneth L. | Béhanzin, Luc | Guédou, Fernand A. | Geraldo, Nassirou | Mastétsé, Ella Goma | Sossa, Jerôme Charles | Zannou, Marcel Djimon | Alary, Michel | Osawe, Sophia | Okpokoro, Evaezi | Okolo, Felicia | Umaru, Stephen | Abimiku, Rebecca | Audu, Sam | Datong, Pam | Abimiku, Alash’le | Nyange, Jacquelyn | Olenja, Joyce | Mutua, Gaudensia | Jaoko, Walter | Omosa-Manyonyi, Gloria | Farah, Bashir | Khaniri, Maureen | Anzala, Omu | Cockcroft, Anne | Tonkin, Kendra | Girish, Indu | Mhati, Puna | Cunningham, Ashley | Andersson, Neil | Farah, Bashir | Indangasi, Jackton | Jaoko, Walter | Mutua, Gaudensia | Khaniri, Maureen | Nyange, Jacquelyn | Anzala, Omu | Diphoko, Thabo | Gaseitsiwe, Simani | Maiswe, Victoria | Iketleng, Thato | Maruapula, Dorcas | Bedi, Keabetswe | Moyo, Sikhulile | Musonda, Rosemary | Wainberg, Mark | Makhema, Joseph | Novitsky, Vladimir | Marlink, Richard | Essex, Max | Okoboi, Stephen | Ssali, Livingstone | Kalibala, Sam | Birungi, Josephine | Egessa, Aggrey | Wangisi, Jonathan | Okullu, Lyavala Joanne | Bakanda, Celestin | Obare, Francis | Boer, I. Marion Sumari-de | Semvua, Hadija H. | van den Boogaard, Jossy | Kiwango, Krisanta W. | Ngowi, Kennedy M. | Nieuwkerk, Pythia T. | Aarnoutse, Rob E. | Kiwelu, Ireen | Muro, Eva | Kibiki, Gibson S. | Datiri, Ruth | Choji, Grace | Osawe, Sophia | Okpokoro, Evaezi | Okolo, Felicia | Umaru, Stephen | Abimiku, Rebecca | Audu, Samuel | Datong, Pam | Abimiku, Alash’le | Fomsgaard, A. | Karlsson, I. | Jensen, K. J. | Jensen, S. S. | Leo-Hansen, C. | Jespersen, S. | Da Silva Té, D. | Rodrigues, C. M. | da Silva, Z. J. | Janitzek, C. M. | Gerstoft, J. | Kronborg, G. | Okpokoro, Evaezi | Osawe, Sophia | Daitiri, Ruth | Choji, Grace | Umaru, Stephen | Okolo, Felicia | Datong, Pam | Abimiku, Alash’le | Emily, Nyariki | Joyce, Olenja | Robert, Lorway R. | Anzala, Anzala | Viljoen, Katie | Wendoh, Jerome | Kidzeru, Elvis | Karaoz, Ulas | Brodie, Eoin | Botha, Gerrit | Mulder, Nicola | Gray, Clive | Cameron, William | Stintzi, Alain | Jaspan, Heather | Levett, Paul N. | Alexander, David | Gulzar, Naveed | Grewal, Prabvir S. | Poon, Art F. Y. | Brumme, Zabrina | Harrigan, P. Richard | Brooks, James I. | Sandstrom, Paul A. | Calvez, Stryker | Sanche, Stephen E. | Scott, Jamie K. | Swartz, Leslie | Kagee, Ashraf | Lesch, Anthea | Kafaar, Zuhayr | De Wet, Anneliese | Okpokoro, Evaezi | Osawe, Sophia | Daitiri, Ruth | Choji, Grace | Umaru, Stephen | Okolo, Felicia | Datong, Pam | Abimiku, Alash’le | Dietrich, Janan | Smith, Tricia | Cotton, Laura | Hornschuh, Stefanie | van der Watt, Martin | Miller, Cari L. | Gray, Glenda | Smit, Jenni | Jaggernath, Manjeetha | Ndung’u, Thumbi | Brockman, Mark | Kaida, Angela | Akolo, Maureen | Kimani, Joshua | Gelmon, Larry | Chitwa, Michael | Osero, Justus | Cockcroft, Anne | Marokoane, Nobantu | Kgakole, Leagajang | Maswabi, Boikhutso | Mpofu, Neo | Ansari, Umaira | Andersson, Neil | Nakinobe, Elizabeth | Miiro, George Mukalazi | Zalwango, Flavia | Nakiyingi-Miiro, Jessica | Kaleebu, Potiano | Semwanga, John Ross | Nyanzi, Emily | Musoke, Saidat Namuli | Nakinobe, Elizabeth | Miiro, George | Mbidde, Edward Katongole | Lutalo, Tom | Kaleebu, Pontiano | Handema, Ray | Chianzu, Graham P. | Thiam, Moussa | Diagne-Gueye, Diabou | Ndiaye, Mame K. | Mbow, Moustapha | Ndiaye, Birahim P. | Traore, Ibrahima | Dia, Mamadou C. | Thomas, Gilleh | Tour-Kane, Coumba | Mboup, Souleymane | Jaye, Assan | Nyanzi, Emily | Mbidde, Edward Katongole | Kaleebu, Pontiano | Mpendo, Juliet | Kimani, Joshua | Birungi, Josephine | Muyindike, Winnie | Kambugu, Andrew | Sebastian, Hachizovu | Ray, Handema | Mike, Chaponda | Bertin, Kabuya Jean | Modest, Mulenga | Thiam, Moussa | Janha, Omar | Davis, Alberta | Amambua-Ngwa, Alfred | Nwakanma, Davis C. | Mboup, Souleymane | Jaye, Assan | Jespersen, Sanne | Hønge, Bo Langhoff | Esbjörnsson, Joakim | Medina, Candida | Da Silva TÉ, David | Correira, Faustino Gomes | Laursen, Alex Lund | Østergaard, Lars | Andersen, Andreas | Aaby, Peter | Erikstrup, Christian | Wejse, Christian | Dieye, Siry | Sarr, Moussa | Sy, Haby | Mbodj, Helene D. | Ndiaye, Marianne | Ndiaye, Amy | Moussa, Seydi | Jaye, Assan | Mboup, Souleymane | Nyombi, Balthazar M. | Shao, Elichilia R. | Chilumba, Innocent B. | Moyo, Sikhulile | Gaseitsiwe, Simani | Musonda, Rosemary | Datong, Pam | Inyang, Bucky | Osawe, Sophia | Izang, Abel | Cole, Chundung | Okolo, Felicia | Cameron, Bill | Rosenthal, Kenneth | Gray, Clive | Jaspan, Heather | Abimiku, Alash’le | Seraise, Boitumelo | Andrea-Marobela, Kerstin | Moyo, Sikhulile | Musonda, Rosemary | Makhema, Joseph | Essex, Max | Gaseitsiwe, Simani
BMC Infectious Diseases  2016;16(Suppl 2):315.
