Infection with KSHV is required but not sufficient for development of KS, and the prevalence of KSHV seropositivity far exceeds the incidence of KS. The genes encoding HLA and related genes are centrally involved in the immunological response to infectious diseases and thus may affect the risk of developing KSHV infection or KS. We compared HLA class I and KIR HLA ligand frequencies in a 2 phase study that included 250 persons with classic KS, 280 KSHV seropositive controls, and 576 KSHV seronegative controls in Italy. This is the first comprehensive study to assess the role of HLA and KIR on the risk of KSHV seroprevalence and classic KS. The risk of KS was significantly reduced in people with A1101, and it was increased for those with C0701. A1101 is well known to be associated with decreased risk for the EBV associated nasopharyngeal carcinoma. Both KSHV and EBV are gamma herpes virus. This implies that A1101 may present herpesvirus related antigenic epitopes to cytotoxic T lymphocytes, resulting in effective control of the virus in the lytic phase. HLA C group 1 alleles, which serve as ligands for the inhibitory KIR2DL2 and 3, were significantly associated with protection against KSHV seroprevalence, but with increased risk of KS among KSHV infected subjects. This KIR HLA combination has a relatively weak NK cell inhibitory potential relative to that of KIR2DL1 in the presence of its HLA C group 2 ligand, which is strongly inhibitory. Likewise, the activating KIR3DS1 with HLA B Bw4 80I was protective against seroprevalence but associated with an increased risk of KS. We hypothesize that strong NK cell activation protects against seropositivity but is a risk factor for classic KS after KSHV infection, perhaps because of the known association of KS with inflammation. The HLA C locus is distinct relative to HLA A and HLA B in that it is less polymorphic, and it encodes molecules that have lower cell surface expression levels and more extensive interactions with the KIRs expressed by NK cells. Pathogen driven downregulation of HLA class I molecules on infected cells can result in strongly diminished CTL recognition but also enhance NK cell mediated lysis of the infected cell because of the failure of HLA ligand to bind inhibitory KIRs. The specificity of HIV1 Nef in downregulating HLA A and B molecules, but not HLA C, has been interpreted as a viral mechanism to subvert adaptive HLA A and HLA B restricted CTL responses while simultaneously protecting infected cells against innate NK cell immunity through recognition of unmodulated HLA C levels by inhibitory NK cell receptors. We measured surface expression levels of HLA class I on primary CD4+ cells infected in vitro with primary HIV1 strains. Unlike the widely studied laboratory adapted HIV1 isolate NL4 3, most primary clones of HIV1 do in fact downregulate HLA C to some extent. We determined, using several primary HIV1 strains, that the viral Vpu protein is responsible for HLA C downregulation. Notably, specific naturally occurring amino acid variants in the N terminal region of Vpu that affect the differential ability to downregulate HLA C are located within peptides known to bind HLA alleles, suggesting that the ability of HIV1 to modulate HLA C could be altered over the course of viral adaptation to certain CTL responses. Differences in HLA C expression levels have been shown to influence the outcome of HIV1 infection where higher expression levels associate inversely with viral load in the absence of antiretroviral therapy. Higher HLA C expression levels also correlate with greater frequencies of HLA C associated CTL responses and a higher degree of viral mutation, illustrating the immune pressure that higher HLA C expression exerts on the virus. That higher HLA C expression levels associate with viral control is consistent with HIV targeting HLA C for downregulation. Revision of the prevailing model in which HIV evades both CTL and NK cell immune responses through selective downregulation of HLA loci is required and must now take into account mechanisms by which HIV infected cells evade innate immune cells when HLA C expression is downregulated. Previous GWAS of HIV1 infected populations have been underpowered to detect common variants with moderate impact on disease outcome and have not assessed the phenotypic variance explained by genome wide additive effects. Combining the majority of available genome wide genotyping data in HIV infected populations, about 8 million variants were tested for association with viral load in 6,315 individuals of European ancestry. The strongest signal of association was observed in the HLA class I region that was fully explained by independent effects mapping to five variable amino acid positions in the peptide binding grooves of the HLA B and A proteins. The strong associations at positions 97 and 67 in HLA B were confirmed and additional signals at position 45 in HLA B and positions 77 and 95 in HLA A were identified. These amino acids are all located in the peptide binding groove and supports the hypothesis that the presentation of specific viral epitopes, is critical in determining the efficiency of the CTL response. A second genome wide significant association signal in the chemokine receptor gene cluster (CCR) on chromosome 3 was also observed. The top SNP identified on chromosome 3, rs1015164, is only weakly correlated to CCR5delta32 (r2 = 0.03). This SNP is located within or near an antisense transcribed sequence that overlaps CCR5 and thus may play a role in regulating its expression. Demonstration of causality of these variants and or a silencing effect of the antisense transcribed sequence will require functional studies. Overall, the data suggest that that common human genetic variation, mostly in the HLA and CCR5 regions, explains 25% of the variability in viral load. This study suggests that analyses in non European populations and of variant classes not assessed by GWAS should be priorities for the field going forward. Genetic association studies have implicated over 40 genetic loci in the pathogenesis of psoriasis, with the largest signal observed at the HLA class I locus for HLA C0602. However, recent data also suggest a role for HLA B. Both of these molecules participate in adaptive immunity through antigen presentation, and they also regulate the innate immune response through interaction with KIRs. Previous studies have shown that the presence of activating KIR3DS1 and KIR2DS1 is associated with increased susceptibility to psoriasis and psoriatic arthritis, which is consistent with a model wherein expression of activating KIRs increases the risk of developing immune mediated diseases. Whether decreased expression of inhibitory KIRs is also associated with increased risk of psoriasis has not been fully explored. Cell surface expression of KIR3DL1 varies greatly between alleles, and alleles can be classified into three allotypes: KIR3DL1NULL, KIR3DL1LOW and KIR3DL1HIGH. The ligand for KIR3DL1 is the Bw4 epitope present on several HLA B molecules. To investigate the association of KIR3DL1 and HLA Bw4 with psoriasis, genotyping of KIR3DL1 and HLA B in a cohort of 203 subjects with psoriasis and 111 healthy controls of European descent was carried out. Association testing of the compound KIR3DL1/Bw4 genotypes revealed a statistically significant association with 3DL1LOW/Bw4 and increased risk for psoriasis. Overall, the results suggest that low cell surface expression of KIR3DL1 in the presence of the HLA Bw4 epitope is associated with an increased risk for developing psoriasis which is consistent with a model whereby a reduction in the inhibitory signal in natural killer or T cells results in a heightened immune cell response.