Presence of HIV-1 Gag-Specific IFN-γ+IL-2+ and CD28+IL-2+ CD4 T Cell Responses Is Associated with Nonprogression in HIV-1 Infection

Abstract

HIV immunity is likely CD4 T cell dependent. HIV-specific CD4 T cell proliferative responses are reported to correlate inversely with virus load and directly with specific CD8 responses. However, the phenotype and cytokine profile of specific CD4 T cells that correlate with disease is unknown. We compared the number/function of Gag p24-specific CD4 T cells in 17 HIV-infected long-term nonprogressors (LTNPs) infected for a median of 14.6 years with those of 16 slow progressors (SPs), also HIV infected for a median of 14 years but whose CD4 count had declined to <500 cells/μl. Compared with SPs, LTNPs had higher numbers of specific CD4s that were double positive for IFN-γ and IL-2 as well as CD28 and IL-2. However, CD4 T cells that produced IL-2 alone (IL-2+IFN-γ−) or IFN-γ alone (IFN-γ+IL-2−) did not differ between LTNPs and SPs. The decrease in p24-specific CD28+IL-2+ cells with a concomitant increase of p24-specific CD28−IL-2+ cells occurred before those specific for a non-HIV Ag, CMV. p24-specific CD28−IL-2+ cells were evident in LTNPs and SPs, whereas the CMV-specific CD28−IL-2+ response was confined to SPs. The difference between LTNPs and SPs in the Gag p24 IFN-γ+IL-2+ response was maintained when responses to total Gag (p17 plus p24) were measured. The percentage and absolute number of Gag-specific IFN-γ+IL-2+ but not of IFN-γ+IL-2− CD4s correlated inversely with virus load. The Gag-specific IFN-γ+IL-2+ CD4 response also correlated positively with the percentage of Gag-specific IFN-γ+ CD8 T cells in these subjects. Accumulation of specific CD28−IL-2+ helpers and loss of IFN-γ+IL-2+ CD4 T cells may compromise specific CD8 responses and, in turn, immunity to HIV.

Programmed Death 1 Expression on HIV-Specific CD4+ T Cells Is Driven by Viral Replication and Associated with T Cell Dysfunction

“…HIV-specific CD4 ϩ T Em cells from subjects with chronic HIV infection proliferate poorly and lack the ability to secrete IL-2 (2-4). The loss of these functions is correlated with HIV disease progression and is thought to contribute to the inability of the immune system to control infection (3,(5)(6)(7)(8). In recent years, significant effort has been devoted to the identification of biomarkers of HIV disease progression and T cell dysfunction.…”

MVA-nef induces HIV-1-specific polyfunctional and proliferative T-cell responses revealed by the combination of short- and long-term immune assays

“…A correlation between the presence of antigen-specific CD4 T cells coproducing multiple cytokines and nonprogressive chronic HIV-1 infection has been shown in several cross-sectional studies. [9][10][11][12] Multifunctional CD4 or CD8 T cells are further proposed to represent a correlate of vaccinemediated protection against various infectious diseases. 6,[13][14][15] Although initial studies characterized the expression profile of IFN-g and interleukin (IL)-2, 9-11 more recent studies have expanded the investigation and analyzed more complex functional patterns.…”

Immunisation with recombinant modified vaccinia virus Ankara expressing HIV‐1 gag in HIV‐1‐infected subjects stimulates broad functional CD4+ T cell responses

“…In humans, cross-sectional studies suggest that high HIV-1 RNA loads are associated with loss of virus-specific CD4 + T cells with proliferative and IL-2-secreting capacity although virus-specific IFN-c-secreting CD4 + T cells are detectable throughout the course of HIV-1 infection [4, 8,16]. The presence of higher levels of CD4 + IL-2 + T cells in aviraemic subjects suggests that these cells have a role in HIV-1 control, but whether this is cause or effect is uncertain [17,18]. A recent prospective study showed that the presence of functional virus-specific CD4 + T cells in acute HIV-1 infection did not predict long-term control [19].…”