Table of contents
A1 Introduction to the 2nd synchronicity forum of GHRI/CHVI-funded Canadian and African HIV prevention and vaccine teams
O1 Voluntary medical male circumcision for prevention of heterosexual transmission of HIV in adult males in Soweto: What do indicators and incidence rate show?
Hillary Mukudu, Neil Martinson, Benn Sartorius
O2 Developing a peer-led community mobilization program for sex workers in Soweto: HIV risk and demographics
Jenny Coetzee, Janan Dietrich, Kgaugelo Mokgatswana, Rachel Jewkes, Glenda E. Gray
O3 Salient beliefs about adherence: A qualitative survey conducted as part of the demonstration study on "treatment as prevention" (TasP) and "pre-exposure prophylaxis" (PrEP) among female sex workers (FSWS) in Cotonou, Benin
Marylène Dugas, Luc Béhanzin, Fernand A. Guédou, Marie-Pierre Gagnon, Michel Alary
O4 Relative perception of risk as a driver of unsafe sexual practices among key populations: Cases of fisherfolk and women and their partners involved in multiple sexual partnerships in Uganda
Rwamahe Rutakumwa, Martin Mbonye, Thadeus Kiwanuka, Sarah Nakamanya, Richard Muhumuza, Winfred Nalukenge, Janet Seeley
O5 Exploring the acceptability of new biomedical HIV prevention technologies among MSM, adolescents and heterosexual adults in South Africa
Millicent Atujuna, Melissa Wallace, Ben Brown, Linda Gail Bekker, Peter A. Newman
O6 HIV-susceptible target cells in foreskins after voluntary medical male circumcision in South Africa
Rushil Harryparsad, Abraham J. Olivier, Heather B. Jaspan, Douglas Wilson, Janan Dietrich, Neil Martinson, Hillary Mukudu, Nonhlanhla Mkhize, Lynn Morris, Gianguido Cianci, Minh Dinh, Thomas Hope, Jo-Ann S. Passmore, Clive M. Gray
O7 HIV-1 proteins activate innate immune responses via TLR2 heterodimers
Bethany M. Henrick, Xiao-Dan Yao, Kenneth L. Rosenthal, the INFANT Study Team
O8 Characterization of an innate factor in human milk and mechanisms of action against HIV-1
Bethany M. Henrick, Xiao-Dan Yao, Anna G. Drannik, Alash’le Abimiku, Kenneth L. Rosenthal, the INFANT Study Team
O9 Secretor status and susceptibility to HIV infections among female sex workers in Nairobi, Kenya
Nadia Chanzu, Walter Mwanda, Julius Oyugi, Omu Anzala
O10 Natural Killer cell recall responsiveness to Gag-HIV-1 peptides of HIV-1 exposed but uninfected subjects are associated with peripheral CXCR6+ NK cell subsets
Moustapha Mbow, Sabelle Jallow, Moussa Thiam, Alberta Davis, Assane Diouf, Cheikh T. Ndour, Moussa Seydi, Tandakha N. Dieye, Souleymane Mboup, Martin Goodier, Eleanor Rilley, Assan Jaye
O11 Profiles of resistance: Local innate mucosal immunity to HIV-1 in commercial sex workers
Xiao-Dan Yao, RW. Omange, Bethany M. Henrick, Richard T. Lester, Joshua Kimani, T. Blake Ball, Francis A. Plummer, Kenneth L. Rosenthal
O12 Early antiretroviral therapy and pre-exposure prophylaxis for HIV prevention among female sex workers in Cotonou, Benin: A demonstration project
Luc Béhanzin, Fernand A. Guédou, Nassirou Geraldo, Ella Goma Mastétsé, Jerôme Charles Sossa, Marcel Djimon Zannou, Michel Alary
O13 Building capacity for HIV prevention trials: Preliminary data from a Nigerian cohort of HIV exposed sero-negatives (HESN)
Sophia Osawe, Evaezi Okpokoro, Felicia Okolo, Stephen Umaru, Rebecca Abimiku, Sam Audu, Pam Datong, Alash’le Abimiku
O14 Equipping healthcare professionals with skills required for the conduct of clinical trials in an effort to build capacity. Lessons learned
Jacquelyn Nyange, Joyce Olenja, Gaudensia Mutua, Walter Jaoko, Gloria Omosa-Manyonyi, Bashir Farah, Maureen Khaniri, Omu Anzala
O15 Educational technology to support active learning for HIV researchers and planners
Anne Cockcroft, Kendra Tonkin, Indu Girish, Puna Mhati, Ashley Cunningham, Neil Andersson
O16 From Lake Kivu (Rwanda) and Lake Malawi (Tanzania) to the shores of Lake Victoria (Uganda): Strengthening laboratory capacity through Good Clinical Laboratory Practice training
Bashir Farah, Jackton Indangasi, Walter Jaoko, Gaudensia Mutua, Maureen Khaniri, Jacquelyn Nyange, Omu Anzala
O17 Rilpivirine and etravirine resistance mutations in HIV-1 subtype C infected patients on a non-nucleoside reverse transcriptase inhibitor-based combination antiretroviral therapy in Botswana
Thabo Diphoko, Simani Gaseitsiwe, Victoria Maiswe, Thato Iketleng, Dorcas Maruapula, Keabetswe Bedi, Sikhulile Moyo, Rosemary Musonda, Mark Wainberg, Joseph Makhema, Vladimir Novitsky, Richard Marlink, Max Essex
