Preface [Hot Topic: Regulatory / Accessory HIV-1 Proteins (Guest Editor: Maurizio Federico)]

HIV-1 belongs to the Lentiviridae subfamily of the Retroviridae virus family. Lentiviruses (from Latin lenti, slow, for the long incubation times of the diseases) are enveloped viruses carrying two copies of single-strand positive (i.e., codifying) RNA and are considered the etiologic agents of acquired immunodeficiency syndromes from a broad range of animal species. Most likely as the consequence of the adaptation of the viruses to the respective natural hosts, lentiviruses evolved a set of genes coding for non structural proteins. These, defined as regulatory or accessory genes, are six in the case of HIV-1, and termed, starting from the 5' end of the genome, vif, vpr, tat, rev, vpu and nef. Even if in in vitro systems the virus survives the loss of function of each of these genes, except tat and rev, the fact that the far most part of in vivo HIV-1 isolates expresses the whole set of functional regulatory proteins strongly suggests that they play functions critical for the in vivo propagation. However, while in the case of vif, tat and rev the mechanisms underlying their pivotal functions have been revealed in great detail, the roles of vpr, vpu and nef in the viral replication appear at the present more intriguing. In this respect, the case of nef is paradigmatic. This protein, evolved exclusively in SIV and HIV lentiviruses, has been found interacting with a surprisingly high number of cell proteins and also with Gag and Env HIV-1 products. This led the investigators to envision different models that, while at least in part reflecting the ability of HIV to replicate in different cell types and in different cell activation states, appear however not always consistent. Both the uniqueness and the complexity of the Nef mode of action suggested to pay particular attention to such a fascinating and still partly mysterious viral protein in this issue. Anti-HIV compounds part of the high active anti-retroviral therapy (HAART), at the present the most effective firewall against the viral spread, recognize exclusively HIV structural proteins as targets, in particular the integrase, the reverse transcriptase, and the transmembrane envelope subunit. Clearly, due to the well established limits of efficacy of HAART, expanding the drug targets towards the HIV regulatory proteins and / or the relative cell protein partners appears mandatory. In this issue, each HIV-1 regulatory protein is described in detail in terms of structure, function and strategies of pharmacological attack already proven and / or of a potential exploiting. Of course, the reader will be easily aware that the drug research developed much more efficiently for those proteins whose mechanism of action has been more accurately revealed, i.e. Tat and Rev. In the case of Vif, the recent outstanding outbreaks on its mechanism of action will certainly allow the design of innovative drugs interfering with its functions in a short time. On the other hand, the recovery of effective anti-HIV compounds targeting the remainder regulatory proteins will be facilitated by hopeful advancements in the knowledge of the respective effects on the viral replication. In conclusion, several lines of evidences support the idea that the HIV-1 regulatory proteins represent the heel of Achilles of the virus. In a near future, effective drugs against one or more HIV regulatory proteins could contribute in developing strategies of HIV eradication still not affordable by HAART currently in use.