Studies on the efficacy of potent anti-HIV-1 therapy on virological and immunological factors

<p>The aim of this thesis was to assess to which extent treated human immunodeficiency virus type I (HIV-1) infected patients with a seemingly controlled, defined as undetectable plasma HIV-1 RNA levels (< 50 copies/ml), or low-grade viral replication, exhibited pattems in virological and immunological factors which could suggest a continuation of the disease process.</p><p>We have therefore analysed the kinetics of HIV-1 DNA levels (Papers I and II), the viral evolution (Paper II), the changes in Beta-chemokine levels (Paper 111) and sCD27 levels (Paper IV), and the appearance of drug resistance associated mutations (Paper V) in such patients.</p><p>The HIV-1 DNA levels in peripheral blood mononuclear cells were analysed by a competitive PCR assay in patients with triple (n= 37) or double combination therapy (n= 11) and in 10 untreated patients during one year (Paper 1). In patients on triple therapy, a significant decline of the HIV- I DNA load was seen, independent of whether it was expressed as copies/ 106 CD4+ cells or copies/nil blood. In contrast, in patients given two drugs, a decline was only seen when the proviral load was expressed as copies/106 CD4+ cells. During a prolonged follow-up period of up to 30 months in patients with undetectable plasma HIV-1 RNA levels, the cellular HIV-1 DNA levels continued to decrease and the frequency of patients with undetectable proviral DNA increased.</p><p>Also, sequence changes in the V3 region of the major viral population, as signs of ongoing viral replication, were monitored in Paper H. Of 18 patients with viral suppression to < 50 copies/ml, variations of the V3 sequences were observed in 10 patients. 69% of these changes occurred in the first sample interval after initiation of therapy.</p><p>The kinetics of the beta-chemokines, MIP-1alpha, MIP-1beta, RANTES and MCP-1, in plasma during one year of therapy (n= 26) and in untreated subjects (n= 11) were studied by ELISA (Paper III). During therapy, decreases of MCP-1 and RANTES levels were found, while no durable changes of MIP-1alpha, and MIP-10 were seen. The MCP-1 levels rebounded back to baseline after one year despite a good virological response.</p><p>Plasma levels of sCD27 were measured by ELISA during two years of therapy in 26 patients and in additional seven patients after interruption of therapy (Paper IV). A full normalisation of plasma sCD27 levels was observed in responders with HIV-1 RNA < 50 copies/ml and in patients with moderate immunodeficiency. Discontinuation of therapy resulted in a rapid increase of sCD27 plasma levels, associated with viral rebound. Crosssectional examination on lymphocytes from 36 subjects showed a reduced cellular expression of CD27, which was further decreased in patients on combination therapy.</p><p>The pol gene was analysed by direct sequencing in 14 patients who had an initial treatment response of a viral load < 500 copies/ml, but who thereafter had a viral rebound to a low-grade viremia. During up to 30 months of follow-up, new primary resistance associated mutations in RT or protease appeared in 11 and 9 patients, respectively, despite concomitantly increasing CD4+ T cell counts. Drug-resistance was even detected in a patient with HIV- I RNA < 50 copies/ml. Further mutations accumulated frequently after the initial mutations.</p><p>Our data suggest that the viral replication can be highly restricted and that measures of immune activation can normalise during two-three years of antiretroviral combination therapy in patients with plasma HIV-1 RNA levels < 50 copies/ml. However, the disease process may continue in some patients. A low-grade viremia can be sufficient to allow drug-resistance mutations, which may exhaust future drug-options. Thus, currently used anti-HIV-1 therapy is frequently very efficient, but it is still possible to further improve the virological and immmunological effects in otherwise successfully treated individuals.</p><h3>List of scientific papers</h3><p>I. Aleman S, Visco-Comandini U, Lore K, Sonnerborg A (1999). "Long-term effects of antiretroviral combination therapy on HIV type 1 DNA levels." AIDS Res Hum Retroviruses 15(14): 1249-54 <br><a href="https://pubmed.ncbi.nlm.nih.gov/10505673">https://pubmed.ncbi.nlm.nih.gov/10505673</a><br><br></p><p>II. Birk M, Aleman S, Visco-Comandini U, Sonnerborg A (2000). "Proviral HIV-1 dynamics and evolution in patients receiving efficient long-term antiretroviral combination therapy." HIV Medicine 1: 205-211</p><p>III. Aleman S, Pehrson P, Sonnerborg A (1999). "Kinetics of beta-chemokine levels during anti-HIV therapy. " Antivir Ther 4(2): 109-15 <br><a href="https://pubmed.ncbi.nlm.nih.gov/10682156">https://pubmed.ncbi.nlm.nih.gov/10682156</a><br><br></p><p>IV. De Molito A A, Aleman S, Marenzi R, Sonnerborg A, Zazzi M, Chiodi F (2001). "Plasma levels of soluble CD27: a simple marker to monitor immune activation during potent antiretroviral therapy in HIV-infected subjects." (Submitted)</p><p>V. Aleman S, Soderbarg K, Visco-Comandini U, Sitbon G, Sonnerborg A (2001). "Drur-resistance at low viremia in treated HIV-1 infected patients." (Submitted)</p>