O18 From home-based HIV testing to initiation of treatment: The AIDS Support Organization (TASO) Experience with Home-based HIV Counselling and Testing (HBHCT) among Adolescents in Uganda, 2005-2011
Stephen Okoboi, Livingstone Ssali, Sam Kalibala, Josephine Birungi, Aggrey Egessa, Jonathan Wangisi, Lyavala Joanne Okullu, Celestin Bakanda, Francis Obare41
O19 Feasibility study on using real time medication monitoring among HIV infected and Tuberculosis patients in Kilimanjaro, Tanzania
I. Marion Sumari-de Boer, Hadija H. Semvua, Jossy van den Boogaard, Krisanta W. Kiwango, Kennedy M. Ngowi, Pythia T. Nieuwkerk, Rob E. Aarnoutse, Ireen Kiwelu, Eva Muro, Gibson S. Kibiki
O20 Deaths still among sero-discordant cohort in Nigeria despite Access to treatment
Ruth Datiri, Grace Choji, Sophia Osawe, Evaezi Okpokoro, Felicia Okolo, Stephen Umaru, Rebecca Abimiku, Samuel Audu, Pam Datong, Alash’le Abimiku
O21 Therapeutic HIV-1 vaccine trials in Denmark and Guinea-Bissau
Fomsgaard A, Karlsson I, Jensen KJ, Jensen SS, Leo-Hansen C, Jespersen S, Da Silva Té D, Rodrigues CM, da Silva ZJ, Janitzek CM, Gerstoft J, Kronborg G, the WAPHIR Group
O22 Willingness to participate in a HIV vaccine Trial among HIV exposed sero-negative (HESN) persons in Jos, Nigeria
Evaezi Okpokoro, Sophia Osawe, Ruth Daitiri, Grace Choji, Stephen Umaru, Felicia Okolo, Pam Datong, Alash'le Abimiku
O23 Clinical research volunteers’ perceptions and experiences of screening for enrolment at KAVI-Institute of Clinical Research, Kenya
Nyariki Emily, Olenja Joyce, Lorway R. Robert, Anzala Anzala
O24 Gut microbiome, HIV-exposure, and vaccine responses in South African infants
Katie Viljoen, Jerome Wendoh, Elvis Kidzeru, Ulas Karaoz, Eoin Brodie, Gerrit Botha, Nicola Mulder, Clive Gray, William Cameron, Alain Stintzi, Heather Jaspan, for the INFANT study team
O25 Analysis of HIV pol diversity in the concentrated HIV epidemic in Saskatchewan
Paul N. Levett, David Alexander, Naveed Gulzar, Prabvir S. Grewal, Art F. Y. Poon, Zabrina Brumme, P. Richard Harrigan, James I. Brooks, Paul A. Sandstrom, Stryker Calvez, Stephen E. Sanche, Jamie K. Scott
P1 Evaluating a HIV vaccine research community engagement programme at two HIV prevention research centres in the Western Cape
Leslie Swartz, Ashraf Kagee, Anthea Lesch, Zuhayr Kafaar, Anneliese De Wet
P2 Validating HIV acquisition risk score using a cohort HIV exposed sero-negative persons in a discordant relationship in Jos, Nigeria, West Africa
Evaezi Okpokoro, Sophia Osawe, Ruth Daitiri, Grace Choji, Stephen Umaru, Felicia Okolo, Pam Datong, Alash'le Abimiku
P3 Bridging the gap between adults and adolescents and youth adults (AYA) – Employing a youth-centred approach to investigate HIV risk among AYA in Soweto and Durban, South Africa
Janan Dietrich, Tricia Smith, Laura Cotton, Stefanie Hornschuh, Martin van der Watt, Cari L. Miller, Glenda Gray, Jenni Smit, Manjeetha Jaggernath, Thumbi Ndung’u, Mark Brockman, Angela Kaida, on behalf of the AYAZAZI study teams
P4 Neighbours to sex workers: A key population that has been ignored
Maureen Akolo, Joshua Kimani, Prof Larry Gelmon, Michael Chitwa, Justus Osero
P5 Young women’s access to structural support programmes in a district of Botswana
Anne Cockcroft, Nobantu Marokoane, Leagajang Kgakole, Boikhutso Maswabi, Neo Mpofu, Umaira Ansari, Neil Andersson
P6 Voices for action from peri-urban Ugandan students, teachers and parents on HIV/STI prevention: Qualitative research results
Nakinobe Elizabeth, Miiro George Mukalazi, Zalwango Flavia, Nakiyingi-Miiro Jessica, Kaleebu Potiano
P7 Engaging Social Media as an education tool on the fly: The use of Facebook for HIV and Ebola prevention and awareness amongst adolescents in Uganda
John Ross Semwanga, Emily Nyanzi, Saidat Namuli Musoke, Elizabeth Nakinobe, George Miiro, Edward Katongole Mbidde, Tom Lutalo, Pontiano Kaleebu
P8 Circulating HIV-1 subtypes among sexual minority populations in Zambia
Ray Handema, Graham P. Chianzu
P9 The Development of HIV Bio-bank resource management to support clinical trial and Intervention research: WAPHIR experience
Moussa Thiam, Diabou Diagne-Gueye, Mame K. Ndiaye, Moustapha Mbow, Birahim P. Ndiaye, Ibrahima Traore, Mamadou C. Dia, Gilleh Thomas, Coumba Tour-Kane, Souleymane Mboup, Assan Jaye
