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Investigation of mechanisms of immunological inefficiency of antiretroviral therapy in HIV-infected patients

Part of the HIV-infected patients receiving HAART does not demonstrate significant increase in CD4+ T cells, despite the complete suppression of viral load (VL). Such persons are called «immunological nonresponders» (INRs). Their weight can reach 30%. The literature suggests various reasons for the formation of INRs: impaired bone marrow function, depletion of the thymus gland, deficiency of IL-2 or IL-7, etc. However, there are known clinical factors influencing the level of INRs. Patient age, duration of HIV infection, concomitant diseases are among them. In the past few years, the Institute of Ecology and Genetics of Microorganisms, UB RAS and Perm regional center for HIV infection are carried out a joint cohort study on the effectiveness of antiretroviral therapy. It includes more than 400 patients receiving HAART over 2.5 years. An electronic database containing information on clinical and laboratory parameters of the patients and prescribed drugs was created. INRs group comprises 11.3% of the total number of patients. In this group as compared with the immunological responders (IRs) men were predominant (53.2% and 41.7%, respectively; R=0.227; P<0.05) and intravenous route of infecting was more frequently observed (78.7% and 64.8%; R=0.336; P<0.01). Initial level of CD4+ blood lymphocytes significantly (P<0.001) affected the immunity reconstitution following the therapy. For IRs it was 223.46.5 cell/mm3, and for INRs – 155.212.0 cell/mm3. The VL baseline has no influence on the success of HAART. We can assume that the prospects for recovery of immunity on antiviral therapy are determined not by the virus quantity, but the degree of damage the immune system. In addition, it was found that the presence of co-infection with hepatitis C (HCV) is an important factor hindering the success of antiretroviral therapy. The research of dependence of immunological response on HCV co-infection has revealed the presence of reliable inverted relation between these parameters (R = -0.318; P <0.01). The very presence of HCV in patients studied was completely associated with the intravenous route of HIV infection (R = 0.999; P <<0.001) and continued drug usage (R = 0.833; P <0.001). In this situation, the chances for acquiring HCV co-infection in patients infected with HIV through sexual contact were more than 4000 times lower. The probability of HCV infection in non-active drug users, was 11-fold, and in women infected with HIV – 5.5 times less. Given the problems for patients, associated with prolonged drug administration, well-known complications of HAART and the high cost of the therapy, we believe it is necessary to conduct studies aimed at identifying the causes of immunological treatment failure. Among the areas of research we consider as an actual the detection of differences between the IRs and INRs in: 1) the thymus function (a method of TREC determining is now in progress), 2) the degree of immune system activation and lymphocyte apoptosis, 3) serum cytokine concentration. It is also necessary to investigate the role of HCV in the defeat of the immune system.

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