Could Enfuvirtide Ameliorate the Pathogenesis of HIV Infection?

Enfuvirtide (ENF; T-20) is the first approved entryinhibitor for the treatment of HIV infection. Many aspectsregarding HIV response to this new drug remainunknown. One of them concerns the selectionof ENF-resistance mutations, their impact on susceptibilityto ENF, and their influence on viral fitness.Although information derived from HIV-1 pol resistancemutations has proven this relationship (Deeks,et al. N Engl J Med 2001;344:472-80), this has notbeen proven yet for ENF. If this is the case, it mayhave important clinical implications, since ENF tendsto be used in heavily pre-treated individuals in whomimpairment of viral fitness may be one goal of HIVtherapeutics. In the pol gene, specific resistancemutations such as D30N (PR) or K65R and M184I/V(RT) have been particularly associated with significantreductions in the replication capacity of thevirus, which may account for viro-immunologic discordantresponses to HAART (Nicastri, et al. J ClinMicrobiol 2003;41:3007-12).Recent evidences have suggested that long-termENF-treated patients might experience an immunologicalbenefit, in spite of the rapid selection ofENF-resistance mutations within the HR1 region ofgp41 and subsequent virological failure (Poveda,et al. AIDS 2002;16:1959-61). More recently, it hasbeen reported that these patients may show a reducedT-cell activation. Two recent articles mayoffer an explanation for this fact, revealing how anadditional benefit of ENF on HIV pathogenesiscould be obtained in some instances. In the first(Lu, et al. J Virol 2004;78:4628-36), the presence of ENF-resistance mutations within the HR1 region ofgp41 was clearly associated with a reduction inviral fitness. Thus, ENF-resistant viruses are less fitthan wild-type viruses and, consequently, could beless pathogenic. In a second study (Schaeffer, etal. J Virol 2004;78:1375-83), an inhibition of the HIVfusion pathway to enter the cells was associatedwith a compensatory increase in the endocytosispathway. While virion endocytosis by macrophagesmay result in a productive infection, HIV entry intoCD4+ T-cells by endocytosis does not seem to leadto productive infection. If these observations arefurther confirmed, they might explain, at least inpart, the recognition of CD4-viral load disconnectsin some individuals failing ENF-based therapies.Thus, the benefit of ENF may go beyond its intrinsicantiviral activity.