P10 Capacity building for clinical trials as a novel approach for scaling up HIV prevention research initiatives in East Africa: achievements and challenges
Emily Nyanzi, Edward Katongole Mbidde, Pontiano Kaleebu, Juliet Mpendo, Joshua Kimani, Josephine Birungi, Winnie Muyindike, Andrew Kambugu
P11 Community and media perspective of research; an advocacy workshop on HIV prevention research
Hachizovu Sebastian, Handema Ray, Chaponda Mike, Kabuya Jean Bertin, Mulenga Modest
P12 Development of a quantitative HIV-1 and HIV-2 real time PCR (qRT-PCR) viral load assay
Moussa Thiam, Omar Janha, Alberta Davis, Alfred Amambua-Ngwa, Davis C. Nwakanma, Souleymane Mboup, Assan Jaye
P13 Differential effects of sex in a West African Cohort of HIV-1, HIV-2 and HIV-1/2 dual infected patients: Men are worse off
Sanne Jespersen, Bo Langhoff Hønge, Joakim Esbjörnsson, Candida Medina, David Da Silva TÉ, Faustino Gomes Correira, Alex Lund Laursen, Lars Østergaard, Andreas Andersen, Peter Aaby, Christian Erikstrup, Christian Wejse, for the Bissau HIV Cohort study group
P14 HIV-infected adolescents in transition from pediatric to adult HIV care in Dakar, Senegal: sample characteristics and immunological and virological profiles
Siry Dieye, Moussa Sarr, Haby Sy, Helene D Mbodj, Marianne Ndiaye, Amy Ndiaye, Seydi Moussa, Assan Jaye, Souleymane Mboup100
P15 Molecular characterization of vertically transmitted HIV-1 among children born to HIV-1 seropositive mothers in Northern Tanzania
Balthazar M. Nyombi, Elichilia R. Shao, Innocent B. Chilumba, Sikhulile Moyo, Simani Gaseitsiwe, Rosemary Musonda
P16 Breast-fed HIV-1 exposed infants play catch up. A preliminary report
Pam Datong, Bucky Inyang, Sophia Osawe, Abel Izang, Chundung Cole, Felicia Okolo, Bill Cameron, Kenneth Rosenthal, Clive Gray, Heather Jaspan, Alash’le Abimiku, the INFANT study team
P17 The frequency of N348I mutation in patient failing combination antiretroviral treatment In Botswana
Boitumelo Seraise, Kerstin Andrea-Marobela, Sikhulile Moyo, Rosemary Musonda, Joseph Makhema, Max Essex, Simani Gaseitsiwe
doi:10.1186/s12879-016-1466-6
PMCID: PMC4943497  PMID: 27410689
6.  Identification of a Pyridoxine-Derived Small-Molecule Inhibitor Targeting Dengue Virus RNA-Dependent RNA Polymerase 
The viral RNA-dependent RNA polymerase (RdRp) activity of the dengue virus (DENV) NS5 protein is an attractive target for drug design. Here, we report the identification of a novel class of inhibitor (i.e., an active-site metal ion chelator) that acts against DENV RdRp activity. DENV RdRp utilizes a two-metal-ion mechanism of catalysis; therefore, we constructed a small library of compounds, through mechanism-based drug design, aimed at chelating divalent metal ions in the catalytic site of DENV RdRp. We now describe a pyridoxine-derived small-molecule inhibitor that targets DENV RdRp and show that 5-benzenesulfonylmethyl-3-hydroxy-4-hydroxymethyl-pyridine-2-carboxylic acid hydroxyamide (termed DMB220) inhibited the RdRp activity of DENV serotypes 1 to 4 at low micromolar 50% inhibitory concentrations (IC50s of 5 to 6.7 μM) in an enzymatic assay. The antiviral activity of DMB220 against DENV infection was also verified in a cell-based assay and showed a 50% effective concentration (EC50) of <3 μM. Enzyme assays proved that DMB220 was competitive with nucleotide incorporation. DMB220 did not inhibit the enzymatic activity of recombinant HIV-1 reverse transcriptase and showed only weak inhibition of HIV-1 integrase strand transfer activity, indicating high specificity for DENV RdRp. S600T substitution in the DENV RdRp, which was previously shown to confer resistance to nucleoside analogue inhibitors (NI), conferred 3-fold hypersusceptibility to DMB220, and enzymatic analyses showed that this hypersusceptibility may arise from the decreased binding/incorporation efficiency of the natural NTP substrate without significantly impacting inhibitor binding. Thus, metal ion chelation at the active site of DENV RdRp represents a viable anti-DENV strategy, and DMB220 is the first of a new class of DENV inhibitor.
doi:10.1128/AAC.02203-15
PMCID: PMC4704158  PMID: 26574011
7.  Characterization of the Drug Resistance Profiles of Integrase Strand Transfer Inhibitors in Simian Immunodeficiency Virus SIVmac239 
Journal of Virology  2015;89(23):12002-12013.
