Always one of the most thoughtful and smart HIV researchers, Steve Deeks from San Francisco General Hospital & UCSF has lately developed an interest in the immunological aspects of HIV infection. In particular Deeks has focused on his large cohort of patients that continue to do clinically and immunologically well on antiretroviral therapy despite the fact that their viral load is not fully suppressed by the drugs. He has dubbed such individuals PCATs, for "partial controllers on antiretroviral therapy." In the latest Journal of Virology, Deeks and colleagues present a detailed immunological analysis of PCATs, including their HIV-specific T cell responses. The researchers report that compared to individuals with progressing disease, PCATs have significantly greater numbers of IL-2-producing HIV-specific CD4 T cells, as do untreated individuals with long-term non-progressing infection (LTNPs). PCATs also have significantly lower levels of T cell activation (as measured by CD38 expression). In the discussion section of the paper, they summarize the findings thusly:
“A comprehensive assessment of the immune system in those controlling HIV versus those not controlling HIV reveals a number of consistent trends across a variety of patient groups. Among antiretroviral-treated and untreated patients, durable control of HIV replication is associated with high levels of HIV-specific IL-2+ and IFN-gamma+ CD4+ T cells, low levels of T-cell activation, and preservation of an expanded population of HIV-specific T cells with a less differentiated immunophenotype. This immunologic profile suggests that control of HIV in the setting of chronic disease may require durable maintenance of HIV-specific memory T cells and the absence of generalized immune activation. Our finding that such a state can be achieved in some patients with a history of progressive disease suggests that immunodeficiency associated with HIV may be reversible; hence, efforts at reconstituting a functional immune response to HIV should be pursued, particularly for those with limited antiretroviral treatment options. Our data defining correlates of control in the setting of chronic HIV infection may also be relevant to efforts aimed at developing preventative vaccines to control HIV replication in those who become infected.”
Journal of Virology, November 2005, p. 14169-14178, Vol. 79, No. 22
Phenotypic, Functional, and Kinetic Parameters Associated with Apparent T-Cell Control of Human Immunodeficiency Virus Replication in Individuals with and without Antiretroviral Treatment
Brinda Emu, Elizabeth Sinclair, David Favre, Walter J. Moretto, Priscilla Hsue, Rebecca Hoh, Jeffrey N. Martin, Douglas F. Nixon, Joseph M. McCune, and Steven G. Deeks
The human immunodeficiency virus (HIV)-mediated immune response may be beneficial or harmful, depending on the balance between expansion of HIV-specific T cells and the level of generalized immune activation. The current study utilizes multicolor cytokine flow cytometry to study HIV-specific T cells and T-cell activation in 179 chronically infected individuals at various stages of HIV disease, including those with low-level viremia in the absence of therapy ("controllers"), low-level drug-resistant viremia in the presence of therapy (partial controllers on antiretroviral therapy [PCAT]), and high-level viremia ("noncontrollers"). Compared to noncontrollers, controllers exhibited higher frequencies of HIV-specific interleukin-2-positive gamma interferon-positive (IL-2+ IFN-+) CD4+ T cells. The presence of HIV-specific CD4+ IL-2+ T cells was associated with low levels of proliferating T cells within the less-differentiated T-cell subpopulations (defined by CD45RA, CCR7, CD27, and CD28). Despite prior history of progressive disease, PCAT patients exhibited many immunologic characteristics seen in controllers, including high frequencies of IL-2+ IFN-+ CD4+ T cells. Measures of immune activation were lower in all CD8+ T-cell subsets in controllers and PCAT compared to noncontrollers. Thus, control of HIV replication is associated with high levels of HIV-specific IL-2+ and IFN-+ CD4+ T cells and low levels of T-cell activation. This immunologic state is one where the host responds to HIV by expanding but not exhausting HIV-specific T cells while maintaining a relatively quiescent immune system. Despite a history of advanced HIV disease, a subset of individuals with multidrug-resistant HIV exhibit an immunologic profile comparable to that of controllers, suggesting that functional immunity can be reconstituted with partially suppressive highly active antiretroviral therapy.