Immunological and virologica response to antiretroviral treatment (art) in patients infected with different HIV-1 genetic subtypes

Genetic analyses of different strains of HIV- 1 have shown that isolates can be subdivided into groups, subtypes and circulating recombinant forms. Nine different genetic HIV-1 subtypes have been identified so far, named as A, B, C, D, F, G, H, J and K. An increasing interest has emerged on the outcome of antiretroviral therapy (ART) in patients infected with non-B HIV-1 genetic subtypes since global initiatives are planned to provide ART to patients resident in Continents where all genotypes are present. It is still an open question whether HIV-1 genetic subtypes might have a different impact on disease progression and response to ART.

The overall aim of this thesis is to contribute to knowledge on immunological and virological correlates in patients infected with different HIV-1 genotypes.

Paper I: Chronic HIV- 1 infection leads to a continuous stimulation and activation of the immune system that can be measured by upregulation of molecules involved in apoptosis and cell-cell signalling. We measured the plasma levels of an immune activation marker, soluble CD27 (sCD27), in a cohort of 64 patients infected with HIV-1 subtypes A-D, at baseline and after ART. Plasma sCD27 was significantly higher in the whole HIV-1-infected population as compared to healthy subjects (p < 0.001). Among the four different HIV- 1 subtypes, patients with subtype C virus had significantly higher plasma sCD27 as compared to subtype A (p < 0.05) and B (p < 0.05). After 1 year of ART, plasma sCD27 significantly decreased in all groups but patients with subtype C viruses had the largest reduction of sCD27. The data indicate that a similar immune activation profile is present with HIV-1 subtypes A, B, and D and that in presence of successful ART these subtypes respond similarly.

Paper II: Other parameters of immune activation that we have evaluated are IL-7 and its receptor. The expression of the EL-7Ralpha, in T cells from HIV-1 patients was studied in relation to CD4+T cell counts, IL-7 concentration, T cell subpopulations and survival in culture using specimens from 38 HIV-1 patients and 17 controls. Down-regulation of IL-7Ralpha on T cells correlated with depletion of CD4+ T cells (p<0.001) and also with increased concentration of serum IL-7 (p<0.05). The decreased IL-7Ralpha expression was associated with the reduced survival capacity of T cells in presence of IL-7 in vitro. The positive effects of IL-7 on survival and homeostatic proliferation of T cells might be severely impaired in HIV-1 infected individuals due to IL-71Ralpha down-regulation.

Paper III. We investigated the short-term virological outcome of ART in relation to HIV-1 genetic subtypes. A group of ART naive patients were prospectively enrolled and followed for 6 months when starting ART. Plasma HIV-1 RNA levels, CD4+ T cell counts, and type of ART regimen were recorded. Data from 172 patients who harbored subtypes A, B, C, D, G, and CRF01_AE were analyzed (32 A, 44 B, 34 C, 18 D, 5 G, and 19 CRF01_AE). Of all patients 84% had undetectable plasma HIV-1 RNA levels after 6 months of ART. Patients infected with CRF01_AE more often had undetectable HIV-1 RNA plasma levels than patients infected with subtypes A or D. Of the patients with African origin, 77% had undetectable viral load after 6 months of treatment, while the corresponding figures for Caucasians and Asians were 91% and 100%, respectively. We found a good short-term virological outcome of ART in a cohort of ART-naive patients of diverse ethnic background infected with different HIV-1 genetic subtypes. In univariate analysis ethnicity, but not genetic subtype, correlated with virological response.

Paper IV. The levels of CD4+ T cell count and HIV-1 RNA are two important parameters used when taking the decision to initiate ART and when monitoring response to ART but much is still unexplained on the correlation between these two factors. Accordingly, we examined whether the ratio of CD4+ T cell count divided by HIV-1 RNA, defined as log 10 [CD4+ T cell count/ HIV-RNA], represented a useful marker of response to ART in relation to CD4+ T cell counts, HIV-1 RNA, HIV-1 genetic subtypes and gender. We analysed a cohort of 59 adult individuals (39 on ART and 20 treatment naive) infected with HIV-1 genetic subtypes A, B, C and D; the ratio was calculated at ART initiation, after 6, 12 and 24 months. We observed a systematically increase (p<0.001) in the log 10 [CD4+ T cell count/ HIV-RNA] at 6 months of ART which was maintained during the 24 months of therapy. Outcomes at 6, 12 and 24 months of ART, showed that the majority of patients (62%-77%) clustered above -4 log 10 [CD4+ T cell count/HIV-RNA] units, suggesting that the patients reached a sort of response level. No differences were seen for the log 10 [CD4+ T cell count/ HIV-RNA] in relation to different HIV-1 genetic subtypes and gender. By calculating the log 10 [CD4+ T cell count/ HIVRNA] it may be possible to introduce a new tool for to evaluate when to initiate ART and to monitor therapy response.

List of scientific papers

I. Atlas A, Thanh Ha TT, Lindstrom A, Nilsson A, Alaeus A, Chiodi F, De Milito A (2004). Effects of potent antiretroviral therapy on the immune activation marker soluble CD27 in patients infected with HIV-1 subtypes A-D. J Med Virol. 72(3): 345-51.
https://pubmed.ncbi.nlm.nih.gov/14748056

II. Rethi B, Fluur C, Atlas A, Krzyzowska M, Mowafi F, Grutzmeier S, De Milito A, Bellocco R, Falk KI, Rajnavolgyi E, Chiodi F (2005). Loss of IL-7Ralpha is associated with CD4 T-cell depletion, high interleukin-7 levels and CD28 down-regulation in HIV infected patients. AIDS. 19(18): 2077-86.
https://pubmed.ncbi.nlm.nih.gov/16284456

III. Atlas A, Granath F, Lindstrom A, Lidman K, Lindback S, Alaeus A (2005). Impact of HIV type 1 genetic subtype on the outcome of antiretroviral therapy. AIDS Res Hum Retroviruses. 21(3): 221-7.
https://pubmed.ncbi.nlm.nih.gov/15795528

IV. Atlas A, Nilsson A, Kowalski J, Chiodi F, Alaeus A (2006). The log 10[CD4+ T cell count/HIV-RNA] as an integrated measurement for the antiretroviral treatment (ART) response in individuals infected with HIV-1 genetic subtypes A-D. [Manuscript]