ABSTRACT
We previously showed that the simian immunodeficiency virus SIVmac239 is susceptible to human immunodeficiency virus (HIV) integrase (IN) strand transfer inhibitors (INSTIs) and that the same IN drug resistance mutations result in similar phenotypes in both viruses. Now we wished to determine whether tissue culture drug selection studies with SIV would yield the same resistance mutations as in HIV. Tissue culture selection experiments were performed using rhesus macaque peripheral blood mononuclear cells (PBMCs) infected with SIVmac239 viruses in the presence of increasing concentrations of dolutegravir (DTG), elvitegravir (EVG), and raltegravir (RAL). We now show that 22 weeks of selection pressure with DTG yielded a mutation at position R263K in SIV, similar to what has been observed in HIV, and that selections with EVG led to emergence of the E92Q substitution, which is a primary INSTI resistance mutation in HIV associated with EVG treatment failure. To study this at a biochemical level, purified recombinant SIVmac239 wild-type (WT) and E92Q, T97A, G118R, Y143R, Q148R, N155H, R263K, E92Q T97A, E92Q Y143R, R263K H51Y, and G140S Q148R recombinant substitution-containing IN enzymes were produced, and each of the characteristics strand transfer, 3′-processing activity, and INSTI inhibitory constants was assessed in cell-free assays. The results show that the G118R and G140S Q148R substitutions decreased Km′ and Vmax′/Km′ for strand transfer compared to those of the WT. RAL and EVG showed reduced activity against both viruses and against enzymes containing Q148R, E92Q Y143R, and G140S Q148R. Both viruses and enzymes containing Q148R and G140S Q148R showed moderate levels of resistance against DTG. This study further confirms that the same mutations associated with drug resistance in HIV display similar profiles in SIV.
IMPORTANCE Our goal was to definitively establish whether HIV and simian immunodeficiency virus (SIV) share similar resistance pathways under tissue culture drug selection pressure with integrase strand transfer inhibitors and to test the effect of HIV-1 integrase resistance-associated mutations on SIV integrase catalytic activity and resistance to integrase strand transfer inhibitors. Clinically relevant HIV integrase resistance-associated mutations were selected in SIV in our tissue culture experiments. Not only do we report on the characterization of SIV recombinant integrase enzyme catalytic activities, we also provide the first research anywhere on the effect of mutations within recombinant integrase SIV enzymes on drug resistance.
doi:10.1128/JVI.02131-15
PMCID: PMC4645305  PMID: 26378179
8.  CRISPR/Cas9: a double-edged sword when used to combat HIV infection 
Retrovirology  2016;13:37.
doi:10.1186/s12977-016-0270-0
PMCID: PMC4882869  PMID: 27230886
9.  Will LEDGIN molecules be able to play a role in a cure for HIV infection? 
EBioMedicine  2016;8:14-15.
doi:10.1016/j.ebiom.2016.05.007
PMCID: PMC4919589  PMID: 27428407
10.  Effect on HIV-1 viral replication capacity of DTG-resistance mutations in NRTI/NNRTI resistant viruses 
Retrovirology  2016;13:31.
Background
Recommended regimens for HIV-positive individuals include the co-administration of dolutegravir (DTG) with two reverse transcriptase inhibitors (RTIs). Although rare, emerging resistance against DTG is often associated with the R263K substitution in integrase. In-vitro-selected R263K was associated with impaired viral replication capacity, DNA integration, and integrase strand-transfer activity, especially when accompanied by the secondary mutation H51Y. Given the reduced fitness of RTI-resistant viruses, we investigated potential impacts on viral replication of combining R263K and H51Y/R263K with major RTI-resistance substitutions including K65R, L74V, K103N, E138K, and M184I/V.
Results
We combined the R263K or H51Y/R263K with RTI-resistance mutations into the proviral plasmid pNL4.3 and measured the resulting viral infectiousness, replication capacity, and ability to integrate viral DNA into host cells. Infectiousness was determined by luciferase assay in TZM-bl cells. Replicative capacity was monitored over 7 days and viral DNA integration was studied by real-time Alu-qPCR in PM1 cells. We found that viral infectiousness, replication capacities and integration levels were greatly reduced in triple mutants, i.e. H51Y/R263K plus a RT mutation, and moderately reduced in double mutants, i.e. R263K plus a RT mutation, compared to wild-type and single RT-mutant viruses.
Conclusions
Our findings help to explain the absence of RTI mutations in individuals who experienced DTG-treatment failure.
doi:10.1186/s12977-016-0265-x
PMCID: PMC4851780  PMID: 27130466
HIV-1; Integrase; Viral replication; Integrase inhibitors; R263K; H51Y; Reverse transcriptase inhibitors; K65R, L74V, K103N, E138K and M184V/I
11.  Dolutegravir-Selected HIV-1 Containing the N155H and R263K Resistance Substitutions Does Not Acquire Additional Compensatory Mutations under Drug Pressure That Lead to Higher-Level Resistance and Increased Replicative Capacity 
Journal of Virology  2015;89(20):10482-10488.
ABSTRACT
We have previously shown that the addition of the raltegravir/elvitegavir (RAL/EVG) primary resistance mutation N155H to the R263K dolutegravir (DTG) resistance mutation partially compensated for the fitness cost imposed by R263K while also slightly increasing DTG resistance in vitro (K. Anstett, T. Mesplede, M. Oliveira, V. Cutillas, and M. A. Wainberg, J Virol 89:4681–4684, 2015, doi:10.1128/JVI.03485-14). Since many patients failing RAL/EVG are given DTG as part of rescue therapy, and given that the N155H substitution often is found in combination with other compensatory resistance mutations in such individuals, we investigated the effects of multiple such substitutions within integrase (IN) on each of integrase function, HIV-1 infectivity, and levels of drug resistance. To this end, each of the L74M, E92Q, T97A, E157Q, and G163R substitutions were introduced into NL4.3 subtype B HIV-1 vectors harboring N155H and R263K in tandem [termed NL4.3IN(N155H/R263K)]. Relevant recombinant integrase enzymes also were expressed, and purified and biochemical assays of strand transfer efficiency as well as viral infectivity and drug resistance studies were performed. We found that the addition of T97A, E157Q, or G163R somewhat improved the affinity of INN155H/R263K for its target DNA substrate, while the presence of L74M or E92Q had a negative effect on this process. However, viral infectivity was significantly decreased from that of NL4.3IN(N155H/R263K) after the addition of each tertiary mutation, and no increases in levels of DTG resistance were observed. This work shows that the compensatory mutations that evolve after N155H under continued DTG or RAL/EVG pressure in patients are unable to improve either enzyme efficiency or viral infectivity in an N155H/R263K background.
