Reverse transcriptase (RT) inhibitors comprise two different classes, nucleos(t)ide RT inhibitors (NRTIs) and nonnucleoside RTIs (NNRTIs), which act by entirely different mechanisms. However, their extensive use has led to the emergence of drug resistance mutations that may affect use of new RTIs. As new drugs like rilpivirine (RPV) become increasingly available to patients infected with HIV strains of subtypes other than B (HIV-nonB), it is important to understand how RPV resistance-associated mutations determined in HIV-1B samples (RAMB) affect susceptibility patterns in both drug-nave or -treated HIV-nonB patients. This proposal aims to understand differences in drug resistance among different HIV subtypes (HIV-1B vs. HIV-nonB). Recent collaborative clinical data (with A. Snnerborg and U. Neogi) identified RAMBs in treatment-nave (6- 11%, depending on subtype) and nevirapine (NVP) or efavirenz (EFV)-based therapy-failed patients (22-34%, depending on subtype). Hence, it is hypothesized that patients who failed NVP/EFV-based therapy are more likely to fail RPV-based therapy. Moreover, patients treated with TDF/FTC/RPV failed therapy through RPV- associated mutations in ~9% of HIV-1B patients compared to ~25% of HIV-nonB patients. Preliminary analysis of RT sequences from clinical cohorts of HIV-1B and HIV-nonB patients that are treatment-nave or -failed (NVP/EFV-based) showed an increase in prevalence of predicted RAMBs. Hence, it is also hypothesized that RPV resistance emerges through different mechanisms in various subtypes. Furthermore, until recently, it was thought resistance to one class of RTIs was unrelated to the other. However, RT connection subdomain mutations (CSMs), namely N348I in HIV-1B, have been identified, which give multi-class drug resistance (MCDR) to both NRTIs and NNRTIs. It is hypothesized that CSMs affect MCDR differently in various HIV subtypes. The following aims will be addressed: SA 1. Determine how the presence of CSMs and RAMBs affect RPV susceptibility of HIV-1B and -nonB SA 2. Virologically characterize the contribution of CSMs and RAMBs on fitness and multi-class resistance in multiple subtypes SA 3. Unravel biochemical and structural mechanisms of the MCDR phenotype in HIV-1B and HIV-nonB The goal of this application is to elucidate the molecular mechanisms underlying MCDR and how CSMs may impact the RPV susceptibility of different HIV subtypes, providing important insights into the feasibility of RPV as first-line therapy in HIV 1B and HIV-nonB patients.
This project will determine the how resistance to two classes of HIV reverse transcriptase inhibitors develop in different subtypes of HIV. These studies will provide important insights useful to help determine effective treatment strategies for a wider range of HIV-infected patients, particularly those in low and middle income countries.
|Markowitz, Martin; Sarafianos, Stefan G (2018) 4'-Ethynyl-2-fluoro-2'-deoxyadenosine, MK-8591: a novel HIV-1 reverse transcriptase translocation inhibitor. Curr Opin HIV AIDS 13:294-299|
|Neogi, Ujjwal; Singh, Kamalendra; Aralaguppe, Shambhu G et al. (2018) Ex-vivo antiretroviral potency of newer integrase strand transfer inhibitors cabotegravir and bictegravir in HIV type 1 non-B subtypes. AIDS 32:469-476|
|Njenda, Duncan T; Aralaguppe, Shambhu G; Singh, Kamalendra et al. (2018) Antiretroviral potency of 4'-ethnyl-2'-fluoro-2'-deoxyadenosine, tenofovir alafenamide and second-generation NNRTIs across diverse HIV-1 subtypes. J Antimicrob Chemother 73:2721-2728|
|Rogers, Leonard; Obasa, Adetayo E; Jacobs, Graeme B et al. (2018) Structural Implications of Genotypic Variations in HIV-1 Integrase From Diverse Subtypes. Front Microbiol 9:1754|
|Neogi, Ujjwal; Siddik, Abu Bakar; Kalaghatgi, Prabhav et al. (2017) Recent increased identification and transmission of HIV-1 unique recombinant forms in Sweden. Sci Rep 7:6371|
|Neogi, Ujjwal; Häggblom, Amanda; Singh, Kamalendra et al. (2016) Factors influencing the efficacy of rilpivirine in HIV-1 subtype C in low- and middle-income countries. J Antimicrob Chemother 71:367-71|
|Salie, Zhe Li; Kirby, Karen A; Michailidis, Eleftherios et al. (2016) Structural basis of HIV inhibition by translocation-defective RT inhibitor 4'-ethynyl-2-fluoro-2'-deoxyadenosine (EFdA). Proc Natl Acad Sci U S A 113:9274-9|