Building on previous findings that amiloride analogues inhibit HIV-1 replication in monocyte-derived macrophages (MDM), Biotron Limited has generated a library of over 300 small-molecule compounds with significant improvements in anti-HIV-1 activity. Our lead compound, BIT225, blocks Vpu ion channel activity and also shows anti-HIV-1 activity, with a 50% effective concentration of 2.25 ؎ 0.23 M (mean ؎ the standard error) and minimal in vitro toxicity (50% toxic concentration, 284 M) in infected MDM, resulting in a selectivity index of 126. In this study, we define the antiretroviral efficacy of BIT225 activity in macrophages, which are important drug targets because cells of the monocyte lineage are key reservoirs of HIV-1, disseminating virus to the peripheral tissues as they differentiate into macrophages. In assays with acutely and chronically HIV-1 Ba-L -infected MDM, BIT225 resulted in significant reductions in viral integration and virus release as measured by real-time PCR and a reverse transcriptase (RT) activity assay at various stages of monocyte-to-macrophage differentiation. Further, the TZM-bl assay showed that the de novo virus produced at low levels in the presence of BIT225 was less infectious than virus produced in the absence of the compound. No antiviral activity was observed in MDM chronically infected with HIV-2, which lacks Vpu, confirming our initial targeting of and screening against this viral protein. The activity of BIT225 is post-virus integration, with no direct effects on the HIV-1 enzymes RT and protease. The findings of this study suggest that BIT225 is a late-phase inhibitor of the viral life cycle, targeting Vpu, and is a drug capable of significantly inhibiting HIV-1 release from both acute and chronically infected macrophages.
We report a cluster of male pseudohermaphrodites from the Simbari Anga linguistic group in the Eastern Highlands of Papua New Guinea. These subjects are born with a rudimentary clitoral-like penis and pseudovaginal perineoscrotal hypospadias. At puberty, the penis enlarges with concurrent growth of pubic and axillary hair and significant muscular development. There is significant facial hair, but it is less than that of their normal male siblings or other male relatives. Plasma collected from four adult subjects revealed elevated plasma testosterone levels, low to low normal dihydrotestosterone levels, and elevated testosterone/dihydrotestosterone ratios. All subjects had high urinary aetiocholanolone/androsterone ratios, and C19 and C21 5 beta/5 alpha metabolite ratios. Decreased 5 alpha-reductase activity was demonstrated in fibroblasts cultured from genital skin. The data indicate a phenotypic and biochemical profile similar to patients studied in the Dominican Republic, except for a greater abundance of facial and body hair. The phenotypic variability, as pertains to facial and body hair, may be related to differences in familial expression, as well as the degree of enzyme deficiency. Infants, thought to be females at birth, were reared as girls until puberty in a society practising one of the strictest gender segregations known. At puberty, these 'girls' were discovered to be boys, and a switch of gender roles was instituted. Recently, however, some Muniri, Dunkwi and northern Simbari hamlets recognize these individuals as male in infancy and rear them as boys, calling them 'kwalatmala' to distinguish them from normal males, accepting them as an intersex destined to occupy male adult roles.
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