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

thesis
posted on 2024-09-02, 18:58 authored by Soo Aleman

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.

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.

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.

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.

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.

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.

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.

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.

List of scientific papers

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
https://pubmed.ncbi.nlm.nih.gov/10505673

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

III. Aleman S, Pehrson P, Sonnerborg A (1999). "Kinetics of beta-chemokine levels during anti-HIV therapy. " Antivir Ther 4(2): 109-15
https://pubmed.ncbi.nlm.nih.gov/10682156

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)

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)

History

Defence date

2001-08-31

Department

  • Department of Laboratory Medicine

Publication year

2001

Thesis type

  • Doctoral thesis

ISBN-10

91-628-4914-X

Number of supporting papers

5

Language

  • eng

Original publication date

2001-08-10

Author name in thesis

Aleman, Soo

Original department name

Department of Immunology, Microbiology, Pathology and Infectious Diseases

Place of publication

Stockholm

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