328 BIOTECHNOL. & BIOTECHNOL. EQ. 21/2007/3 MEDICAL BIOTECHNOLOGY ARTICLES MB Key words: HIV, co-receptors, genetic polymorphism Introduction HIV is a multifactorial infection, representing a lifetime long fight between the causative agent – Human Immunodeficiency Virus (HIV) and the host (6). Similarly to other retroviral infections, the intensive research on HIV-replication dynamics in vivo during the last years has clearly defined both viral and human/host factors influencing transmission, course, progression and outcome of infection (6, 11). HIV-transmission depends on biological properties of viral strains, as well as on the individual susceptibility. On the other hand, the latter is closely associated to a range of immunological and genetic factors. Among those, a number of chemokine receptors have been identified to function as co-receptors for HIV-1 entry in human CD4+ T-lymphocytes and monocytes (16). CCR5 is a chemokine receptor, whose α- chemokine ligands participate in chemotaxis of lymphocytes during inflammation. CCR5-protein is expressed on the surface of monocytes, macrophages, memory T-cells and dendritic cells, as well as on microglial cells correlating to the ability of HIV to infect the central nervous system (7). This is the major co-receptor, necessary for macrophage-tropic (M- tropic) non-syncytium inducing (NSI) HIV-1 strains entry (5). A complicated interaction between HIV-1 glycoprotein gp120, CD4 and CCR5 on the surface of CD4+ cells is crucial to HIV entry. As known, Ɇ-tropic strains are associated predominantly with sexual transmission of HIV. Detailed studies of the coding region of CCR5 showed a variety of genetic polymorphisms. 32-base pair deletion (CCR5del32 mutation) in one or both alleles seems the most common polymorphism. When occurring in both alleles (homozygous pattern), this polymorphism leads to a formation of truncated, non-functional receptor protein, incapable to bind gp120 during the adhesion of HIV to the cell (20). The same mutation could also exist in only one allele (heterozygous pattern), leading to a limited production of the functional protein. The homozygous (CCR5del32/CCR5del32) individuals were reported insusceptible to infection with Ɇ-tropic HIV- 1 strains (8). Data showed that heterozygous (CCR5del32/ CCR5) individuals had better prognosis during natural course of infection compared to those bearing “wild type” (CCR5/ CCR5) alleles. The individuals with heterozygous pattern show a decreased expression of CCR5 on the cell surface and are more frequently considered as Long Term Non Progressors (LTNPs) compared to patients with a rapid/moderate progression of infection (4). In addition, HIV-infected heterozygous individuals also demonstrate better response to Highly Active Anti Retroviral Therapy (HAART) and decreased lymphoma incidence (19). These data clearly indicate that CCR5 density on cell surface could be a limiting factor for HIV-replication both in vitro and in vivo. GENETIC POLYMORPHISM OF THE CHEMOKINE CO-RECEPTORS CCR5, CXCR4 AND CCR2 IN BULGARIANS LIVING WITH HIV K. Borissov 1 , R. Markova 2 , I. Elenkov 3 , K. Kostov 3 , A. Savov 4 , I. Kremensky 4 , R. Argirova 1 Lab. of Retroviruses, Natl. Center of Infectious and Parasitic Diseases, Sofia 1 Dept. of Immunology, Natl. Center of Infectious and Parasitic Diseases, Sofia 2 Infectious Disease Hospital, Sofia 3 Lab. of Molecular Pathology, Medical University, Sofia 4 Correspondence to: Kalin Borissov E-mail: borissov_kalin@yahoo.com ABSTRACT The aim of this study was to investigate the most spread genetic polymorphisms of the chemokine co-receptors CCR5, CXCR4 and CCR2 – namely the allele frequency of CCR5del32, SDF-1 3’A and CCR2 V64I in 177 Bulgarians living with HIV, as well as to correlate the results to the clinical course of HIV-infection and the same allele frequency for general population. The persons studied were of different duration of HIV-infection – registered during the period 1987-2004. Fourteen persons (7.9%) showed slow progression to AIDS, received therapy after no treatment for 7 – 10 years and were considered Long Term Survivors (LTSs). All HIV(+)s have been screened for CCR5 (CCR5del32) and 48 - for CXCR4 (SDF-1) (SDF-1 3’A) and CCR2 (CCR2 V64I) polymorphisms. No one from HIV positives has been found with a homozygous - CCR5del32/CCR5del32 - status, 6 out of all studied (3.2%) had heterozygous (CCR5/CCR5del32) genotype (only two LTSs). Seven out of 48 persons studied (14.6 %) had homozygous (SDF–1 3’A/SDF– 1 3’A) genotype, (3 – LTSs), another 12 (25%) showed heterozygocity for CCR2 (CCR2/CCR2V64I - 2 – LTSs). The LTSs heterozygous by CCR5 (CCR5/CCR5del32), those displaying (SDF-1 3’A/SDF-1 3’A) homozygocity and both (13.33%) demonstrating (CCR2/CCR2V64I) heterozygous genotype were different persons. Although low numbers of persons studied, the results obtained coincide well to the literature ones. The genetic studies will be used to predict the results of HAART treatment as well as the onset to AIDS.