Evidence for the innate immune response as a correlate of protection in human immunodeficiency virus (HIV)-1 highly exposed seronegative subjects (HESN)

Abstract

SummaryThe description of highly exposed individuals who remain seronegative (HESN) despite repeated exposure to human immunodeficiency virus (HIV)-1 has heightened interest in identifying potential mechanisms of HIV-1 resistance. HIV-specific humoral and T cell-mediated responses have been identified routinely in HESN subjects, although it remains unknown if these responses are a definitive cause of protection or merely a marker for exposure. Approximately half of HESN lack any detectible HIV-specific adaptive immune responses, suggesting that other mechanisms of protection from HIV-1 infection also probably exist. In support of the innate immune response as a mechanism of resistance, increased natural killer (NK) cell activity has been correlated with protection from infection in several highrisk cohorts of HESN subjects, including intravenous drug users, HIV-1 discordant couples and perinatally exposed infants. Inheritance of protective NK KIR3DL1 high 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 antiviral factors such as b-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.

Epitope Specificity Delimits the Functional Capabilities of Vaccine-Induced CD8 T Cell Populations

“…Despite emerging insights from studies of exposed uninfected individuals (1,2), much of the global research effort has necessarily focused on individuals who exhibit a degree of viral suppression, such as elite controllers and longterm nonprogressors (3). It is clear from these studies that CD8 T cells play a critical role in the containment of HIV replication (4).…”

HIV-1 Transmission and Viral Adaptation to the Host

“…The KIR 3DS1 allele on NK cells is associated with protection from infection, especially in combination with certain HLA alleles (HLA Bw4-80I, including HLA B*57), which serve as ligands for KIR3DS1 [77]. Furthermore, polymorphisms within genes coding for intracellular restriction factors like Trim5a, PPIA and APOBEC3G have also been reported to affect the susceptibility to HIV-1 infection [78][79][80][81][82][83][84].…”

Impaired NK Cell Activation and Chemotaxis toward Dendritic Cells Exposed to Complement-Opsonized HIV-1

“…Exposure of NK cells to factors produced by DCs at sites of inflammation and infection can lead to their activation with changes in phenotype and function (44)(45)(46) and affect NK cell-mediated destruction of infected cells (47). At the site of genital infection, NK cell migration and activity are an important defense against infections such as HSV2 (14) and NK cell cytotoxicity, and the ability to secrete antiviral cytokines has been correlated with protection in HIV-exposed noninfected individuals (17). NK cells may help to limit the initial HIV infection (41), whereas viremia leads to decreased numbers and impaired functionality of NK cells (48).…”

“…Besides, NK cells can be important in antiviral host defense by killing infected cells (15) and have been shown to secrete factors such as CCL3, CCL4, and CCL5 that can restrict HIV replication in vitro (16). NK cell activity has been correlated with protection in exposed uninfected individuals (17). Furthermore, the preservation of NK functions is associated with improved disease outcome (18), indicating that these cells might have an important role in HIV pathogenesis.…”