IMPORTANCE In contrast to other drugs, dolutegravir has not selected for resistance in HIV-positive individuals when used in first-line therapy. We had previously shown that HIV containing the primary raltegravir/elvitegravir resistance substitution N155H could select for R263K under dolutegravir pressure and that this virus was fit and displayed low-level resistance to dolutegravir (Anstett et al., J Virol 89:4681–4684). Therefore, the current study aimed to uncover whether accessory mutations that appear after N155H in response to raltegravir/elvitegravir were compatible with N155H and R263K. We found, however, that the addition of a third mutation negatively impacted both the enzyme and the virus in terms of activity and infectivity without large shifts in integrase inhibitor resistance. Thus, it is unlikely that these substitutions would be selected under dolutegravir pressure. These data support the hypothesis that primary resistance against DTG cannot evolve through RAL/EVG resistance pathways and that the selection of R263K leads HIV into an evolutionary dead-end.
doi:10.1128/JVI.01725-15
PMCID: PMC4580168  PMID: 26246578
12.  Beyond Condoms: Risk Reduction Strategies Among Gay, Bisexual, and Other Men Who Have Sex With Men Receiving Rapid HIV Testing in Montreal, Canada 
AIDS and Behavior  2016;20(12):2812-2826.
Gay, bisexual, and other men who have sex with men (MSM) have adapted their sexual practices over the course of the HIV/AIDS epidemic based on available data and knowledge about HIV. This study sought to identify and compare patterns in condom use among gay, bisexual, and other MSM who were tested for HIV at a community-based testing site in Montreal, Canada. Results showed that while study participants use condoms to a certain extent with HIV-positive partners and partners of unknown HIV status, they also make use of various other strategies such as adjusting to a partner’s presumed or known HIV status and viral load, avoiding certain types of partners, taking PEP, and getting tested for HIV. These findings suggest that MSM who use condoms less systematically are not necessarily taking fewer precautions but may instead be combining or replacing condom use with other approaches to risk reduction.
doi:10.1007/s10461-016-1344-7
PMCID: PMC5108827  PMID: 26961381
Risk-reduction strategies; Condom use; Men who have sex with men; Latent class analysis; Combination HIV prevention
13.  The Combination of the R263K and T66I Resistance Substitutions in HIV-1 Integrase Is Incompatible with High-Level Viral Replication and the Development of High-Level Drug Resistance 
Journal of Virology  2015;89(22):11269-11274.
ABSTRACT
The R263K substitution in integrase has been selected in tissue culture with dolutegravir (DTG) and has been reported for several treatment-experienced individuals receiving DTG as part of salvage therapy. The R263K substitution seems to be incompatible with the presence of common resistance mutations associated with raltegravir (RAL), a different integrase strand transfer inhibitor (INSTI). T66I is a substitution that is common in individuals who have developed resistance against a different INSTI termed elvitegravir (EVG), but it is not known whether these two mutations might be compatible in the context of resistance against DTG or what impact the combination of these substitutions might have on resistance against INSTIs. E138K is a common secondary substitution observed with various primary resistance substitutions in RAL- and EVG-treated individuals. Viral infectivity, replicative capacity, and resistance against INSTIs were measured in cell-based assays. Strand transfer and 3′ processing activities were measured biochemically. The combination of the R263K and T66I substitutions decreased HIV-1 infectivity, replicative capacity, and strand transfer activity. The addition of the E138K substitution partially compensated for these deficits and resulted in high levels of resistance against EVG but not against DTG or RAL. These findings suggest that the presence of the T66I substitution will not compromise the activity of DTG and may also help to prevent the additional generation of the R263K mutation. Our observations support the use of DTG in second-line therapy for individuals who experience treatment failure with EVG due to the T66I substitution.
IMPORTANCE The integrase strand transfer inhibitors (INSTIs) elvitegravir and dolutegravir are newly developed inhibitors against human immunodeficiency virus type 1 (HIV-1). HIV drug-resistant mutations in integrase that can arise in individuals treated with elvitegravir commonly include the T66I substitution, whereas R263K is a signature resistance substitution against dolutegravir. In order to determine how different combinations of integrase resistance mutations can influence the outcome of therapy, we report here the effects of the T66I, E138K, and R263K substitutions, alone and in combination, on viral replicative capacity and resistance to integrase inhibitors. Our results show that the addition of R263K to the T66I substitution diminishes viral replicative capacity and strand transfer activity while not compromising susceptibility to dolutegravir. This supports the use of dolutegravir in second-line therapy for patients failing elvitegravir therapy who harbor the T66I resistance substitution.
doi:10.1128/JVI.01881-15
PMCID: PMC4645644  PMID: 26311878
14.  HIV-1 Drug Resistance Mutations: Potential Applications for Point-of-Care Genotypic Resistance Testing 
PLoS ONE  2015;10(12):e0145772.
