In Vitro Antiviral Activity of Cabotegravir against HIV-2.

ANTIVIRAL AGENTS crossm In Vitro Antiviral Activity of Cabotegravir against HIV-2 Robert A. Smith,a Vincent H. Wu,a Christopher G. Zavala,a Dana N. Raugi,a Selly Ba,c Moussa Seydi,c Geoffrey S. Gottlieb,a,b for the University of Washington-Dakar HIV-2 Study Group a Center for Emerging and Reemerging Infectious Diseases and Department of Medicine, Division of Allergy and Infectious Diseases, University of Washington, Seattle, Washington, USA b Department of Global Health, University of Washington, Seattle, Washington, USA c Service des Maladies Infectieuses et Tropicales, CHNU de Fann, Dakar, Senegal ABSTRACT We examined the antiviral activity of the integrase inhibitor (INI) cabotegravir against HIV-2 isolates from INI-naive individuals. HIV-2 was sensitive to cabotegravir in single-cycle and spreading-infection assays, with 50% effective concentrations (EC50s) in the low to subnanomolar range; comparable results were obtained for HIV-1 in both assay formats. Our findings suggest that cabotegravir should be evaluated in clinical trials as a potential option for antiretroviral therapy and preexposure prophylaxis in HIV-2-prevalent settings. KEYWORDS HIV-2, PrEP, West Africa, antiretroviral therapy, cabotegravir, human immunodeficiency virus, treatment H uman immunodeficiency virus type 2 (HIV-2) is endemic in West Africa and has spread to other locales with socioeconomic ties to the region (1, 2). Relative to HIV-1, HIV-2 infection involves a slower rate of CD4 cell decline, lower plasma viral loads, and slower disease progression (3–7). Nevertheless, significant numbers of HIV-2 and HIV-1/2 dually infected individuals eventually progress to AIDS and can benefit from antiretroviral therapy (ART) (7–11). There are important differences between HIV-1 and HIV-2 with regard to antiretroviral (ARV) drug sensitivity (12, 13). HIV-2 is intrinsically resistant to nonnucleoside reverse transcriptase inhibitors (NNRTIs) (14, 15) and shows relatively poor sensitivity to several HIV-1-active protease inhibitors (PIs); saquinavir, darunavir, and lopinavir appear to be the only PIs with clinically effective potency against HIV-2 (16–20). These distinctions complicate HIV treatment in West Africa and other regions where HIV-1 and HIV-2 cocirculate. Difficulties in differentiating HIV-2 or HIV-1/2 dual infection from HIV-1 infection can lead to the inappropriate use of NNRTI-based regimens in HIV-2infected patients and to premature use of PI-based regimens as first-line ART in patients infected solely with HIV-1 (21–23). Efforts are needed to simplify ART in areas where HIV-1/HIV-2 discriminatory testing is unreliable and stockouts of HIV-2-active antivirals are commonplace (24). ARV regimens containing two nucleoside reverse transcriptase inhibitors (NRTIs) plus an integrase inhibitor (INI) or an NNRTI are currently recommended by the World Health Organization for first-line treatment of HIV-1 infection (25). A growing body of evidence suggests that INI-based regimens might fulfill the need for universally active first-line ART in settings where HIV-2 is endemic. HIV-2 is susceptible to the INIs raltegravir, elvitegravir, and dolutegravir, with 50% effective concentrations (EC50s) in the low-nanomolar to picomolar range (26–31). Data from case studies and small case series indicate that raltegravir- and elvitegravir-based regimens can suppress HIV-2 viral loads in ART-naive individuals (32, 33) and in ART-experienced patients whose treatment history does not include an INI (32, 34–39). More recently, two groups conducting clinical trials in ART-naive HIV-2-infected patients reported favorable immunovirologic October 2018 Volume 62 Issue 10 e01299-18 Antimicrobial Agents and Chemotherapy Received 19 June 2018 Returned for modification 29 June 2018 Accepted 12 July 2018 Accepted manuscript posted online 16 July 2018 Citation Smith RA, Wu VH, Zavala CG, Raugi DN, Ba S, Seydi M, Gottlieb GS, for the University of Washington-Dakar HIV-2 Study Group. 2018. In vitro antiviral activity of cabotegravir against HIV-2. Antimicrob Agents Chemother 62:e01299-18. https://doi.org/10 .1128/AAC.01299-18. Copyright © 2018 American Society for Microbiology. All Rights Reserved. Address correspondence to Robert A. Smith, . aac.asm.org 1 Smith et al. Antimicrobial Agents and Chemotherapy outcomes in response to INI-based regimens (40, 41). In addition, some evidence suggests that dolutegravir might be effective in a subset of HIV-2-infected patients who have developed resistance to raltegravir (42–44). Cabotegravir (S/GSK1265744; Shionogi/GlaxoSmithKline) is an investigational INI currently in development for the prevention and treatment of HIV-1 infection (45, 46). The antiviral potency and pharmacokinetic properties of cabotegravir render the drug amenable to once-daily oral dosing, and long-acting injectable formulations of the drug have been evaluated in nonhuman primate models of HIV-1 infection and in clinical trials (47–58). In contrast, there are no published data regarding the activity of cabotegravir against HIV-2, although one group reported a mean EC50 of 0.12 nM for four HIV-2 isolates at an international meeting (59). In the current study, we tested the susceptibility of 15 different HIV-2 isolates (8 from group A, 6 from group B, and 1 A/B intergroup recombinant) to cabotegravir in single-cycle infections of MAGIC-5A indicator cells. A detailed description of the singlecycle assay has been published elsewhere (60). We further tested a subset of our HIV-2 library in 6-day spreading infections of an immortalized T-cell line (CEMss) as described below. In both assay formats, HIV-1 isolates from ART-naive individuals were included for comparison. The 50% cytotoxic concentrations (CC50) of cabotegravir in MAGIC-5A and CEMss cells were ⬎1 and ⬎10 ␮M, respectively, as assessed by CellTiter-Glo luminescent cell viability assay (Promega) (see Fig. S1 in the supplemental material). Single-cycle assays: HIV-1NL4-3 and HIV-2ROD9. We initially compared the susceptibility of two prototypic HIV strains to cabotegravir, i.e., HIV-1NL4-3 (group M, subtype B) and HIV-2ROD9 (group A). These viruses were derived from 293T/17 cultures that were transfected with corresponding full-length plasmid molecular clones as previously described (61). Both strains were tested against cabotegravir from two sources, GlaxoSmithKline (GSK) and Selleck Chemicals, Inc. All dilutions of the drug were prepared in 10% vol/vol dimethyl sulfoxide (DMSO); the final concentration of DMSO in the assay wells was 1%. Cabotegravir from both suppliers was highly active against HIV-1NL4-3 and HIV2ROD9, with EC50s ranging from 1.2 to 1.7 nM (see Table S1 in the supplemental material). These values are consistent with the EC50s reported for HIV-1NL4-3-based vectors in a single round of replication (EC50s of 0.5 nM [47] and 1.6 nM [62]). Altogether, HIV-1NL4-3 and HIV-2ROD9 were similar in their susceptibility to cabotegravir; after 15 an (...truncated)