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Mechanisms leading to the observed immune dysregulation in chronic HIV infection are not well understood. The MHC-II class ligand, lymphocyte activation gene-3 (LAG-3, CD223), has been implicated in the complex regulation mechanism of immune functions. In this study, we describe a new population of HIV-specific CD8(+) T cells expressing LAG-3. These LAG-3(+)CD8(+) T cells do not display immunophenotypic patterns traditionally attributed to regulatory T cells. The LAG3(+)CD8(+) T cells are CCR7(+),CD127(-), and display heterogeneous surface expressions of CD45RA and CD25. Interestingly, HIV-specific LAG-3(+)CD8(+) T cells do not substantially express CTLA-4 and LAG-3 expression does not correlate with interleukin (IL)-10 or tumor growth factor (TGF)-β production. In addition, HIV-specific LAG3(+)CD8(+) T cells do not produce interferon (IFN-γ) or express CD107a. The frequency of HIV-specific LAG3(+)CD8(+) T cells negative correlated with plasma viral load. Our study introduces a new population of HIV-specific CD8(+) T cells and proposes additional mechanisms of immune regulation in chronic HIV infection.

CD4(+) T cell dysfunction in HIV-1 infection is associated with increased CTLA-4 and TGF-beta expression. In this study we described a population of TGF-beta-positive CD4(+) T cells with multiple HIV specificities. These HIV-specific TGF-beta-positive CD4(+) T cells did not display the immunophenotypic patterns traditionally attributed to regulatory CD4(+) T cells. TGF-beta-positive CD4(+) T cells were FOXP3 negative, CD25 negative, and displayed a heterogeneous surface expression of CD127. We also examined one potential mechanism for regulating TGF-beta expression by HIV-specific CD4(+) T cells. Blocking of the TGF-beta receptor II led to increased HIV-specific IFN-gamma-positive CD4(+) and CD8(+) T cell responses. Interestingly, HIV-specific TGF-beta-positive CD4(+) T cells did not substantially express CTLA-4. Nevertheless, CTLA-4 blockade resulted in a significant decrease in HIV-specific TGF-beta-positive CD4(+) T cell responses, and a concomitant increase in HIV-specific IFN-gamma-positive CD4(+) T cell responses. Our study proposes a mechanism by which HIV-specific TGF-beta production may be regulated by CTLA-4 engagement.

CD8(+) T cells play an important role in controlling HIV infection and qualitative differences in HIV-specific CD8(+) responses may determine the degree of immune control. We studied 56 HIV-infected, ARV-naive Ugandans and examined the role of subtypes in modulating their HIV-specific T cell responses. Gag-specific responses were readily detectable in our study population. Interestingly, we found significantly decreased Gag-specific cytolysis (as measured by CD107 expression) in subtype D (n = 21) compared to subtype A (n = 35) HIV infection. Sequence analyses within identified epitopes suggest patterns of conservation that are subtype specific. We conclude that HIV subtypes may promote distinct profiles of T cells responses and immune control.

HIV infection is characterized by a decrease in total CD4 cell count, rising viral load, as well as an increase in immune activation levels. Increased activation can lead to an increase in apoptosis and contribute to CD4 depletion. We evaluated the clinical and immunologic responses of 23 HIV-positive Ugandan volunteers following initiation of antiretroviral therapy (ART). All volunteers achieved and maintained complete viral suppression within the first 3 months of therapy (p > 0.05). CD4+ and CD8+ T cell activation also decreased significantly, although it never reached the level of HIV negative Ugandan volunteers. Viral suppression and CD4 cell recovery were also associated with an improved profile in CD8+ T cell functional markers, but had no effect on HIV-specific proliferation. We conclude that ART in a cohort of therapy-naive Ugandans with AIDS partially restores but does not fully reverse the immune dysfunction observed in chronic HIV infection.