The increasing prevalence of acquired and transmitted HIV-1 drug resistance is an obstacle to successful antiretroviral therapy (ART) in the low- and middle-income countries (LMICs) hardest hit by the HIV-1 pandemic. Genotypic drug resistance testing could facilitate the choice of initial ART in areas with rising transmitted drug resistance (TDR) and enable care-providers to determine which individuals with virological failure (VF) on a first- or second-line ART regimen require a change in treatment. An inexpensive near point-of-care (POC) genotypic resistance test would be useful in settings where the resources, capacity, and infrastructure to perform standard genotypic drug resistance testing are limited. Such a test would be particularly useful in conjunction with the POC HIV-1 viral load tests that are currently being introduced in LMICs. A POC genotypic resistance test is likely to involve the use of allele-specific point mutation assays for detecting drug-resistance mutations (DRMs). This study proposes that two major nucleoside reverse transcriptase inhibitor (NRTI)-associated DRMs (M184V and K65R) and four major NNRTI-associated DRMs (K103N, Y181C, G190A, and V106M) would be the most useful for POC genotypic resistance testing in LMIC settings. One or more of these six DRMs was present in 61.2% of analyzed virus sequences from ART-naïve individuals with intermediate or high-level TDR and 98.8% of analyzed virus sequences from individuals on a first-line NRTI/NNRTI-containing regimen with intermediate or high-level acquired drug resistance. The detection of one or more of these DRMs in an ART-naïve individual or in a individual with VF on a first-line NRTI/NNRTI-containing regimen may be considered an indication for a protease inhibitor (PI)-containing regimen or closer virological monitoring based on cost-effectiveness or country policy.
doi:10.1371/journal.pone.0145772
PMCID: PMC4696791  PMID: 26717411
16.  World AIDS Day 2015 
Retrovirology  2015;12:101.
doi:10.1186/s12977-015-0228-7
PMCID: PMC4667473  PMID: 26627883
18.  Subtype-Specific Analysis of the K65R Substitution in HIV-1 That Confers Hypersusceptibility to a Novel Nucleotide-Competing Reverse Transcriptase Inhibitor 
Compound A is a novel nucleotide-competing HIV-1 reverse transcriptase (RT) inhibitor (NcRTI) that selects for a unique W153L substitution that confers hypersusceptibility to tenofovir, while the K65R substitution in RT confers resistance against tenofovir and enhances susceptibility to NcRTIs. Although the K65R substitution is more common in subtype C viruses, the impact of subtype variability on NcRTI susceptibility has not been studied. In the present study, we performed experiments with compound A by using purified recombinant RT enzymes and viruses of subtypes B and C and circulating recombinant form CRF_A/G. We confirmed the hypersusceptibility of K65R substitution-containing RTs to compound A for subtype C, CRF_A/G, and subtype B. Steady-state kinetic analysis showed that K65R RTs enhanced the susceptibility to compound A by increasing binding of the inhibitor to the nucleotide binding site of RT in a subtype-independent manner, without significantly discriminating against the natural nucleotide substrate. These data highlight the potential utility of NcRTIs, such as compound A, for treatment of infections with K65R substitution-containing viruses, regardless of HIV-1 subtype.
doi:10.1128/AAC.00315-15
PMCID: PMC4432161  PMID: 25779585
19.  Combination of the R263K and M184I/V Resistance Substitutions against Dolutegravir and Lamivudine Decreases HIV Replicative Capacity 
We investigated the effect of combining the dolutegravir-specific R263K integrase resistance substitution with either M184I or M184V, two reverse transcriptase drug resistance substitutions that are frequently detected in individuals failing therapeutic regimens containing either lamivudine or emtricitabine. The presence of R263K and M184I/V in a single virus resulted in substantial further decreases in the viral replicative capacity compared to that in the presence of single substitutions alone.
doi:10.1128/AAC.05181-14
PMCID: PMC4394770  PMID: 25666155
20.  Dolutegravir Resistance Mutation R263K Cannot Coexist in Combination with Many Classical Integrase Inhibitor Resistance Substitutions 
Journal of Virology  2015;89(8):4681-4684.
The new integrase strand transfer inhibitor (INSTI) dolutegravir (DTG) displays limited cross-resistance with older drugs of this class and selects for the R263K substitution in treatment-experienced patients. We performed tissue culture selections with DTG, using viruses resistant to older INSTIs and infectivity and resistance assays, and showed that the presence of the E92Q or N155H substitution was compatible with the emergence of R263K, whereas the G140S Q148R, E92Q N155H, G140S, Y143R, and Q148R substitutions were not.
doi:10.1128/JVI.03485-14
PMCID: PMC4442391  PMID: 25653436
21.  Addition of E138K to R263K in HIV integrase increases resistance to dolutegravir, but fails to restore activity of the HIV integrase enzyme and viral replication capacity 
Journal of Antimicrobial Chemotherapy  2014;69(10):2733-2740.
Background
The results of several clinical trials suggest that the integrase inhibitor dolutegravir may be less prone than other drugs to the emergence of HIV drug resistance mutations in treatment-naive patients. We have shown that the R263K mutation commonly emerged during tissue culture selection studies with dolutegravir and conferred low levels of resistance to this drug while simultaneously diminishing both HIV replication capacity and integrase enzymatic activity. E138K has been identified as a secondary mutation for dolutegravir in selection studies and has also been observed as a secondary mutation in the clinic for the integrase inhibitors raltegravir and elvitegravir.
Methods
We used biochemical cell-free strand-transfer assays and tissue culture assays to characterize the effects of the E138K/R263K combination of mutations on resistance to dolutegravir, integrase enzyme activity and HIV-1 replication capacity.
Results
We show here that the addition of the E138K substitution to R263K increased the resistance of HIV-1 to dolutegravir but failed to restore viral replication capacity, integrase strand-transfer activity and integration within cellular DNA. We also show that the addition of E138K to R263K did not increase the resistance to raltegravir or elvitegravir. The addition of the E138K substitution to R263K was also less detrimental to integrase strand-transfer activity and integration than a different secondary mutation at position H51Y that had also been selected in culture.
