Inheritance of protective NK KIR3DL1high and KIR3DS1 receptor alleles have also been observed to be over-represented in a high-risk cohort of HESN intravenous drug users and HESN partners of HIV-1-infected subjects. Other intrinsic mechanisms of
innate immune protection correlated with resistance in HESN subjects include heightened dendritic cell responses and increased secretion of anti-viral CB-839 factors such as β-chemokines, small anti-viral factors and defensins. This review will highlight the most current evidence in HESN subjects supporting the role of epithelial microenvironment and the innate immune system in sustaining resistance against HIV-1 infection. We will argue that as a front-line defence the innate immune response determines the threshold of infectivity that HIV-1 must overcome to establish a productive infection. From the earliest
selleck days of the human immunodeficiency virus (HIV)-1 epidemic, anecdotal evidence of high-risk HIV-exposed but persistently uninfected individuals generated hope that natural resistance to HIV-1 existed in some individuals. The description of persistently seronegative prostitutes in Nairobi, Kenya who maintained resistance to HIV-1 infection despite numerous years of high-risk activity confirmed that resistance to HIV-1, although rare, was possible . This early interest led to the recruitment of HIV-exposed but -seronegative individuals into geographically diverse cohorts of high-risk subjects based upon the route of exposure to HIV-1 (Table 1). Mucosal exposure to HIV-1 in the absence of infection was documented in numerous cohorts from across the
globe, including commercial sex workers [1,2] and individuals practising unprotected heterosexual or homosexual sexual intercourse with an HIV-1-infected partner [3–7]. Importantly, the phenotype of vaginal  and rectal [8,9] mucosal resistance to infection in the absence of adaptive T cell responses has been recapitulated in low-dose simian immunodeficiency virus (SIV) rhesus macaque studies, where macaques remained uninfected even after multiple mucosal exposures to SIV, and yet could be Methane monooxygenase infected if virus was given intravenously (i.v.). The absence of vertical transmission has been observed in children born to HIV-1-infected mothers and exposed to HIV-1 through natural birth and/or breast feeding [10–13]. Resistance to infection despite direct blood-borne exposures to HIV-1 were also seen among HIV-seronegative occupationally exposed health workers , haemophiliacs receiving tainted blood products [15,16] and i.v. drug users sharing needles [17–20]. The potential diversity of the exposure routes and varied epidemiological background of HIV-1 exposed, uninfected subjects initially complicated the creation of a unifying definition for these seemingly resistant individuals .