Human Immunodeficiency Virus Type 1 Nucleocapsid Inhibitors Impede trans Infection in Cellular and Explant Models and Protect Nonhuman Primates from Infection

Abstract

Here, we report that the S-acyl-2-mercaptobenzamide thioester (SAMT) class of human immunodeficiency virus type 1 (HIV-1) nucleocapsid protein (NCp7) inhibitors was able to prevent transmission of HIV-1 from infected cells, including primary cells. Furthermore, when SAMTs were introduced during an HIV-1 challenge of cervical explant tissue, inhibition of dissemination of infectious virus by cells emigrating from the tissue explants was observed. Preliminary studies using a rhesus macaque vaginal challenge model with mixed R5 and X4 simian-human immunodeficiency virus infection found that five of six monkeys were completely protected, with the remaining animal being partially protected, infected only by the R5 virus. These data suggest that SAMTs may be promising new drug candidates for further development in anti-HIV-1 topical microbicide applications.

One Percent Tenofovir Applied Topically to Humanized BLT Mice and Used According to the CAPRISA 004 Experimental Design Demonstrates Partial Protection from Vaginal HIV Infection, Validating the BLT Model for Evaluation of New Microbicide Candidates

“…4). Prior to selection for in vivo efficacy evaluation here, each inhibitor was shown to efficiently inhibit HIV in vitro (3,5,39,43,50,52,54,56). Our experimental approach for testing these six inhibitors was a single dose of the product administered prior to exposure rather than the two doses of drug administered within 24 h as used in CAPRISA 004 (1).…”

“…The comparison between the two in vivo preclinical models is further enhanced due to the similar experimental designs between the NHP and BLT studies where a single dose of the inhibitor preceded the viral exposure in each case (38,50,52). Despite the higher drug dosing used for macaques (37.6 mM versus 0.5 mM), TC247 offered similar protection in both models (5 of 6 macaques and 4 of 7 BLT mice) (52). C52L (500 M) protected 7 of 7 BLT mice.…”

“…An example of the successful use of an NHP model in HIV prevention is the study of Parikh, et al, which used SHIV SF162P3 and pig-tailed macaques to predict that tenofovir gel could block vaginal HIV transmission as was subsequently determined in the CAPRISA 004 clinical trial (1,38). Yet because many new-generation microbicides being considered contain antiretrovirals that often exhibit exquisite specificity for HIV, multiple SIV/SHIV macaque models need to be developed for efficacy testing in vivo (20,27,28,38,46,50,52). Furthermore, within different NHP models there are differences in viral (i.e., HIV versus SHIV envelope variable region 3) and host (i.e., human versus macaque CCR5) sequences, resulting in distinctions that preclude the use of certain HIV-specific inhibitors and can confound the interpretation of the data obtained (4,33,42,49).…”

“…each sexual encounter" protocol has been the most common microbicide application protocol applied in clinical trials and animal model studies (19,23,29,35,38,44,47,50,52). The six additional candidate microbicides that we tested using this experimental design represent a broad spectrum of inhibitors with distinct mechanisms capable of blocking HIV infection at several different steps of the viral replication cycle from preentry to postbudding (Table 1).…”

HIV Type 1 Gag as a Target for Antiviral Therapy

“…Several molecules that disrupted in vitro CA assembly and virus infectivity resulted from this effort. 136 Debnath and co-workers also designed a dimer interface peptide, NYAD-201, containing the sequence AQEVKXW MTXTLLVA [based on the sequence of CA amino acids [178][179][180][181][182][183][184][185][186][187][188][189][190][191][192], where X represents the (S)-2-(2¢-pentenyl) alanines that are connected by hydrocarbon stapling 137 ]. This stapled peptide penetrates into cells and inhibits HIV-1 production by 3-fold.…”