Conclusions
The E138K substitution failed to restore the defect in viral replication capacity that is associated with R263K, confirming previous selection studies that failed to identify compensatory mutation(s) for the latter primary mutation. This study suggests that the R263K resistance pathway may represent an evolutionary dead end for HIV in treatment-naive individuals who are treated with dolutegravir and will need to be confirmed by the long-term use of dolutegravir in the clinic.
doi:10.1093/jac/dku199
PMCID: PMC4164141  PMID: 24917583
HIV-1; integrase inhibitors; antiviral
22.  Simian-Tropic HIV as a Model To Study Drug Resistance against Integrase Inhibitors 
Drug resistance represents a key aspect of human immunodeficiency virus (HIV) treatment failure. It is important to develop nonhuman primate models for studying issues of drug resistance and the persistence and transmission of drug-resistant viruses. However, relatively little work has been conducted using either simian immunodeficiency virus (SIV) or SIV/HIV recombinant viruses for studying resistance against integrase strand transfer inhibitors (INSTIs). Here, we used a T-cell-tropic SIV/HIV recombinant virus in which the capsid and vif regions of HIV-1 were replaced with their SIV counterparts (simian-tropic HIV-1 [stHIV-1](SCA,SVIF)) to study the impact of a number of drug resistance substitutions in the integrase coding region at positions E92Q, G118R, E138K, Y143R, S153Y, N155H, and R263K on drug resistance, viral infectivity, and viral replication capacity. Our results show that each of these substitutions exerted effects that were similar to their effects in HIV-1. Substitutions associated with primary resistance against dolutegravir were more detrimental to stHIV-1(SCA,SVIF) infectiousness than were resistance substitutions associated with raltegravir and elvitegravir, consistent with data that have been reported for HIV-1. These findings support the role of stHIV-1(SCA,SVIF) as a useful model with which to evaluate the role of INSTI resistance substitutions on viral persistence, transmissibility, and pathogenesis in a nonhuman primate model.
doi:10.1128/AAC.04829-14
PMCID: PMC4356797  PMID: 25583721
23.  Differential Effects of the G118R, H51Y, and E138K Resistance Substitutions in Different Subtypes of HIV Integrase 
Journal of Virology  2014;89(6):3163-3175.
ABSTRACT
Dolutegravir (DTG) is the latest antiretroviral (ARV) approved for the treatment of human immunodeficiency virus (HIV) infection. The G118R substitution, previously identified with MK-2048 and raltegravir, may represent the initial substitution in a dolutegravir resistance pathway. We have found that subtype C integrase proteins have a low enzymatic cost associated with the G118R substitution, mostly at the strand transfer step of integration, compared to either subtype B or recombinant CRF02_AG proteins. Subtype B and circulating recombinant form AG (CRF02_AG) clonal viruses encoding G118R-bearing integrases were severely restricted in their viral replication capacity, and G118R/E138K-bearing viruses had various levels of resistance to dolutegravir, raltegravir, and elvitegravir. In cell-free experiments, the impacts of the H51Y and E138K substitutions on resistance and enzyme efficiency, when present with G118R, were highly dependent on viral subtype. Sequence alignment and homology modeling showed that the subtype-specific effects of these mutations were likely due to differential amino acid residue networks in the different integrase proteins, caused by polymorphic residues, which significantly affect native protein activity, structure, or function and are important for drug-mediated inhibition of enzyme activity. This preemptive study will aid in the interpretation of resistance patterns in dolutegravir-treated patients.
IMPORTANCE Recognized drug resistance mutations have never been reported for naive patients treated with dolutegravir. Additionally, in integrase inhibitor-experienced patients, only R263K and other previously known integrase resistance substitutions have been reported. Here we suggest that alternate resistance pathways may develop in non-B HIV-1 subtypes and explain how “minor” polymorphisms and substitutions in HIV integrase that are associated with these subtypes can influence resistance against dolutegravir. This work also highlights the importance of phenotyping versus genotyping when a strong inhibitor such as dolutegravir is being used. By characterizing the G118R substitution, this work also preemptively defines parameters for a potentially important pathway in some non-B HIV subtype viruses treated with dolutegravir and will aid in the inhibition of such a virus, if detected. The general inability of strand transfer-related substitutions to diminish 3′ processing indicates the importance of the 3′ processing step and highlights a therapeutic angle that needs to be better exploited.
doi:10.1128/JVI.03353-14
PMCID: PMC4337543  PMID: 25552724
24.  XMRV as a Human Pathogen? 
Cell host & microbe  2011;9(4):260-262.
Summary
XMRV has been proposed to be associated with Prostate Cancer and Chronic Fatigue Syndrome. This proposition has been controversial because many investigators have failed to replicate the reported associations. Here, we explore whether XMRV is an authentic human pathogen in the light of recent findings that indicate otherwise.
doi:10.1016/j.chom.2011.04.001
PMCID: PMC4551452  PMID: 21501825
25.  The R262K Substitution Combined with H51Y in HIV-1 Subtype B Integrase Confers Low-Level Resistance against Dolutegravir 
Clinical studies have shown that integrase strand transfer inhibitors (INSTIs) can be used effectively against HIV-1 infection. To date, no resistance substitution has been found in INSTI-naive patients treated with the new integrase inhibitor dolutegravir (DTG). In a recent selection study with DTG, using a virus bearing the H51Y substitution in integrase, the emergence of an R to K substitution at position 262 (R262K) was observed. We characterized this double mutant with respect to integrase strand transfer activity and susceptibility to DTG both biochemically and in tissue culture. We showed that the addition of R262K to H51Y decreased recombinant integrase strand transfer activity but improved integrase DNA-binding affinity, compared to wild-type or H51Y-containing enzymes. The defect in strand transfer activity did not translate into a decrease in HIV-1 infectivity. The combination of H51Y and R262K substitutions slightly decreased susceptibility to DTG (fold change = 1.87) in cell-based resistance assays. Although viral replication was not affected and enzyme efficiency was impaired by the addition of R262K to H51Y, there was an overall increase in the level of biochemical drug resistance against DTG. Our findings suggest that the R at position 262 plays an important role in DNA binding.
doi:10.1128/AAC.04274-14
PMCID: PMC4291366  PMID: 25348535

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