AIDS in Oman: Genetic determinants of patients' different responses to HAART: insight into CCL3L1/CCR5 genotypes and HLA antigens

The acquired immunodeficiency syndrome (AIDS) is a major global health emergency, and it is the sixth leading cause of death in the world and the third in low income countries. Not all individuals infected with human immunodeficiency virus (HIV) will progress at the same rate towards the terminal stages of the disease. and nbsp; Natural resistance to HIV/AIDS can be considered at different levels: 1) Resistance to becoming infected with the virus 2) Resistance to progression of the disease after infection e.g. long term non-progressors; and nbsp; 3) After symptoms appears (CD4 and lt;200) e.g. long term AIDS survivors. It has been observed, that HIV-infected patients on Highly Active Antiretroviral Therapy (HAART) do not respond equally to treatment, despite proper compliance to therapy. Immunological and/or virological failure is commonly observed. The observed variation has been attributed to non genetic factors such as the existence of different HIV subtypes and the evolution of drug resistance mutations on the HIV genome. Recent studies have demonstrated that the genetic make up of the individual is an important contributing factor to the variation observed on HAART response among different individuals. It is believed that, human leukocyte antigens (HLA) allele type, CC chemokine ligand 3-like 1 (CCL3L1) and CC chemokine receptor 5 (CCR5) genotypes are among the candidate host genetic factors that may explain the fast or slow deterioration among AIDS patients on HAART. and nbsp; We aim to investigate: 1) whether or not certain CCL3L1-CCR5 genotype and/or HLA alleles play a significant role in the response to HAART among Omani AIDS patients on HAART. This can be achieved by determining the HLA alleles by molecular technique. CCR5 gene polymorphisms can be detected by PCR and DNA sequencing of the entire gene. CCL3L1 copy number will be determined by Real Time PCR. and nbsp; The above mentioned procedures are to be carried out among controls and AIDS patients on HAART. The distribution of HLA alleles and CCL3L1-CCR5 genotype among controls will be compared against AIDS patients on HAART, 2) the influence of these genetic markers on the different immunological and virological parameters among AIDS patients on HAART and 3) Determining alleles (which are to be identified) among good and poor responders to HAART among Omani AIDS patients and deciphering the mechanism(s) that may explain HLA/AIDS association such as HLA assembly, and nbsp;trafficking and proteomic studies of CD4+ T helper cells and macrophages on and nbsp;the study groups. To the best of our knowledge, this novel approach has not been investigated thoroughly and we hope to implement and address this among Omani AIDS patients. Finally, we are proposing that, the outcome of our study and nbsp;will 1) help determining factors involved in the variability of immune response observed among AIDS patients on HAART, 2) aid in optimizing the best treatment for Omani AIDS patients based on our population genetic background and limiting the exposure to unnecessary toxicity due to antiretrovirals. Understanding HLA involvement in AIDS progression will open gates for possible development of effective therapy among Omani HIV-infected patients.

The acquired immunodeficiency syndrome (AIDS) is a major global health emergency, and it is the sixth leading cause of death in the world and the third in low income countries. Not all individuals infected with human immunodeficiency virus (HIV) will progress at the same rate towards the terminal stages of the disease. and nbsp; Natural resistance to HIV/AIDS can be considered at different levels: 1) Resistance to becoming infected with the virus 2) Resistance to progression of the disease after infection e.g. long term non-progressors; and nbsp; 3) After symptoms appears (CD4 and lt;200) e.g. long term AIDS survivors. It has been observed, that HIV-infected patients on Highly Active Antiretroviral Therapy (HAART) do not respond equally to treatment, despite proper compliance to therapy. Immunological and/or virological failure is commonly observed. The observed variation has been attributed to non genetic factors such as the existence of different HIV subtypes and the evolution of drug resistance mutations on the HIV genome. Recent studies have demonstrated that the genetic make up of the individual is an important contributing factor to the variation observed on HAART response among different individuals. It is believed that, human leukocyte antigens (HLA) allele type, CC chemokine ligand 3-like 1 (CCL3L1) and CC chemokine receptor 5 (CCR5) genotypes are among the candidate host genetic factors that may explain the fast or slow deterioration among AIDS patients on HAART. and nbsp; We aim to investigate: 1) whether or not certain CCL3L1-CCR5 genotype and/or HLA alleles play a significant role in the response to HAART among Omani AIDS patients on HAART. This can be achieved by determining the HLA alleles by molecular technique. CCR5 gene polymorphisms can be detected by PCR and DNA sequencing of the entire gene. CCL3L1 copy number will be determined by Real Time PCR. and nbsp; The above mentioned procedures are to be carried out among controls and AIDS patients on HAART. The distribution of HLA alleles and CCL3L1-CCR5 genotype among controls will be compared against AIDS patients on HAART, 2) the influence of these genetic markers on the different immunological and virological parameters among AIDS patients on HAART and 3) Determining alleles (which are to be identified) among good and poor responders to HAART among Omani AIDS patients and deciphering the mechanism(s) that may explain HLA/AIDS association such as HLA assembly, and nbsp;trafficking and proteomic studies of CD4+ T helper cells and macrophages on and nbsp;the study groups. To the best of our knowledge, this novel approach has not been investigated thoroughly and we hope to implement and address this among Omani AIDS patients. Finally, we are proposing that, the outcome of our study and nbsp;will 1) help determining factors involved in the variability of immune response observed among AIDS patients on HAART, 2) aid in optimizing the best treatment for Omani AIDS patients based on our population genetic background and limiting the exposure to unnecessary toxicity due to antiretrovirals. Understanding HLA involvement in AIDS progression will open gates for possible development of effective therapy among Omani HIV-infected patients.