Specific human leukocyte antigens (HLAs), notably HLA-B*27 and HLA-B*57 allele groups, have long been associated with control of HIV-1. Although the majority of HIV-specific CD8+ T cells lose proliferative capacity during chronic infection, T cells restricted by HLA-B*27 or HLAB*57 allele groups do not. Here we show that CD8+ T cells restricted by 'protective' HLA allele groups are not suppressed by Tref cells, whereas, within the same individual, T cells restricted by 'nonprotective' alleles are highly suppressed ex vivo. This differential sensitivity of HIV-specific CD8+ T cells to Tref cell–mediated suppression correlates with their expression of the inhibitory receptor T cell immunoglobulin domain and mucin domain 3 (Tim-3) after stimulation with their cognate epitopes. Furthermore, we show that HLA-B*27– and HLA-B*57–restricted effectors also evade Tref cell–mediated suppression by directly killing Tref cells they encounter in a granzyme B (GzmB)-dependent manner. This study uncovers a previously unknown explanation for why HLA-B*27 and HLA-B*57 allele groups are associated with delayed HIV-1 disease progression.

؉ T-cell counts (4 to 8 times longer), while responses to variable epitopes presented by B35 alleles (DL9 and IL9) resulted in more rapid progression. The plasma viral load was higher in B57/58 ؉ and B27 ؉ subjects lacking the conserved B57/58-and B27-restricted responses. The presence of certain B57/58-, B27-, and B35-restricted HIV-specific CD8 ؉ T-cell responses after primary HIV-1 infection better defined disease progression than the HLA genotype alone, suggesting that it is the HIV-specific CD8 ؉ T cells and not the presence of a particular HLA allele that determine disease progression. Further, the most effective host CD8 ؉ T-cell responses to HIV-1 were prevalent within an HLA allele, represented a high total allele fraction of the host CD8 ؉ T-cell response, and targeted conserved regions of HIV-1. These data suggest that vaccine immunogens should contain only conserved regions of HIV-1.

A successful HIV vaccine will likely induce both humoral and cell-mediated immunity, however, the enormous diversity of HIV has hampered the development of a vaccine that effectively elicits both arms of the adaptive immune response. To tackle the problem of viral diversity, T cell-based vaccine approaches have focused on two main strategies (i) increasing the breadth of vaccine-induced responses or (ii) increasing vaccine-induced responses targeting only conserved regions of the virus. The relative extent to which set-point viremia is impacted by epitope-conservation of CD8+ T cell responses elicited during early HIV-infection is unknown but has important implications for vaccine design. To address this question, we comprehensively mapped HIV-1 CD8+ T cell epitope-specificities in 23 ART-naïve individuals during early infection and computed their conservation score (CS) by three different methods (prevalence, entropy and conseq) on clade-B and group-M sequence alignments. The majority of CD8+ T cell responses were directed against variable epitopes (p<0.01). Interestingly, increasing breadth of CD8+ T cell responses specifically recognizing conserved epitopes was associated with lower set-point viremia (r = - 0.65, p = 0.009). Moreover, subjects possessing CD8+ T cells recognizing at least one conserved epitope had 1.4 log10 lower set-point viremia compared to those recognizing only variable epitopes (p = 0.021). The association between viral control and the breadth of conserved CD8+ T cell responses may be influenced by the method of CS definition and sequences used to determine conservation levels. Strikingly, targeting variable versus conserved epitopes was independent of HLA type (p = 0.215). The associations with viral control were independent of functional avidity of CD8+ T cell responses elicited during early infection. Taken together, these data suggest that the next-generation of T-cell based HIV-1 vaccines should focus on strategies that can elicit CD8+ T cell responses to multiple conserved epitopes of HIV-1.

Lipodystrophy in HIV-infected (LDHIV) patients receiving protease inhibitors (PIs) is associated with dyslipidaemia. Whether lifestyle factors play a role in dyslipidaemia in LDHIV subjects on PIs is not well characterized. MethodsA total of 45 LDHIV male and six LDHIV female patients on PIs were recruited, and data were collected on smoking, exercise, diet (by 3-day food record), and fasting levels of serum lipids and lipoproteins. The relationships between lifestyle factors and metabolic variables were analysed in male patients by Spearman's correlation test and the significant relationships were further analysed by adjusting for age, PI duration, and waist circumference by Spearman's partial correlation test. ResultsIn men, mean (AE standard deviation) serum concentrations of total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), triglycerides (TG), and non-HDL-C were 212 AE 70, 35 AE 7.3, 325 AE 230 and 169 AE 44 mg/dL, respectively. Sixty-seven percent of the men exercised regularly and 31.1% smoked. The reported diet was high in cholesterol (390 AE 212 mg) and percentage energy from saturated (12.2 AE 3.3%) and trans (2.4 AE 1.2%) fats, and low in soluble fibre (6.9 AE 2.3 g) compared with recent dietary guidelines. Following adjustments for the confounding variables, percentage energy intake from total protein and animal protein was positively related to TC (r 5 0.44, Po0.01 and r 5 0.37, Po0.05, respectively), TG (r 5 0.40, Po0.01 and r 5 0.46, Po0.01, respectively) and non-HDL-C (r 5 0.56, Po0.001 and r 5 0.49, Po0.01, respectively), that from trans fat was positively related to TG (r 5 0.34, Po0.05), and soluble fibre was negatively related to non-HDL-C (r 5 À 0.41, Po0.01). Moderate to heavy aerobic exercise tended to be associated with higher HDL-C (r 5 0.30, P 5 0.07) whereas smoking was not associated with any of the metabolic variables. ConclusionsIncreased intake of total protein, animal protein and trans fat, and reduced soluble fibre consumption contribute to dyslipidaemia in LDHIV subjects on PIs.Keywords: diet, dyslipidaemia, exercise, HIV, lipodystrophy, smoking In subjects not infected with HIV, lifestyle factors such as diet, physical activity and smoking contribute significantly to dyslipidaemia [10]. However, there is a paucity of data regarding the role of lifestyle factors in inducing dyslipidaemia in LDHIV individuals on PI-containing HAART. Previous studies [11][12][13] included not only HIV-infected subjects on PI therapy but also PI-naïve subjects. Also, two of these studies [11,12] did not examine or adjust for the role of exercise and smoking in dyslipidaemia. Furthermore, these studies [11][12][13] did not comprehensively examine the relationship between intakes of macronutrients and levels of lipids and lipoproteins. For example, Batterham et al.[11] evaluated only the role of total and saturated fat in dyslipidaemia. Hadigan et al.[12] did not study the role of unsaturated fats such as polyunsaturated, monounsaturated and trans fats. Gavrila et al. [13] did not ...