Novel genetic associations and gene-gene interactions of chemokine receptor and chemokine genetic polymorphisms in HIV/AIDS.

OBJECTIVE: To investigate the influence of candidate polymorphisms on chemokine receptor/ligand genes on HIV infection and AIDS progression (HIV/AIDS). DESIGN: Fifteen polymorphisms of the CCR3, CCR4, CCR5, CCR6, CCR8, CXCR3, CXCR6, CCL20, CCL22 and CXCL10 genes were analysed in 206 HIV-positive patients classified as rapid progressors (n = 40), or nonrapid progressors (n = 166), and in 294 HIV-seronegative patients. METHODS: The polymorphisms were genotyped using minisequencing. Genetic models were tested using binomial logistic regression; nonparametric multifactor dimensionality reduction (MDR) was used to detect gene-gene interactions. RESULTS: The CCR3 rs3091250 [TT, adjusted odds ratio (AOR): 2.147, 95% confidence interval (CI) 1.076-4.287, P = 0.030], CCR8 rs2853699 (GC/CC, AOR: 1.577, 95% CI 1.049-2.371, P = 0.029), CXCL10 rs56061981 (CT/TT, AOR: 1.819, 95% CI 1.074-3.081, P = 0.026) and CCL22 rs4359426 (CA/AA, AOR: 1.887, 95% CI 1.021-3.487, P = 0.043) polymorphisms were associated with susceptibility to HIV infection. The CCL20 rs13034664 (CC, OR: 0.214, 95% CI 0.063-0.730, P = 0.014) and CCL22 rs4359426 (CA/AA, OR: 2.685, 95% CI 1.128-6.392, P = 0.026) variants were associated with rapid progression to AIDS. In MDR analyses revealed that the CXCL10 rs56061981 and CCL22 rs4359426 combination was the best model, with 57% accuracy (P = 0.008) for predicting susceptibility to HIV infection. CONCLUSION: Our results provide new insights into the influence of candidate chemokine receptor/ligand polymorphisms and significant evidence for gene-gene interactions on HIV/AIDS susceptibility.

Rapid and Slow Progressors Show Increased IL-6 and IL-10 Levels in the Pre-AIDS Stage of HIV Infection.

Cytokines are intrinsically related to disease progression in HIV infection. We evaluated the plasma levels of Th1/Th2/Th17 cytokines in extreme progressors, including slow (SPs) and rapid (RPs) progressors, who were thus classified based on clinical and laboratory follow-up covering a period of time before the initiation of HAART, ranging from 93-136.5 months for SPs and 7.5-16.5 months for RPs. Analyses were also performed based on the different stages of HIV infection (chronic, pre-HAART individuals-subjects sampled before initiating HAART but who initiated therapy from 12 to 24 months-and those receiving HAART). The plasma cytokine levels of 16 HIV-infected rapid progressors and 25 slow progressors were measured using a Human Th1/Th2/Th17 CBA kit. The IL-6 and IL-10 plasma levels differed significantly between the stages of HIV infection. The IL-6 levels were higher in slow progressors pre-HAART than in chronically infected SPs and HIV-seronegative individuals. The IL-10 levels were higher in slow progressors pre-HAART than in slow progressors receiving HAART and HIV-seronegative controls, and in rapid progressors, the IL-10 levels were higher in pre-HAART subjects than in HIV-seronegative controls. The results reflect the changes in the cytokine profile occurring during different clinical stages in HIV+ subjects. Our results suggest an association between increased IL-6 and IL-10 levels and pre-HAART stages independent of the slow or rapid progression status of the subjects. Thus, increased IL-6 and IL-10 levels could indicate a global inflammatory status and could be used as markers of the disease course in HIV-infected individuals.

New insights into the in silico prediction of HIV protease resistance to nelfinavir.

The Human Immunodeficiency Virus type 1 protease enzyme (HIV-1 PR) is one of the most important targets of antiretroviral therapy used in the treatment of AIDS patients. The success of protease-inhibitors (PIs), however, is often limited by the emergence of protease mutations that can confer resistance to a specific drug, or even to multiple PIs. In the present study, we used bioinformatics tools to evaluate the impact of the unusual mutations D30V and V32E over the dynamics of the PR-Nelfinavir complex, considering that codons involved in these mutations were previously related to major drug resistance to Nelfinavir. Both studied mutations presented structural features that indicate resistance to Nelfinavir, each one with a different impact over the interaction with the drug. The D30V mutation triggered a subtle change in the PR structure, which was also observed for the well-known Nelfinavir resistance mutation D30N, while the V32E exchange presented a much more dramatic impact over the PR flap dynamics. Moreover, our in silico approach was also able to describe different binding modes of the drug when bound to different proteases, identifying specific features of HIV-1 subtype B and subtype C proteases.

Temporal dynamics of HIV-1 circulating subtypes in distinct exposure categories in southern Brazil.

BACKGROUND: The HIV-1 epidemic in Brazil is predominantly driven by subtype B. However, in Brazilian Southern region subtype C prevails and a relatively high AIDS incidence rate is observed. The aim of the present study was to assess the temporal dynamics of HIV-1 subtypes circulating in patients from distinct exposure categories in Southern Brazil. For this purpose 166 HIV-1 samples collected at the years of 1998 (group I) and 2005-2008 (group II) were analyzed. RESULTS: Analysis of group I revealed statistically significant (p < 0.05) associations between MSM and subtype B as well as between IDU and subtype C; while no statistical significant association between HIV-1 subtypes and exposure category was verified for group II. An overall temporal increase in the prevalence of subtype C and BC recombinants was observed in both HET and MSM populations, accompanied by a proportional decrease in the prevalence of the pure subtype B. CONCLUSIONS: The present study shows an association between HIV subtypes and exposure categories at the middle 1990s in Southern Brazil. Our findings suggest that MSM and IDU populations might have played a major role in the introduction and initial dissemination of subtypes B and C, respectively, in Southern Brazil. This study also suggests a trend towards homogenization of HIV-1 strains across distinct exposure categories as a consequence of an overall increase in the prevalence of subtype C and BC recombinants in both HET and MSM populations.