Rationale for testing chemokine inhibitors (Virustats) for prevention of HIV-1 transmission.

Abstract

HIV infection is dependent upon utilization of chemokine co-receptors to facilitate cellular entry. Of the numerous chemokine co-receptors that can be used by HIV for in vitro infection, the beta chemokine receptor CCR5 plays the most important role in acquisition of HIV-1 infection in vivo. High levels of beta chemokines, MIP-1a, MIP-1b and RANTES can block HIV-1 replication in vitro and persons who are homozygous for 32 base pair deletion in the coding sequences for CCR5 that results in failure of surface expression of this receptor are protected from acquisition of HIV-1 infection. This is reflected in a resistance to infection by CCR-5 utilizing HIV-1 strains in vitro. Targeting this coreceptor in vivo may be better tolerated than other host-directed therapies since there is no deleterious phenotype associated with the d32 homozygous state. The IP/CP chemokine receptor inhibitor team is examining a number of N-terminus modified beta chemokines for their utility as inhibitors of HIV-1 replication and as agents that may be used to block mucosal HIV-1 transmission. The lead molecule-aminooxypentane (AOP)-RANTES is more active than RANTES in blocking HIV-1 propagation and is active in nanomolar or subnanomolar concentrations against numerous HIV-1 isolates including selected isolates from clades A,B,C,D,E and F. It is important to note that AOP-administration does not induce monocyte chemotaxis thus suggesting that mucosal administration of this compound may not induce inflammatory responses. Although AOP-RANTES and other chemokine inhibitors can compete with natural ligands for chemokine receptor binding, inhibition of fusion activity may be more dependent upon induction of coreceptor internalization that persists for many hours after drug is withdrawn from culture. Thus topical administration of these compounds may provide durable 'resistance' to HIV-1 cellular entry. In the hu-PBL-SCID mouse model, AOP-RANTES can decrease the magnitude of HIV-1 replication but did not prevent infection and in 6 of ten mice challenged, NNY-RANTES blocked parenteral acquisition of HIV-1 infection but in two of the infected mice, emergence of X4 utilizing strains was demonstrated. A number of additional modified chemokine inhibitors are under study that inhibit HIV-1 replication in subnanomolar concentrations and provide durable suppression of CCR5 surface expression. The effects of these agents on vaginal inflammatory responses, on vaginal flora, pH and other STD pathogens remains to be determined. Likewise, the immunogenicity of these large molecules must be examined. The development of these molecules as 'virustats'-inhibitors of mucosal HIV transmission may provide an inexpensive method for women to protect against sexual transmission of HIV.