EDITORIAL COMMENT Locking the door to HIV entry: how far can we go? Suzanne M. Crowe a and Birgitta Asjo b AIDS 2004, 18:2197–2198 Whilst virologists continue the hunt for new antiretro- viral strategies, clinicians are predominantly concerned with the side-effects attributed to combination antire- troviral regimens. Therapy is generally initiated once the CD4 count has fallen to about 350 3 10 6 cells/l, in contrast to the previous dogma of ‘treat early and treat hard’. This is largely because of considerations relating to the long-term toxicity of combination antiretroviral therapy. Therefore, enthusiasm for any new antiretro- viral drug is tempered by concerns about its potential untoward effects and drug interactions. The paper in this issue by Vermeire and his colleagues describes the antiviral activity of the synthetic macro- cylce cyclotriazadisulfonamide (CADA) [1], a chemi- cally novel HIV inhibitor that is likely to inhibit HIV replication by downregulating CD4 on lymphoid cells [2]. Their prior work has demonstrated its potent activity against a range of laboratory-adapted strains of HIV-1 and HIV-2 [3]. This paper expands these earlier data by showing that the drug inhibits the replication of 16 well-characterized X4 and R5 primary HIV-1 isolates in peripheral blood mononuclear cells (PBMC). Using a series of two-drug combination assays, they further report that the antiviral activity of CADA synergizes with reverse transcriptase, protease and entry/fusion inhibitors against a laboratory-adapted strain in the MT4 cell line, an expected outcome given the mechanism of action of CADA. The authors’ data are promising but, as to be expected at this early stage, leave some unanswered questions about the antiviral activity of this drug. The investiga- tors have selected a single time point for their analyses of CADA efficacy in PBMC, rather than providing viral replication kinetics for each isolate. As such, they may have missed the replication peaks of the various primary isolates: consequently, the efficacy of the drug might be very different to that shown in this paper. Primary isolates have varied replication kinetics in PBMC. X4 and R5X4 viruses usually achieve high levels of replication within 3–5 days in culture, while many R5 strains peak later and at lower levels [4]. In addition, the peak levels of virus replication may differ dramatically between primary viruses, as noted by the investigators (personal communication). Therefore, there is no ‘one-size-fits-all’ time-point to assess virolo- gical efficacy in terms of replication kinetics of primary viruses in PBMC. Although CADA effectively reduced CD4 expression in PBMC, the investigators have not yet reported whether CADA reduces CD4 expression on both CD4 T cells and monocytes and thus inhibits HIV replica- tion in each of these cell populations. Will CADA inhibit cell-to-cell transmission as effectively as trans- mission of cell-free virus? As cell-to-cell transmission of HIV-1 is more difficult to block than infection by cell- free virus (and as a 10-fold-lower amount of virus is required for cell-to-cell transmission of HIV-1 than for cell-free infection) [5], this may not be so. Will CADA penetrate into the central nervous system and inhibit HIV infection and replication within the brain? CADA must also withstand the enormous potential of HIV to develop resistance. Prolonged use of CADA might select for CD4-independent strains. The investi- gators consider that these strains are unlikely to persist in vivo because of their increased neutralization sensitiv- ity. However strains with reduced CD4 dependence Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. From the a AIDS Pathogenesis and Clinical Research Program, Macfarlane Burnet Institute for Medical Research and Public Health, Melbourne, Australia and the b Center for Research in Virology, University of Bergen, Bergen, Norway. Correspondence to Professor S. Crowe, AIDS Pathogenesis and Clinical Research Program, Macfarlane Burnet Institute for Medical Research and Public Health, Commercial Rd, GPO Box 2284, Melbourne, Victoria 3001, Australia. Email: crowe@burnet.edu.au Received: 6 July 2004; revised: 8 August 2004; accepted: 17 August 2004. ISSN 0269-9370 & 2004 Lippincott Williams & Wilkins 2197