Date Published: September 12, 2017
Publisher: BioMed Central
Author(s): Nicole F. Bernard.
The anti-HIV activity of natural killer (NK) cells could be induced fast enough to potentially prevent the establishment of HIV infection. Epidemiological studies identified two genotypes encoding NK receptors that contribute to NK cell function, that were more frequent in people who remained uninfected despite multiple HIV exposures than in HIV-susceptible subjects. NK cells from carriers of the *h/*y+B*57 genotype have higher NK cell functional potential and inhibit HIV replication in autologous HIV-infected CD4+ T cells (iCD4) more potently than those from carriers of non-protective genotypes. HIV suppression depends on the secretion of CC-chemokines that block HIV entry into CD4+ cells. NK cell education and the effect of HIV infection on iCD4 cell surface expression of MHC-I antigens both influenced NK cell responses to autologous iCD4. The second KIR3DS1 homozygous protective genotype encodes an activating receptor that upon interacting with its HLA-F ligand on iCD4 induces anti-viral activity.
Some individuals remain uninfected despite high levels of exposure to HIV. Persons with this profile are called HIV exposed seronegative subjects (HESN) . Understanding why HESN are resistant to HIV infection has the potential to identify correlates of protection from infection. As early as 2003, Scott-Algara et al. found that stimulating NK cells from HESN enrolled in a Vietnamese injection drug user cohort led to activation of higher levels of cytolysis and cytokine/chemokine secretion than did stimulating NK cells from HIV-infected persons or from seroconverters even before they seroconverted . This was the first report suggesting that HESN may have NK cells with superior functionality.
HLA-null cell stimulation of NK cells reveals their functional potential, which is directly related to how potently they were educated during development . HLA-null stimulation of NK cells from *h/*y+B*57 carriers generated higher frequencies of NK cells expressing CD107 (a marker for degranulation) and secreting IFN-γ and TNF-α than NK cells from carriers of other KIR3DL1hmz/HLA-B genotypes [16, 17]. These triple functional cells exhibited a higher intensity of each of these functions than their mono-functional counterparts . Thus, the *h/*y+B*57 genotype encoded iKIR receptor/HLA-B*57 ligand combinations that were particularly potent educating pairs that supported the development of NK cells with high functional activity. NK cells from *h/*y+B*57 carriers inhibited the replication of autologous iCD4 cells more potently than those from carriers of non-protective KIR/HLA genotypes . Induction of NK cell inhibition of HIV replication was dependent on contact with autologous iCD4s. However, once NK cells were activated, their secreted products were sufficient to inhibit HIV replication. Among these, were the CC-chemokines CCL3, CCL4 and CCL5 detected in NK/iCD4 co-culture supernatants as well as by intra-cellular NK cell staining. Levels of CC-chemokines were highest in NK cells from *h/*y+B*57 carriers and higher in stimulated KIR3DL1+ than KIR3DL1− NK cells . Neutralization of all three CC-chemokines in NK/iCD4+ co-cultures reversed inhibition of HIV replication . Thus, the ability of NK cells to inhibit HIV replication is, at least in part, due to their ability to secrete CC-chemokines that block HIV infection of CD4+ T cells .
Natural killer cells respond to stimulation with autologous iCD4. By using fluorochrome conjugated antibody panels it is possible to gate on NK cell populations expressing defined inhibitory NKRs (iNKR) and to detect anti-viral functions such as secretion of IFN-γ/CCL4 and expression of CD107a by flow cytometry. This strategy has been used to explore the factors governing how NK cells from HIV-uninfected persons respond to their first encounter with autologous iCD4.
The KIR3DS1hmz genotype is also associated with protection from HIV infection [13, 14]. The notion that the ligand for KIR3DS1 was a subset of Bw4 antigens with an isoleucine at position 80 of the HLA heavy chain (Bw4*80I) has recently been debunked in favor the non-classical MHC-Ib antigen, HLA-F . HLA-F is expressed on the HLA-null 721.221 and K562 cells and on HIV-infected cells .
Genotypes encoding NKRs that are overrepresented in HESN confer NK cells with superior functional potential to HLA-null cells and with superior responses to autologous iCD4. NK cell education is important in the responsiveness of NK cell populations to iCD4. The higher functionality, in terms of CCL4 secretion, of educated KIR3DL1+ NK cells may be a mechanism underlying the superior viral control and slower time to AIDS observed in epidemiological studies for some carriers of KIR3DL1hmz/Bw4 compared to carriers of other KIR/HLA genotypes . The functionality of NK cell populations to autologous iCD4 is not only dependent on their education but also on HIV-mediated changes in MHC-I expression levels. An important component of the anti-viral activity of stimulated NK cells is secretion of CC-chemokine, which can block HIV entry into new CD4+ target cells.